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Modulation of Growth Factor/Cytokine Synthesis and Signaling by 1,25-Dihydroxyvitamin D₃: Implications in Cell Growth and Differentiation

Departments of Medicine (A.G., R.K.), Dermatology (M.R.P.), and Biochemistry and Molecular Biology (M.R.P., R.K.), Mayo Clinic and Foundation, Rochester, Minnesota 55905

Correspondence: Address all correspondence and requests for reprints to: Rajiv Kumar, M.D., Departments of Medicine, Biochemistry and Molecular Biology, Mayo Clinic and Foundation, 200 First Street SW, 911A Guggenheim Building, Rochester, Minnesota 55905. E-mail: rkumar{at}mayo.edu

	Abstract

Top Abstract I. Introduction II. 1{alpha},25(OH)2D3 as a... III. Effect of... IV. Impact of 1{alpha},25(OH)2D3... V. Summary and Future... References

 
Distinct from its classic functions in the regulation of calcium and phosphorus metabolism as a systemic hormone, 1,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃] is involved in the local control and regulation of cellular growth and differentiation in various tissues, including epidermis (keratinocytes) and bone (osteoblasts and osteoclasts). In this review, the impact of 1,25(OH)₂D₃ on growth factor/cytokine synthesis and signaling is discussed, particularly as it pertains to bone cells and keratinocytes. 1,25(OH)₂D₃ not only regulates growth factor/cytokine synthesis but may also alter growth factor signaling. Recently discovered examples for such interactions are the interactions between the vitamin D receptor and the mothers against decapentaplegic-related proteins that function downstream of TGFß receptors. Inhibitory effects of 1,25(OH)₂D₃ on keratinocytes through TGFß activation and IL-1, IL-6, and IL-8 suppression may provide a rationale for its beneficial effects in the treatment of hyperproliferative skin disorders, whereas stimulatory effects through the epidermal growth factor-related family members and platelet-derived growth factor may be operative in its beneficial effects in skin atrophy and wound healing. Modulation of cytokines and growth factors by 1,25(OH)₂D₃ during bone remodeling plays an important role in the coupling of osteoblastic bone formation with osteoclastic resorption to maintain bone mass.

I. Introduction

II. 1,25(OH)₂D₃ as a Regulator of Cell Growth and Differentiation: Overview

III. Effect of 1,25(OH)₂D₃ on Growth Factors and Cytokines: Role in Keratinocyte Growth and Differentiation and Epidermal Pathologies

A. Physiology and pathophysiology of keratinocyte growth and differentiation

B. Modulation of keratinocyte growth and differentiation by 1,25(OH)₂ D₃

C. Growth factors and cytokines in 1,25(OH)₂D₃ function in the skin

IV. Impact of 1,25(OH)₂D₃ and Growth Factors in Local Control of Bone Cell Development and Function

A. Osteoblasts

B. Osteoclasts

V. Summary and Future Directions

	I. Introduction

Top Abstract I. Introduction II. 1{alpha},25(OH)2D3 as a... III. Effect of... IV. Impact of 1{alpha},25(OH)2D3... V. Summary and Future... References

 
STEROID HORMONES (estrogen, androgens, glucocorticoids) and the secosteroid hormone 1,25 dihydroxyvitamin D₃ [1,25(OH)₂D₃] act on various cell types to modulate development, growth, and differentiation. All steroid hormones mediate these effects by binding to structurally related intracellular receptors, which in turn interact with defined sequences on regulatable genes to modulate their activity (1). Growth factors and cytokines act through membrane-bound receptors, the stimulation of which result in transcription of several genes involved in cell growth and differentiation (2, 3). The transition from proliferation to differentiation is a complex process requiring tightly coordinated control mechanisms.

In the past several years, a substantial amount of evidence has accumulated concerning the interaction of 1,25(OH)₂D₃ with growth factors/cytokines in the regulation of coordinated cell growth and differentiation. The effects of 1,25(OH)₂D₃ may be either antagonized or enhanced by growth factors/cytokines depending on the type of the cell, stage of differentiation, and duration of exposure to the steroid in vitro. The synthesis of growth factors/cytokines as well as their receptors can be altered by 1,25(OH)₂D₃ in various cell types (4, 5). In this review, the impact of 1,25(OH)₂D₃ on growth factor/cytokine synthesis and signaling is discussed particularly as it pertains to bone cells and keratinocytes.

The keratinocyte is an excellent model for the study of cellular differentiation in vitro (6, 7). It has recently become apparent that human keratinocytes are organized into stem cells, transit-amplifying cells, and terminally differentiated cells (8, 9, 10). The hierarchical organization of keratinocytes is maintained in cell culture conditions (10). It has been shown that 1,25(OH)₂D₃ is able to induce keratinocyte differentiation and suppress keratinocyte growth (11, 12). However, mitogenic effects of the sterol on keratinocytes have also been observed (13, 14, 15, 16, 17). This discrepancy seems to be related to concentrations of the hormone and its effects on the synthesis of various local factors implicated in the growth and differentiation of these cells.

It is well known that steroid hormones interact with autocrine/paracrine factors to exert their effects in bone (18, 19, 20, 21). 1,25(OH)₂D₃ also affects synthesis and signaling of growth factors/and cytokines in bone. This interaction has an important impact on osteoblast and osteoclast development and function and, therefore, coordinates control of bone remodeling.

	II. 1,25(OH)2D3 as a Regulator of Cell Growth and Differentiation: Overview

Top Abstract I. Introduction II. 1{alpha},25(OH)2D3 as a... III. Effect of... IV. Impact of 1{alpha},25(OH)2D3... V. Summary and Future... References

 
Although the primary function of the active metabolite of vitamin D, 1,25(OH)₂D₃, is the regulation of calcium and phosphorus metabolism, it also plays important roles in the regulation of growth and differentiation in various cells and tissues, including bone cells and keratinocytes (4), cartilage (22), and hematopoietic cells (23). The observation that 1,25(OH)₂D₃ suppresses cellular growth and induces differentiation of myeloblasts and promyelocytes into macrophages (24), and that it inhibits the proliferation of malignant melanoma cells (25), initially showed that the sterol functioned in areas distinct from its classical transcellular calcium transport function. In a general sense, 1,25(OH)₂D₃ inhibits the proliferation of the cells and induces them toward a more differentiated state in most cell types, such as osteoblasts (26). In dendritic cells, however, 1,25(OH)₂D₃ promotes a persistent state of immaturity leading to inhibition of cellular immune responses (27, 28). Therefore, cell culture conditions, cell types, species differences, as well as interactions with growth factor/cytokine signaling are important determinants of the diversity of the biological actions mediated by the sterol.

The effects of 1,25(OH)₂D₃ are primarily mediated by the vitamin D receptor (VDR), which is a member of the nuclear receptor superfamily (29, 30, 31, 32). Nuclear receptors activate transcription by binding to response elements that consist of hexameric core binding motifs in promoters of their target genes (33). The VDR is a 48-kDa zinc finger protein (34, 35), which activates transcription by binding to vitamin D response elements (VDREs) within the promoter of vitamin D-responsive genes, either as a homodimer (33, 36) or a heterodimer with the retinoid acid X receptor- (37, 38, 39, 40), retinoic acid receptor (41, 42), or thyroid hormone receptors (43).

1,25(OH)₂D₃ regulates the expression of growth factor/cytokine synthesis as well as receptor expression and modulates growth and differentiation in many cell types including epithelial, mesenchymal, neural, vascular endothelial, immune cells, and chondrocytes (Refs. 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68 and Table 1). As seen in Table 1, the increased growth factor and cytokine synthesis by 1,25(OH)₂D₃ generally leads to the inhibition of cellular growth and, in some instances, induction of differentiation. The sterol also exerts immunosuppressive effects through local factors (Table 1). In this review, we will confine our remarks to its effects on growth factors/cytokines using keratinocytes and bone cells as a paradigm. We will also provide information concerning the molecular mechanisms of the interaction of 1,25(OH)₂D₃ with growth factor/cytokine synthesis and signaling when data are available.

View this table: [in this window] [in a new window]   Table 1. Effect of 1,25(OH)2D3 on growth factor/cytokines and their receptors in several cell types (see also Tables 2 and 3)

	III. Effect of 1,25(OH)2D3 on Growth Factors and Cytokines: Role in Keratinocyte Growth and Differentiation and Epidermal Pathologies

Top Abstract I. Introduction II. 1{alpha},25(OH)2D3 as a... III. Effect of... IV. Impact of 1{alpha},25(OH)2D3... V. Summary and Future... References

View larger version (35K): [in this window] [in a new window]   Figure 1. Keratinocyte growth and differentiation in skin. , ß1 integrin expression; , ß4 integrin expression. Note that ß1 and ß4 integrin expressions are at maximum in stem cells, and their expression decreases in transit-amplifying cells. With the advancement of differentiation, the cells no longer express ß1 and ß4 integrins.

B. Modulation of keratinocyte growth and differentiation by 1,25(OH)₂D₃

The administration of 1,25(OH)₂D₃ to keratinocytes is associated with an induction of 25-hydroxyvitamin D₃-24-hydroxylase activity, inhibition of 25-hydroxyvitamin D₃-1- hydroxylase activity (76), an induction in skin calcium-binding protein synthesis (77), and inhibition of PTHrP production (78, 79). Cultured human keratinocytes do not possess receptors for PTHrP (80) and, therefore, they are not considered as a target for this peptide. However, PTHrP is implicated in the regulation of keratinocyte growth and differentiation in vivo. In a recent study, the absence of PTHrP appeared to result in the reduction of the basal keratinocyte compartment and premature acquisition of suprabasal and granular differentiation markers, whereas overexpression of the peptide generated reciprocal findings (81). These findings suggest that the inhibition of PTHrP by 1,25(OH)₂D₃ contributes to some extent to the growth-inhibitory and prodifferentiative effects of the sterol on keratinocytes. The growth-inhibitory and prodifferentiative effect of 1,25(OH)₂D₃ is associated with a decrease in c-myc mRNA levels (12). 1,25(OH)₂D₃ increases involucrin and transglutaminase activity in keratinocytes, and it increases cornified envelope formation (11, 82, 83, 84, 85, 86). An increase in protein kinase C (PKC) activity and translocation of PKC to cellular membranes has been described (87, 88).

The level of expression of the VDR is a major determinant of cellular 1,25(OH)₂D₃ responsiveness in keratinocytes. It has been suggested that VDR expression in normal human keratinocytes is linked to cell cycle control (89). VDR levels are markedly decreased by arresting the cells in G₀, at the G₁-S border, or during the mitotic metaphase. In each of these cases, VDR is rapidly induced when the cells are stimulated to reenter cell cycle. This indicates that VDR expression is restricted to cycling cells but not to a particular cell cycle phase. Proliferating cells should therefore be considered as preferential vitamin D target cells. This is in accord with the identification of the basal keratinocyte as the main VDR-containing cell in the epidermis.

Although previous findings have indicated an antiproliferative effect of 1,25(OH)₂D₃ on keratinocytes ex vivo (90) and in vitro (12, 91), there are also studies reporting a mitogenic effect mediated by the sterol (13, 14, 15, 16, 17). Similar discrepancies also exist in the clinical effects of the sterol. 1,25(OH)₂D₃, calcipotriene (MC 903), and noncalcemic vitamin D analogs used in the treatment of hyperproliferative skin disorders such as psoriasis (92) reduce cell proliferation in such conditions. In contrast, topical application of these compounds has also been reported to result in epidermal hyperplasia of human and mouse skin (93, 94), enhanced cutaneous healing in rats (95), and reversal of glucocorticoid-induced epidermal atrophy in mice (96). As discussed below, however, the discrepancies with respect to its effects in epidermis and skin may be reconciled when its local interactions with various growth factors are taken into account. Moreover, the fluctuation of VDR levels according to the proliferation and differentiation state of the cells is a parameter that may help to explain the paradoxical effects of the sterol in vitro and in vivo. 1,25(OH)₂D₃ inhibits keratinocyte growth in psoriatic lesions due to the dominance of rapidly proliferating cells with up-regulated VDR expression. It has been shown that 1,25(OH)₂D₃-dependent growth inhibition is reversed into a mitogenic effect in cells that are growth arrested or committed to differentiate (16). In this respect, the sterol stimulates epidermal proliferation of normal skin in which the cells are mostly quiescent and have down-regulated VDR expression.

2. Hair follicle keratinocytes.
1,25(OH)₂D₃ has an important impact on hair follicle biology. The VDR is expressed in the epidermal keratinocytes and the mesenchymal dermal papilla cells that are components of the hair follicle (97). VDR expression in the hair follicle is increased during late anagen (hair growth phase) and catagen (regression phase), correlating with decreased proliferation and increased differentiation of the keratinocytes (97). It is well known that VDR knockout mice develop alopecia. It has recently been shown that alopecia in these mice is due to a defect in anagen initiation after the period of hair morphogenesis, which ends during the third week of life (98). Hair reconstitution assays performed in athymic nude mice show that VDR expression in dermal papilla cells is not essential for a normal response to anagen initiation but VDR expression by the hair follicle keratinocytes is required for this process (99). The hair cycle defect that leads to alopecia is corrected in VDR knockout mice by transgenic expression of human VDR in hair follicle keratinocytes (100).

C. Growth factors and cytokines in 1,25(OH)₂D₃ function in the skin
1,25(OH)₂D₃ modulates the growth and differentiation of epidermal keratinocytes and affects inflammatory processes in skin by altering the synthesis and signaling of several growth factors/cytokines, as summarized in Table 2.

View this table: [in this window] [in a new window]   Table 2. Modulation growth factor/cytokine synthesis and signaling by 1,25(OH)2D3 in epidermal keratinocytes

In a recent study by Garach-Jehoshua et al. (13), 1,25(OH)₂D₃ was found to enhance the proliferation of human keratinocyte cell line HaCaT in the absence of exogenous growth factors. It was demonstrated that HER1/HER3 heterodimers were the major mitogenic signals in 1,25(OH)₂D₃-stimulated cells. 1,25(OH)₂D₃ did not affect the levels of the proteoglycan-dependent EGFR ligands AR and heparin-binding EGF. In contrast, a significant increase in the cellular contents of HER1, 2, and 3 was observed, which seemed to be responsible for the stimulatory effect of 1,25(OH)₂D₃ on autonomous proliferation (Fig. 2 and Ref. 13). Furthermore, 1,25(OH)₂D₃-stimulated proliferation was suppressed by a specific inhibitor of EGFR tyrosine kinase and a EGFR-neutralizing antibody (Fig. 3 and Ref. 13).

View larger version (57K): [in this window] [in a new window]   Figure 2. Effect of 1,25(OH)2D3 on the cellular level of the HER/ErbB proteins in keratinocytes (HaCaT cells). 1,25(OH)2D3 was added at different time points (upper panel) or 48 h (lower panel) before the cells were harvested. Cell extracts were subjected to SDS-PAGE and probed with anti-ErbB1, anti-ErbB2, or ErbB3 antibodies. [Reproduced from O. Garach-Jehoshua et al.: Endocrinology 140:713–721, 1999 (13 ). © The Endocrine Society.]

View larger version (23K): [in this window] [in a new window]   Figure 3. The inhibitory effect of tryphostin AG 1478 (A) and the anti-EGFR monoclonal antibody (Ab-225) (B) on keratinocyte (HaCaT cells) proliferation. Cells are treated for 5 d with AG 1478 (A) or Ab-225 (B) in the absence or presence of 1,25(OH)2D3 or EGF. Data are expressed as mean ± SD. [Reproduced from O. Garach-Jehoshua et al.: Endocrinology 140:713–721, 1999 (13 ). © The Endocrine Society.]

2. TGFß.
TGFß is a 25-kDa peptide that has pleiotropic effects within the skin and epidermis. Although it can stimulate the growth and metabolic activity of fibroblasts (114, 115), it is a major growth-inhibitory autocrine factor expressed by keratinocytes (116, 117, 118). TGFß, which is expressed by human keratinocytes, arrests keratinocyte growth in a reversible and G₁ phase-specific manner (119). Overexpression of a constitutively active form of TGFß targeted to epidermis markedly inhibits keratinocyte proliferation without affecting the terminal differentiation markers discussed above (120). In vivo studies demonstrate hyperproliferative epidermis in animals with targeted disruption of the TGFß gene (121). In psoriatic plaques, TGFß is detectable but restricted to suprabasal cells (122, 123).

Kim et al. (124) showed that human keratinocytes cultured in the presence of 1,25(OH)₂D₃ produce increased amounts of TGFß1 and -2. More active than latent TGFß1 was produced after exposure to higher doses of 1,25(OH)₂D₃. Neutralizing antibodies to TGFß blocked the 1,25(OH)₂D₃mediated antiproliferative effect more than 50%. Enhanced secretion of TGFß1 and -2 after 1,25(OH)₂D₃ treatment has also been demonstrated in cultured mouse keratinocytes (125). More recently, we demonstrated that the inhibition of keratinocyte growth by 1,25(OH)₂D₃ was associated with a time- and dose-dependent increase in the TGFß2 concentrations in the supernatant medium of cultured human keratinocytes (91). However, in contrast to the previous observations (124, 125), we did not observe a change in TGFß1 concentrations. We also observed that antibodies directed against TGFß partially blocked the suppression of cellular growth mediated by the sterol (91). Taken together, these results clearly indicate that 1,25(OH)₂D₃ inhibits keratinocyte growth by a mechanism that involves, at least in part, an increase in the release of TGFß. This mechanism may provide a rationale for the beneficial effects of the sterol in hyperproliferative as well as preneoplastic epidermal skin disorders.

3. Platelet-derived growth factor (PDGF).
PDGF plays an important role in wound healing (126). It stimulates proliferation of fibroblasts and muscle cells, promotes collagen and extracellular matrix synthesis, and acts as a chemoattractant for fibroblasts, monocytes, and neutrophils (127, 128, 129). In the process of wound healing, PDGF functions synergistically with many growth factors (126). It is a disulfide-linked dimer with a molecular mass of approximately 30 kDa. The subunits of the dimer are made up of two related chains (A and B), which are encoded by different genes. There are three PDGF isoforms; two homodimeric AA and BB and one heterodimeric AB. PDGF exerts its bioactivity via cellular receptors of 180 kDa that belong to the Ig superfamily (130). Although platelets and macrophages are two major sources of PDGF, AA, BB, and AB isoforms are synthesized by keratinocytes (101, 131). However, PDGF-receptors are not expressed in normal epidermis or keratinocytes. Zhang et al. (101) have shown that PDGF-AB production is up-regulated by 1,25(OH)₂D₃ at a time when cellular growth is suppressed by the sterol in cultured human keratinocytes. These results suggest that the increase in PDGF production is regulated coordinately with the increase in growth-inhibitory factors such as TGFß that play a direct role in inhibiting keratinocyte growth. The findings that keratinocytes are a source of PDGF and can be modulated by 1,25(OH)₂D₃ should foster further investigation of the biological functions of these cells and vitamin D in normal epidermal growth control, dermal-epidermal interaction, and wound healing.

4. IL-1.
Keratinocytes produce the proinflammatory cytokine IL-1 (102, 132, 133). Treatment of unstimulated keratinocytes with 1,25(OH)₂D₃ showed small effects on IL-1 production and secretion (102). However, when the cells were stimulated with TNF, IL-1 secretion was enhanced and this enhancement was significantly inhibited by 1,25(OH)₂D₃ (102). The down-regulation of enhanced IL-1 secretion by proinflammatory cytokine TNF may therefore be one of the explanations for the beneficial effects of the sterol in inflammatory skin disorders like psoriasis.

5. IL-6.
IL-6 is an inflammatory cytokine produced and secreted by keratinocytes and infiltrating mononuclear cells implicated in psoriatic skin lesions (103, 134). It has been demonstrated that 1,25(OH)₂D₃ inhibits the expression of IL-6 from keratinocytes (103) and mononuclear cells (135). Inhibition of IL-6 release from both keratinocytes and infiltrating inflammatory cells also contributes to the beneficial effects of 1,25(OH)₂D₃ in psoriasis.

6. IL-8.
IL-8 is a member of a family of human leukocyte chemotactic and activating cytokines (136, 137). Apart from being chemotactic for neutrophils (138), T lymphocytes (136), and keratinocytes (139), it also induces the proliferation of keratinocytes (139). In psoriasis, increased IL-8 receptor expression has been detected in both neutrophils (140) and keratinocytes (141). These data indicate an altered regulation of the IL-8 receptor expression in psoriasis. Taking into account the beneficial therapeutic effects of 1,25(OH)₂D₃ and its analogs in psoriasis, it is speculated that 1,25(OH)₂D₃ interferes with the expression of IL-8 and its receptor to mediate its antiproliferative and immunosuppresive actions. Accordingly, Larsen et al. (62) have shown that 1,25(OH)₂D₃ inhibits IL-1-induced IL-8 production and mRNA expression in keratinocytes, fibroblasts, and leukocytes, but not in endothelial cells. Optimal concentrations of the sterol to exert these effects varied between 10^-10 and 10^-11 M. With respect to the effects on IL-8 receptor expression, Kemeny et al. (104) were able to demonstrate that 1,25(OH)₂D₃ caused a dose-dependent decrease in IL-8 binding to cultured keratinocytes. Taken together, these data suggest that the inhibition of keratinocyte IL-8 and IL-8 receptor expression by 1,25(OH)₂D₃ may contribute to its therapeutic effects in psoriasis.

7. TNF.
TNF is produced by keratinocytes (142) and promotes their differentiation with only a modest antiproliferative effect (143). Geilen et al. (105) have demonstrated that 1,25(OH)₂D₃ stimulates TNF mRNA expression from human keratinocyte cell line HaCaT. The stimulation of TNF from the cells is associated with increased sphingomyelin hydrolysis and ceramide formation. Because ceramide is an important mediator of cell differentiation (144), the TNF-mediated stimulation of sphingomyelin hydrolysis in keratinocytes might contribute to the prodifferentiative actions of the sterol on these cells.

8. RANTES.
RANTES (regulated on activation, normal T expressed and secreted, small inducible cytokine 5A, SCY5A) is a chemokine that specifically attracts eosinophils, T lymphocytes of memory phenotype, and monocytes in vitro (145, 146). Upon cytokine stimulation, epidermal and oral keratinocytes are induced to produce RANTES (147). Fukuoka et al. (106) have investigated the implication of RANTES in psoriatic skin lesions. They found that RANTES was present in the intercellular spaces between epidermal keratinocytes in these lesions. Stimulation with TNF and IFN synergistically increased the RANTES production of the cells. Moreover, they were able to demonstrate that tacalcitol, an active vitamin D₃ analog, inhibited the RANTES production in cultured normal epidermal keratinocytes (106). Taken together, these observations suggest that the regulation of RANTES expression by keratinocytes partly accounts for the action of the sterol as an antipsoriatic drug.

	IV. Impact of 1,25(OH)2D3 and Growth Factors in Local Control of Bone Cell Development and Function

Top Abstract I. Introduction II. 1{alpha},25(OH)2D3 as a... III. Effect of... IV. Impact of 1{alpha},25(OH)2D3... V. Summary and Future... References

 
A. Osteoblasts
1. Effect of 1,25(OH)₂D₃ on osteoblast growth and differentiation: an overview.
Osteoblasts are the bone-forming cells that deposit bone extracellular matrix in a highly organized fashion. Embryologically, osteoblasts originate from mesenchymal cells that can also give rise to chondrocytes, adipocytes, myocytes, tendon cells, and various fibroblasts (148). The decision of a mesenchymal cell to follow a given differentiation pathway is determined by the expression of key transcription factors, such as myo-D and myogenin in muscle cells and Runx (so-called core binding factor A1) for osteoblasts (148). A characteristic feature of primary osteoblasts, in vitro, is their ability to proliferate, differentiate, and produce extracellular matrix as reviewed in detail by Stein et al. (149).

1,25(OH)₂D₃ has a biphasic effect on osteoblasts: it abrogates or stimulates the normal developmental pathway or gene expression profiles, depending upon whether it is given, respectively, during the proliferation or differentiation stage. It has been shown that 1,25(OH)₂D₃ stimulates the proliferation of nonadherent rat marrow-derived osteoprogenitor cells (150). 1,25(OH)₂D₃ given during the proliferative period of rat calvaria osteoblast cultures inhibits proliferation and down-regulates collagen synthesis and alkaline phosphatase activity; osteocalcin expression is not stimulated (151) and nodule formation is blocked (152), suggesting a stop in osteoblast differentiation. 1,25(OH)₂D₃ administered in vivo also decreases collagen synthesis and procollagen mRNA in mature osteoblasts (153). 1,25(OH)₂D₃ treatment of mature osteoblasts results in up-regulation of osteoblast-associated genes, such as osteocalcin and osteopontin, and in stimulation of calcium accumulation (154). Thus, at this stage of differentiation, 1,25(OH)₂D₃ may promote further maturation of the osteoblast. In summary, despite the controversy in the effects of 1,25(OH)₂D₃ on osteoblast growth in vitro, general agreement is in favor of its antiproliferative and prodifferentiative properties.

2. Growth factors in 1,25(OH)₂D₃ function.
1,25(OH)₂D₃ alters growth factor synthesis, release, and signaling in osteoblasts (Table 3).

View this table: [in this window] [in a new window]   Table 3. Effects of 1,25(OH)2D3 on bone cell and chondrocyte biology via growth factor (GF)/cytokine synthesis and signaling

The biological effects of TGFß are mediated through cell-specific transmembrane serine/threonine kinase receptors in osteoblasts (162). The heterodimeric interaction of liganded type I and type II receptors is needed for signal transduction and, consequently, mediation of the different biological responses (162). TGFß signal transduction and transcriptional control are mediated in the cells by a family of receptor substrates, the Smad proteins (mothers against decapentaplegic-related proteins) that translocate to the nucleus and act as transcription factors (163). Smad3 plays an essential role in TGFß-mediated signal transduction. It has been shown that targeted disruption of Smad3 in mice markedly blunts the cellular effects of TGFß (164).

If primary human osteoblastic cell cultures are treated with 1,25(OH)₂D₃ and TGFß, they stimulate spindle-shaped cells to become stellate in appearance and increase the number of cytoplasmic processes (165). TGFß increases ³H-thymidine incorporation and 1,25(OH)₂D₃ reduces this effect. In contrast, procollagen type I synthesis and secretion are increased in a dose-dependent manner in the presence of TGFß, and these effects are not suppressible by 1,25(OH)₂D₃. TGFß and 1,25(OH)₂D₃ each marginally increase alkaline phosphatase activity whereas cotreatment synergistically increases alkaline phosphatase activity in a dose-and time-dependent manner (165). TGFß suppresses 1,25(OH)₂D₃-induced osteocalcin expression and secretion (165, 166). In summary, these data suggest that TGFß stimulates the human osteoblast to actively produce collagen matrix and proliferate. 1,25(OH)₂D₃ stimulation may induce cells to advance to an endstage where cell proliferation is reduced and osteocalcin expression is promoted.

Evidence is now available with regard to the mechanisms of 1,25(OH)₂D₃-TGFß interaction and the role of TGFß in 1,25(OH)₂D₃ function in osteoblasts. Finkelman et al. (167) have previously shown that there were significant reductions in skeletal TGFß but no differences in IGF-I, IGF-II, or osteocalcin in vitamin D-deficient rats compared with vitamin D-replete ones. To determine whether 1,25(OH)₂D₃ increased TGFß production by bone cells, they treated mouse calvaria for 6 d and mouse osteoblasts for 2 d with 10 nM 1,25(OH)₂D₃ (167). They observed a nearly 100% increase in TGFß production with 1,25(OH)₂D₃ treatment. Similarly, we have shown that treatment with 1,25(OH)₂D₃ increased the transcription rate of TGFß2 in cultured human fetal osteoblasts (Ref. 168 and Fig. 4). Antibodies directed against TGFß partially blocked the antiproliferative effect by 1,25(OH)₂D₃ (168). Furthermore, 1,25(OH)₂D₃ stimulated the mRNA expression of TGFß type I and type II receptors (Ref. 168 and Fig. 5). Taken together, these data suggest that antiproliferative effects of 1,25(OH)₂D₃ on osteoblasts is mediated, at least in part, by TGFß. The release of TGFß, which also influences the activity of the adjacent osteoclasts, plays an important role in bone remodeling.

View larger version (16K): [in this window] [in a new window]   Figure 4. Effects of 1,25(OH)2D3 on the transcription rate of TGFß2 from human fetal osteoblastic (hFOB) cells. Data are mean ± SEM. [Reproduced from Y. Wu et al.: Biochem Biophys Res Commun 239:734–739, 1997 (168 ), with permission of Academic Press.]

View larger version (18K): [in this window] [in a new window]   Figure 5. Effect of 1,25(OH)2D3 on the expression of type I and type II TGFß receptor mRNA in human fetal osteoblastic cells. [Reproduced from Y. Wu et al.: Biochem Biophys Res Commun 239:734–739, 1997 (168 ), with permission of Academic Press.]

View larger version (7K): [in this window] [in a new window]   Figure 6. Major regulatory elements in 5'-region of TGFß2 gene. Transcription starts at the arrow (+1). •, AP-2 binding sites; , TATAA box; , cAMP responsive elements; , vitamin D response elements. [Reproduced from Y. Wu et al.: Biochemistry 38:2654–2660, 1999 (170 ), with permission of the American Chemical Society.]

In recent years, evidence has accumulated with respect to the interactions between 1,25(OH)₂D₃ and events downstream of TGFß receptor stimulation. Yanagisawa et al. (172) showed that Smad3, a regulatory Smad, acts as a coactivator of VDR and positively regulates the vitamin D signaling pathway. These data suggest that TGFß and 1,25(OH)₂D₃ signaling pathways by which osteoblast gene expression is induced converge on Smad3. The consequences of the targeted disruption of Smad3 in osteoblasts were recently evaluated by Borton et al. (173). They showed that TGFß can no longer inhibit the differentiation of osteoblasts in Smad3 null mice; nevertheless, stimulation of the proliferation remains intact (173). The clinical consequence of the lack of Smad3 in these mice was osteopenia, which is attributed to a decreased rate of bone formation. The reduction in bone formation is associated with increased osteocyte number and apoptosis (173). These results suggest that inhibition of osteoblast differentiation and stimulation of osteoblast proliferation is regulated through divergent mechanisms by TGFß. Whether 1,25(OH)₂D₃ signaling is implicated in the diversity of these TGFß actions on osteoblasts is currently not known. In view of the complex interplay between TGFß and 1,25(OH)₂D₃, it is highly likely that other factors downstream from the signaling pathway are also operative. As an example, Yanagi et al. (174) have recently demonstrated that Smad7, an inhibitory Smad, abrogates the Smad3-mediated potentiation of VDR function. However, more work is required to clarify molecular mechanisms of the interplay between TGFß and 1,25(OH)₂D₃ in the context of inhibitory Smads and other Smad coactivator and corepressor partners with which Smads cooperate.

b. IGFs and IGF binding proteins (IGFBPs).
IGF-I and II are traditionally known as the mediators of GH action (175). In addition to their major roles in the growth and differentiation of cartilage, they directly affect bone. IGF-I and IGF-II were found to stimulate cell multiplication as well as collagen synthesis in fetal rat calvaria (176, 177) and in primary osteoblast-enriched cell cultures (178, 179). Studies have shown that IGF-I is also a mediator for some of the anabolic effects of PTH in calvaria cultures (180). IGF-I and -II synthesis and secretion have been detected in the conditioned media of organ cultures (181), osteoblast-like cell cultures (178), and preosteoblastic human bone marrow stromal cells (182). IGF receptor expression has been demonstrated in clonal osteoblastic MC3T3-E1 cells (183). Therefore, it is clear from these observations that IGFs locally mediate for osteoblast development and function. The synthesis and release of IGFs during bone resorption suggest a role of these growth factors in the coupling of bone resorption with formation.

It has previously been reported that there is a synergistic interaction between IGF-I and 1,25(OH)₂D₃ with respect to the stimulation of alkaline phosphatase activity in osteoblastic cell lines (184). Observations vary with regard to the effects of 1,25(OH)₂D₃ on IGF synthesis by osteoblasts and preosteoblastic cells. Kurose et al. (183) have reported that IGF-I production of the murine clonal osteoblastic cells is not affected by 1,25(OH)₂D₃ treatment. In accordance with this observation, Kveiborg et al. (182) recently reported that 1,25(OH)₂D₃ (dose range 10^-10 to 10^-7 M) exerts no effect on either IGF-I or IGF-II mRNA expression in preosteoblastic human bone marrow cells. However, Chenu et al. (185) showed that 1,25(OH)₂D₃, in a time- and dose-dependent manner, increased IGF-I release from human osteoblast-like cells in short-term cultures. Linkhart and Keffer (186) have found that 1,25(OH)₂D₃ stimulates IGF-I but inhibits IGF-II release by cultured neonatal mouse calvarial cells, suggesting differential regulation of IGF subtypes by the sterol. The results of these studies suggest that the effect of 1,25(OH)₂D₃ on IGF synthesis and release are divergent, possibly depending on the differences in cell types, culture conditions, and differentiation status of the cells.

1,25(OH)₂D₃ may also exert modulatory effects on IGF receptor expression by osteoblasts. For example, Kurose et al. (183) found that the affinity and hormone binding capacity of VDRs were not affected by IGF-I in the MC3T3-E1 osteoblastic cell line. However, 1,25(OH)₂D₃ significantly induced IGF-I receptor expression. This was evident by Scatchard analysis, which revealed a significant increase in IGF-I binding sites by 50% after treatment for 3 d with 5 x 10^-11 M 1,25(OH)₂D₃, without any change in affinity (183).

The bioactivity of IGFs is regulated through their interaction with a group of high-affinity IGFBPs. At least six IGFBPs (IGFBPs 1–6) have been identified and were found to have a variety of biological effects that are both IGFBP and cell type specific (187). The activities of IGFBPs are regulated through changes in their rates of degradation by multiple specific and nonspecific proteases and protease inhibitors (188, 189). The exact functions of the different IGFBPs in bone metabolism are complex and are not yet fully understood. However, increasing evidence suggests that they may modulate the activities of IGFs. For example, exogenous IGFBP-5 enhances the mitogenic potential of IGF-I (190) or IGF-II (191) added to mouse osteoblast-like cells in vitro and has an important role in the storage of IGF-II in bone matrix (191). IGFBP-1 (192), IGFBP-3 (193), and IGFBP-4 (194) have been shown to suppress the functions of IGF actions in human osteoblast-like cells. IGFBP-2 has been shown to potentiate (195) or antagonize (196, 197) the IGF-mediated effects, and its role in osteoblast biology is not precisely known.

In human preosteoblastic bone marrow stromal cells, 1,25(OH)₂D₃ has been found to increase steady-state mRNA levels of IGFBPs 2, 3, and 4 (182). Western ligand blot analyses revealed consistently the stimulation of secretion of the IGFBPs (182). 1,25(OH)₂D₃ stimulates IGFBP-5 mRNA expression in cultured neonatal calvarial cells (198) and the osteoblastic UMR-106 cell line (199). Increased mRNA expression and secretion of IGFBP-3 and 4 have also been observed in human osteoblastic cells in several other studies (200, 201, 202, 203). As a common point, the increase in the expression of these IGFBPs was not associated with increased proteolytic activity. The increase in mRNA and protein levels of IGFBPs requires continuous exposure to 1,25(OH)₂D₃ for more than 48 h (182), suggesting that these changes are secondary to effects on immediate responsive genes. As no consensus VDRE has been found in the promoter regions of the IGFBPs, it is plausible that 1,25(OH)₂D₃ effects are mediated through other signaling pathways such as cAMP or AP-1 transcription factors, which have been shown to mediate some of the genomic effects on components of the IGF system (204, 205).

Given the inhibitory effects of IGFBPs in IGF actions on bone cells (206, 207), it is plausible that the inhibitory effects of 1,25(OH)₂D₃ on bone formation may be mediated, at least in part, by the enhanced production of inhibitory IGFBPs. However, the regulatory roles of IGFBPs in the effects of 1,25(OH)₂D₃ on bone cell biology are complex and deserve further evaluation. Based on earlier observations that addition of excessive amounts of IGFBPs to cell cultures resulted in variable effects, more physiological approaches are required. This will rely on the assessment of endogenous levels of IGFBPs and development of IGFBP-specific neutralizing antibodies that will prevent interaction with IGFs.

c. Nerve growth factor (NGF).
NGF belongs to a family of neurotrophic factors named neurotrophins, which includes brain-derived neurotrophic factor and neurotrophins 3, 4, and 5 (208). NGF was initially described on the basis of its trophic effects on sympathetic and some sensory neurons in the peripheral nervous system (208). However, its role now extends to cells belonging to the endocrine and immune systems. In the mouse fibroblastic cell line L929, the expression of the NGF gene has been shown to be positively regulated by an activator of PKC, the phorbol 12-myristate 13-acetate (209), and 1,25(OH)₂D₃ (51). The presence of NGF in the embryonic bone of the chick has been shown by immunochemistry (210), as has the expression of NGF family neurotrophins in the MC3T3-E1 mouse osteoblastic cell line (211). The regulation of NGF expression by 1,25(OH)₂D₃ in osteoblasts was first studied by Jehan et al. (212). In the ROS 17/2.8 rat osteoblastic cell line, they showed that 1,25(OH)₂D₃ caused a dose-dependent increase in NGF mRNA expression. Binding of radiolabeled NGF displayed the presence of low-affinity receptors for the growth factor in these cells (212). In the rat ROS17/2.8 osteoblastic cell line, we have shown that treatment with 1,25(OH)₂D₃ for 6 h resulted in a dose-dependent increase in NGF expression (213).

The biological significance of the 1,25(OH)₂D₃-induced NGF expression by osteoblastic cells has not yet been clarified. Regeneration after limb amputation can be successfully induced by transplanting nervous tissue to the lesioned limb (214, 215), and symphatectomy may result in the loss of a trophic influence important in the regulation of osteogenesis (216). More recently, it was shown that topical application of NGF improves fracture healing in rats (217). However, whether NGF produced by bone cells is associated with the nerve supply of bone, is directly implicated in bone formation, or acts on bone marrow cells to promote proliferation remains to be further explored.

The molecular mechanisms by which 1,25(OH)₂D₃ induces NGF expression in osteoblasts have not yet been fully understood. The NGF gene contains an AP-1 site within the first intron, 35 bp downstream from the transcription initiation site (218). This AP-1 site has been shown to be functionally required for basal level NGF transcription in fibroblasts (219). Members of the fos and jun family of transcription factors are known to bind to these AP-1 sequences. Indeed, lesion-induced increases in NGF expression have been mediated by c-fos (220). In a previous study from our laboratory (213), we have shown that 1,25(OH)₂D₃ induces NGF expression in ROS 17/2.8 osteoblastic cells indirectly by increasing AP-1 binding activity (213).

d. Vascular endothelial growth factor (VEGF).
Osteoblasts are located in proximity to endothelial cells. It is highly likely that a mutual communication exists between endothelial cells and parenchymal cells, as demonstrated in liver and thyroid (221, 222). Osteoblasts and preosteoblastic progenitor cells have been found to locate adjacent to endothelial cells in blood vessels at sites of new bone formation (223). Vascular invasion is a prerequisite for endochondral bone formation and fracture healing (224). Factors produced by endothelial cells may therefore affect osteoblast function or differentiation and vice versa (225, 226). As a clinical clue to the interaction between osteoblasts and endothelial cells, older subjects and patients with osteoporosis have been shown to have decreased blood vessels in their skeletal tissue that is accompanied by a parallel decrease in osteoblast number (227, 228). In this cross-talk between endothelial cells and osteoblasts, VEGF, which acts as an angiogenic factor, may play an important role (59). A recent study by Gerber et al. (229) revealed that blocking the action of endogenous VEGF inhibits both bone formation and resorption in juvenile mice.

VEGF, a homodimeric protein with a signal peptide, specifically stimulates endothelial cell proliferation by binding to VEGF receptors (Flt-1 and KDR) that are expressed exclusively on the cells (230, 231). During osteoblast development, both VEGF and VEGF receptor expression increases in parallel with the advancement of the cell differentiation (232). VEGF mRNA expression has been found to be induced by 1,25(OH)₂D₃ in SaOS-2 osteoblast-like cells (233), human osteoblast-like cells (234), and cocultures of osteoblasts with endothelial cells (235). Stimulation of endothelial proliferation is partly blocked by anti-VEGF antibodies in cocultures of endothelial and osteoblastic cells (59). 1,25(OH)₂D₃induced VEGF expression in osteoblasts is enhanced if the cells are cocultured with endothelial cells (59). Interestingly, 1,25(OH)₂D₃ induces the expression of endothelial, but not osteoblastic, VEGF receptor expression only when these cells are cultured together (59). According to a model proposed by Wang et al. (59), activated endothelial cells expressing a greater amount of VEGF receptor genes, in turn, produce osteotropic growth factors, such as IGF-I and endothelin-1, which synergistically stimulate the proliferation of osteoblastic cells and alkaline phosphatase activity (Fig. 7) (59). In view of these observations, it is plausible to state that there is a mutual communication between osteoblasts and endothelial cells in bone. The anabolic effects of 1,25(OH)₂D₃ on osteoblasts are mediated in a paracrine manner and enhanced by a VEGF/VEGF receptor system between osteoblasts and endothelial cells.

View larger version (32K): [in this window] [in a new window]   Figure 7. Hypothesis relating to the anabolic effects of 1,25(OH)2D3 on osteoblasts in the presence of endothelial cells. [Reproduced from D. S. Wang et al.: Endocrinology 138:2953–2962, 1997 (59 ). © The Endocrine Society.]

e. EGF family.
EGF and related family members have been shown to be important growth factors for a variety of cells including numerous epithelial and epidermal cells (discussed further in Section III.C.1) in vivo and in vitro. Bone cells express EGFRs (239, 240), and EGF has been demonstrated to stimulate DNA synthesis as well as to enhance growth of osteoblast-like cells (241). EGF has also been shown to increase bone resorption (242, 243), decrease collagen synthesis (244), and inhibit the formation of mineralized nodules (245). Previously, PTH has been shown to increase the expression of EGFR in the UMR 106-01 osteoblastic cell line (246). In an early study by Petkovich et al. (247), 1,25(OH)₂D₃ caused a dose- and time-dependent increase in EGFR expression in RCJ 1.20 rat calvarial cells. The increase in EGFRs potentiated the effect of EGF on anchorage-dependent and anchorage-independent growth of these cells (247). More recently, the stimulatory effect of 1,25(OH)₂D₃ on EGFR expression was also confirmed in UMR 106-01 osteoblast-like cells (248). In this study, the effects of 1,25(OH)₂D₃ on EGFRs were completely abolished in the presence of retinoic acid (248). Because EGF and other family members are important factors in the growth and development of osteoblasts, modulation of its receptors by 1,25(OH)₂D₃ plays an important role in its effects on these cells.

B. Osteoclasts
1. Formation and function of the osteoclast.
As discussed previously, bone resorption is one arm of the bone remodeling process that is usually balanced by bone formation to maintain bone mass. Under normal conditions, bone-resorbing osteoclasts are present in appropriate numbers, and they cycle between active and inactive states in a tightly regulated fashion. When in balance, the remodeling process involves equal and linked participation of both osteoblasts and osteoclasts. Deviation of the balance in favor of resorption leads to bone loss and, therefore, osteoporosis (249). Osteoclasts resorb bone by a complex, multistep process that occurs in an orderly sequence and utilizes cross-reacting intracellular signaling pathways (249, 250). The earliest identifiable osteoclast precursors are derived from colony forming unit-granulocyte/macrophage (CFU-GM) from the granulocyte/macrophage lineage (249). Osteoclast precursor cells are attracted to regions of mineralized bone matrices that are identified in an unknown way to undergo resorption to maintain plasma calcium levels.

The osteoclast life span can be subdivided into distinct stages as follows: 1) homing of the precursor cells (CFU-GM) to bone surfaces and proliferation (formation of preosteoclasts), 2) fusion of mononuclear preosteoclasts into multinucleate immature osteoclasts, 3) development of polarity through adherence to bone and assembly of an acidifying resorptive apparatus (ruffled border) indicative of cellular activation, 4) detachment and final inactivation that ends in apoptosis. As discussed in detail below, endocrine and local control by several factors are effective in osteoclastogenesis and function of the cells.

2. Endocrine and local control of osteoclast activity.
Osteoclast function is regulated by a variety of hormones, including 1,25(OH)₂D₃. Bone resorption is stimulated by PTH and 1,25(OH)₂D₃, whereas it is inhibited by sex steroids (discussed earlier) and calcitonin. Most stimulators appear to act indirectly, in contrast to most inhibitors, which act directly. PTH action in bone is a good example for the indirect mechanism. PTH increases bone resorption by increasing the activity and number of osteoclasts (249). However, it has also been noted that isolated osteoclasts do not express PTH receptors and therefore, isolated osteoclasts can not directly respond to PTH (251, 252). The addition of osteoblasts to isolated osteoclasts restores the ability of the osteoclasts to resorb bone in response to PTH (251). This finding suggests that PTH activates osteoclasts indirectly by stimulating osteoblasts and perhaps osteoblast precursors, which then activate osteoclasts.

There are several growth factors and cytokines that are involved in the local control of osteoclastogenesis and osteoclast function (Table 4).

3. Regulatory effects of 1,25(OH)₂D₃ on local factors.
Bone remodeling is a complex process during which previously described osteoblastic bone formation is coupled with osteoclastic bone resorption by systemic and local factors that function together to maintain bone mass as illustrated in Fig. 8. 1,25(OH)₂D₃ is a potent stimulator of osteoclastic bone resorption and osteoclast formation. It has been shown that 1,25(OH)₂D₃ acts as a fusigen for committed osteoclast precursors (270). It is unlikely that 1,25(OH)₂D₃ acts on mature osteoclasts directly, because they do not express VDR (271). Therefore, it seems that 1,25(OH)₂D₃ exerts these effects indirectly by modulating local control mechanisms as summarized in Table 3 and Fig. 8, and discussed in the following sections.

View larger version (42K): [in this window] [in a new window]   Figure 8. Coupling of osteoblastic bone formation with osteoclastic bone resorption through interactions between systemic factors, including 1,25(OH)2D3, and local factors. Note that 1,25(OH)2D3 induces terminal differentiation of osteoblastic cells directly and indirectly and promotes osteoclastogenesis through actions on cytokines, growth factors, and the RANKL/RANK/OPG system (see text for details). Solid lines indicate stimulation; broken lines represent suppression.

Various skeletal and extraskeletal cells such as stromal cells, osteoblasts, osteoclasts, mesenchymal periostal cells, chondrocytes, and endothelial cells express RANKL (275, 276, 277, 278, 279). It has recently been demonstrated that activated T lymphocytes express RANKL to support osteoclast formation (280). RANKL may promote osteoclast differentiation (281, 282, 283), activation (284), survival (285), and adherence to bone surface (286) through RANK. As expected, activation of its decoy receptor, OPG, causes opposite effects.

Regulation of RANKL and OPG gene expression and OPG secretion has been a subject of several studies. RANKL/RANK/OPG system plays an important role in the coupling of osteoblasts with osteoclasts and is under the influence of local factors and hormones (Fig. 8). Analysis of the RANKL gene promoter showed response elements for vitamin D and glucocorticoids (287, 288), suggesting regulation of RANKL by these hormones. Estrogen has the ability to enhance OPG mRNA steady-state levels and OPG protein secretion in human osteoblasts, which contributes to its inhibitory effects on bone resorption (289). 1,25(OH)₂D₃ is also involved in the regulation of RANKL and OPG both directly and indirectly, through local factors (Fig. 8). Nakashima et al. (290) showed that treatment of murine osteoblasts and stromal cells with 1,25(OH)₂D₃ resulted in increases in membrane-bound RANKL expression and inhibition of OPG production. In another study, Horwood et al. (291) observed that PTH, IL-11, and 1,25(OH)₂D₃ increased the RANKL/OPG ratio in mouse calvaria. The inhibition of OPG by 1,25(OH)₂D₃ was also observed in the human fetal osteoblastic cell line, but not in human preosteoblastic marrow stromal cells (292). Recently, Thomas et al. (293) provided data about the effect of the differentiation state of the osteoblastic cells in the regulation of RANKL/OPG ratio by 1,25(OH)₂D₃. OPG mRNA expression was increased in primary murine osteoblastic cultures after the onset of mineralization relative to less mature cultures, but showed no alteration with 1,25(OH)₂D₃ treatment (293). In contrast, basal RANKL mRNA expression did not change during differentiation but was significantly enhanced by 1,25(OH)₂D₃ treatment at all times. The stimulatory effects of 1,25(OH)₂D₃ on RANKL were lessened in more mature cultures (293). Taken together, these results suggest that 1,25(OH)₂D₃ increases the RANKL/OPG ratio and promotes osteoclastogenesis (Fig. 8).

b. IL-1.
IL-1 was one of the earliest cytokines to be identified as having a regulatory role in bone cell function and remains one of the most potent bone-resorbing agents (294). In a previous study by Merry and Gowen (295), human osteoblast-like cells were used to determine the modulators of IL-1 expression. They found that hydrocortisone (10^-8 M) treatment resulted in the suppression of TGFß and IL-1ß mRNA expression. 1,25(OH)₂D₃, however, had no effect on IL-1ß, but it increased TGFß expression (295). Furthermore, 1,25(OH)₂D₃ failed to reverse the hydrocortisone-induced suppression in IL-1ß expression. These results suggest that TGFß and IL-1ß are differentially regulated in osteoblasts and that 1,25(OH)₂D₃ seems to have no direct effect on IL-1ß expression. Interestingly, Lacey et al. (296) demonstrated that 1,25(OH)₂D₃ stimulates the expression of type 1 IL-1 receptors, which mediate the IL-1-induced IL-6 production. As discussed below, IL-6 is also a bone-resorbing cytokine that contributes to the effects of 1,25(OH)₂D₃.

c. IL-4.
Apart from being an immunomodulatory cytokine, IL-4 has been shown to inhibit bone resorption induced by a variety of osteolytic factors in vitro (297) and in vivo (298). IL-4 significantly antagonizes osteoclast generation in vitro (299). It has been shown that IL-4 receptor is expressed by osteoblasts (300), and stimulation of the cells with 1,25(OH)₂D₃ caused steady-state increases in IL-4 mRNA levels in a time-dependent manner. Therefore, it is highly likely that inhibitory effects of IL-4 on osteoclast are mediated by osteoblasts, and 1,25(OH)₂D₃ is implicated in this process. Therefore, local control mechanisms involved in IL-4-mediated regulation of bone resorption by osteoblasts should be further investigated.

d. IL-6.
Most of the evidence suggests that IL-6 affects neither the bone-resorbing capacity of mature osteoclasts (301, 302), nor their differentiation in mouse parietal bones (303), but IL-6 does stimulate the proliferation of osteoclast progenitor cells (304). There is much evidence to indicate that IL-6 is produced by osteoblast-like cells and acts on osteoclasts to exert its effects (305). In a previous study (306), 1,25(OH)₂D₃ did not stimulate IL-6 production in mouse parietal osteoclasts but induced their proliferation. Similarly, 1,25(OH)₂D₃ caused only marginal elevations in mouse stromal/osteoblast-like cell lines (307). On the other hand, there is convincing evidence that stimulatory effects of 1,25(OH)₂D₃ on osteoclastogenesis could be mediated in part by IL-6. In a recent study, Schiller et al. (308) found that 1,25(OH)₂D₃-induced IL-6 expression failed to stimulate osteoclastogenesis in mouse bone marrow cultures. However, they also reported that neutralizing antibodies against IL-6 and anti-IL-6 receptor partly blocked the 1,25(OH)₂D₃-stimulated osteoclastogenesis (308). Apart from a ligand-binding domain, IL-6 receptor also has a non-ligand-binding but signal-transducing component, gp130 (309). In a recent study, Gao et al. (310) have reported that 1,25(OH)₂D₃ significantly increased gp130 expression in preosteoclastic mouse bone marrow stromal cells without affecting IL-6 receptor. Moreover, both ligand-binding domain and gp-130 were stimulated by 1,25(OH)₂D₃ in marrow mononuclear cells (310). The treatment of tartrate-resistant acid phosphatase-positive mononuclear cells with IL-6 clearly increased their bone-resorbing capacity (310). These results suggest 1,25(OH)₂D₃ indirectly increases the bone-resorbing capacity of osteoclasts via stimulating IL-6 receptor and gp130 expression.

e. IL-8.
IL-8 is a chemokine that is involved in many inflammatory disease states associated with local bone loss such as rheumatoid arthritis (311). Human osteoclasts synthesize and secrete high constitutive and inflammation-stimulated levels of IL-8, which enhance bone resorption and recruitment of inflammatory cells (312). IL-8 release from the cells is induced by proinflammatory cytokines IL-1 and TNF, but suppressed by IFN, dexamethasone, and 1,25(OH)₂D₃ (312). Thus, these results suggest that 1,25(OH)₂D₃ might be beneficial in the prevention of local bone loss in inflammatory disease states, such as rheumatoid arthritis, by inhibiting IL-8 expression in osteoclasts.

f. IL-11.
IL-11 is a functionally pleiotropic cytokine that was isolated from a bone marrow-derived stromal cell line (313). Similar to IL-6, IL-11 receptor also contains gp130 as a signal transducer (309). Several lines of evidence suggest that IL-11 is an important osteotropic factor. IL-11 itself is produced by human osteosarcoma SaOS-2 cells (314), and Girasole et al. (259) have shown that IL-11, in a dose-dependent manner, stimulated osteoclast-like multinucleated cell formation in cocultures of mouse osteoblasts and bone marrow cells. The effect of IL-11 on osteoclast function, however, is not yet clear.

Romas et al. (315) examined IL-11 production by primary mouse osteoblasts and the effects of rat monoclonal antimouse glycoprotein 130 (anti-gp130) antibody on osteoclast formation in a coculture system that consists of osteoblasts and marrow cells. They observed that osteotropic factors [1,25(OH)₂D₃, PTH and IL-1] had no effect on IL-11 steady-state mRNA levels. However, steady-state gp130 mRNA levels were significantly induced by these factors. In cocultures, the formation of multinucleated osteoclast-like cells in response to IL-11 was suppressed, in a dose-dependent manner, by anti-gp130 monoclonal antibodies. Furthermore, adding anti-gp130 antibody abolished osteoclast formation by the osteotropic factors including 1,25(OH)₂D₃ (315). These results suggest that 1,25(OH)₂D₃ modulates IL-11 signaling by enhancing gp-130 expression in osteoblasts. This modulation may contribute to its action as a bone-resorbing hormone.

g. TNF.
TNF is a pleiotropic cytokine with actions on the differentiation, growth, and functional activities of normal and malignant cells from numerous tissues (316). Its actions on connective tissue cells include the stimulation of bone resorption, cartilage breakdown (317), collagenase production by synovial cells (318), and the inhibition of rat calvarial bone collagen synthesis (319, 320). TNF has been shown to reduce VDR expression in the osteoblastic ROS 17/2.8 cell line (321) and thus antagonizes the anabolic effects of the sterol on osteoblasts.

Cells that migrate from fragments of human trabecular bone and form monolayers in culture exhibit characteristics of bone-forming cells or osteoblasts (322, 323). Recombinant TNF modulates the proliferation and osteoblastic characteristics of these cells in vitro at concentrations between 10^-12 and 10^-8 M (324). TNF has been proposed, therefore, as a local mediator of the control of bone turnover in situations of chronic inflammation. It has been shown that human osteoblasts derived as outgrowths from trabecular bone release substantial amounts of TNF in response to IL-1 and granulocyte macrophage colony stimulating factor (GM-CSF), but calcitonin, PTH, and 1,25(OH)₂D₃ have no effect on it (325). This result suggests that 1,25(OH)₂D₃ does not contribute to TNF--induced bone loss in chronic inflammatory states associated with increased bone resorption.

h. M-CSF and GM-CSF.
M-CSF, which is essential for osteoclast development (326, 327), could be one of the most important signals elaborated by the osteoblast to initiate a cycle of bone remodeling. Regulation of osteoblast M-CSF expression is therefore a significant target site for factors, including 1,25(OH)₂D₃, that promote osteoclastogenesis. Blocking antibodies against M-CSF prevents osteoclastogenesis by preventing the expansion of the monocytic precursor pool from which osteoclasts arise (327). M-CSF alone, however, is not sufficient for osteoclastogenesis: in the murine primary culture system the presence of accessory osteoblasts is required, suggesting that osteoblasts may need to present a membrane-bound form of M-CSF to developing monocytic cells (328). In the osteopetrotic op/op mouse, which expresses a mutant, inactive M-CSF, no osteoclasts or macrophages are found (329, 330).

The receptor for M-CSF, encoded by the protooncogene c-fms, is found in mature macrophages and osteoclasts as well as the pluripotent precursor (331). Expression of the M-CSF receptor has been shown to increase in murine bone marrow-derived cells as they mature into monocytes and macrophages, thereby providing a lineage-specific marker of differentiation (332, 333). 1,25(OH)₂D₃ has been shown to increase M-CSF receptor expression on early uncommitted nonadherent bone marrow precursor cells (334). Thus, an increase in M-CSF receptor expression may be a mechanism by which 1,25(OH)₂D₃ exerts its differentiational effects on monocyte/macrophage precursors, directly influencing the ability of the cell to bind the cytokine.

Perkins et al. (335) have shed some light on the details of 1,25(OH)₂D₃-induced M-CSF receptor expression. In bone marrow cells, 1,25(OH)₂D₃ caused a marked decrease in cellular proliferation despite a 2- to 3-fold increase in radiolabeled M-CSF binding in a dose-dependent manner. Scatchard analysis demonstrated that increased binding reflects increased receptor capacity without an alteration in affinity. The steroid accelerated the protein appearance rather than overexpression because treated and untreated cells ultimately exhibited equivalent binding. Increased M-CSF receptor expression was mirrored by increased c-fms mRNA levels, and actinomycin D and cycloheximide experiments indicated that new receptor synthesis, rather than mobilization of intracellular pool, is required (335). In contrast to these observations, Biskobing et al. (336) have shown that HL-60 cells, which represent an early precursor in myelomonocytic lineage, present with a decreased M-CSF receptor expression in response to 1,25(OH)₂D₃. Taken together, these findings suggest that the stimulatory effect of 1,25(OH)₂D₃ on M-CSF receptor expression depends on the stage of differentiation of osteoclast precursors.

1,25(OH)₂D₃ is also involved in the regulation of M-CSF synthesis by osteoblastic cells. In an early report by Elford et al. (337), it was shown that 1,25(OH)₂D₃ is able to induce M-CSF secretion by neonatal mouse calvaria. More recently, Rubin et al. (338) found that M-CSF mRNA expression is increased, in a dose-dependent manner, by 1,25(OH)₂D₃ in murine osteoblastic cells. Furthermore, they also showed that 1,25(OH)₂D₃ is able to stimulate a membrane-bound form of M-CSF in these cells, and this regulation is primarily pretranslational (338).

Osteoblasts have also been shown to produce GM-CSF, which increases the formation of osteoclast-like cells from bone marrow cells (339). This activity is enhanced in the presence of 1,25(OH)₂D₃ (339). In murine MC3T3-E1 cell lines, lipopolysaccharide and, to a lesser extent, PTH are capable of inducing GM-CSF secretion by the cells (340). However, 1,25(OH)₂D₃ fails to induce GM-CSF production (340). Therefore, it is unlikely that the interaction between 1,25(OH)₂D₃ and GM-CSF in the context of stimulation of osteoclastogenesis involves a change in the synthesis of cytokine. As discussed below, the stimulation of annexin II by 1,25(OH)₂D₃ results in a GM-CSF-mediated increase in osteoclastogenesis.

i. Annexin II.
Annexin II, a calcium-dependent phospholipid-binding protein, has been found recently to be an osteoclast-stimulatory factor that is also secreted by osteoclasts (341). Annexin II increases osteoclast formation by enhancing proliferation of CFU-GM. This function is accomplished through induction of GM-CSF expression by CD4+ T cells (342). It has been shown that annexin II transcript levels are clearly increased by 1,25(OH)₂D₃ treatment of human bone marrow osteoclast-like cells (342). These results suggest that annexin II is an important mediator of the effects of 1,25(OH)₂D₃ on osteoclastogenesis and involves GM-CSF.

	V. Summary and Future Directions

Top Abstract I. Introduction II. 1{alpha},25(OH)2D3 as a... III. Effect of... IV. Impact of 1{alpha},25(OH)2D3... V. Summary and Future... References

 
In the past several years, numerous studies have suggested that 1,25(OH)₂D₃ interacts with various growth factors and cytokines to mediate its effects in coordinating cell growth and differentiation. This interaction may occur in a variety of cell types including epithelial, mesenchymal, neural, and endothelial cells. In this review, however, we have confined our remarks to its effects in keratinocyte and bone cell (osteoblasts and osteoclasts) biology, both of which are regulated by tightly coordinated local control mechanisms and are highly illustrative of relevant 1,25(OH)₂D₃-growth factor/cytokine interactions.

The effect of 1,25(OH)₂D₃ on keratinocyte growth is controversial with proliferative and antiproliferative effects being observed in different studies. This discrepancy has been attributed to the range of 1,25(OH)₂D₃ concentrations and medium conditions used in in vitro cultures. The antiproliferative effect is predominant in proliferative states such as psoriasis and is due to excessive expression of VDR. The stimulatory effect is mediated by increases in EGF-related growth factors and its receptors, and this is valid in normal skin in which the cells are not proliferative. In contrast, the inhibitory effects are mediated by increases in TGFß. The induction of TNF and increased ceramide formation may account for, at least in part, the prodifferentiative effects of the sterol on keratinocytes. Proinflammatory cytokines IL-1, IL-6, IL-8, and RANTES are all suppressed by 1,25(OH)₂D₃, possibly explaining why the sterol is topically effective in the treatment of hyperproliferative skin disorders such as psoriasis. PDGF, a growth factor implicated in wound healing, is induced in epidermal keratinocytes by 1,25(OH)₂D₃. This may provide a further rationale for the beneficial effects of the sterol in corticosteroid or age-induced cutaneous atrophy and sun-related skin damage, and substantiates the contribution of keratinocytes in the wound healing process.

1,25(OH)₂D₃ has an important impact on the local control of bone remodeling. It affects the activity of both bone-forming osteoblasts and bone-resorbing osteoclasts by modulating growth factor/cytokine synthesis and signaling. Similar to the case in keratinocytes, 1,25(OH)₂D₃ has predominantly antiproliferative and prodifferentiative actions on osteoblasts. It enhances the TGFß and TGFß receptor expression in osteoblasts. TGFß plays an important role in the coupling of bone formation with resorption, and thereby the maintenance of bone mass. 1,25(OH)₂D₃ also interacts with Smad signaling system downstream from TGFß receptor activation. Anabolic effects of 1,25(OH)₂D₃ on osteoblasts are partially mediated through increased synthesis of IGF-I and IGF-II receptors. 1,25(OH)₂D₃ also affects IGFBP synthesis. IGFBPs have complex effects on IGFs, most of which have not yet been completely understood. 1,25(OH)₂D₃ stimulates osteoblasts to express NGF, which might be involved in the generation of neural tissue required for efficient bone remodeling during fracture healing. Endothelial cells and osteoblasts are functionally interconnected by an autocrine and paracrine local network. Induction of VEGF expression in osteoblasts, and VEGF receptor expression in endothelial cells by 1,25(OH)₂D₃, may have an important role in the mutual communication and autocrine/paracrine control of these cells during bone formation.

1,25(OH)₂D₃ plays a crucial role in bone resorption by stimulating osteoclast formation and activity. Unlike osteoblasts, however, osteoclasts do not express the VDR. Therefore, they are indirectly regulated by 1,25(OH)₂D₃. Many cytokines and growth factors involved in the regulation of osteoclastogenesis and osteoclast function are modulated by 1,25(OH)₂D₃. The recently discovered RANKL/RANK/OPG cytokine system has paramount importance in the local control of osteoclast biology. By activating the RANKL and suppressing its decoy receptor, OPG, 1,25(OH)₂D₃ enhances osteoclastogenesis and bone resorption. Several other cytokines and growth factors, which stimulate (IL-1, IL-6, IL-11, annexin II) or inhibit (IL-4, M-CSF, TGFß) bone resorption, are regulated by 1,25(OH)₂D₃. TNF, a cytokine involved in local bone loss associated with inflammatory disorders, does not seem to be influenced by 1,25(OH)₂D₃, although further investigation is required in this area.

In conclusion, strong and mounting evidence suggests that 1,25(OH)₂D₃-mediated effects on cytokine/growth factor synthesis and signaling are important in the local regulation of cellular growth and differentiation. A valid shortcoming in experimental information, however, is that most of the data are derived from in vitro studies. Clearly, in vitro results are not always representative of the effects in vivo. Therefore, further in vivo studies are needed to delineate and validate these interactions, preferably using cytokine/growth factor overexpressing or receptor knockout animals. Also, there remain unknown or ill-defined molecular mechanisms mediating the effects of 1,25(OH)₂D₃. Future research should focus, in particular, on the postreceptor mechanisms (e.g., Smads and Smad partners) implicated in these effects. Also, further investigations are needed to fully elucidate the function of 1,25(OH)₂D₃ in the regulation of other cytokines and growth factors involved in bone cell biology, such as PDGF, leukemia inhibitory factor, IFN, and other novel mediators.

	Footnotes

 
This work was supported by a Fulbright Scholarship Program grant (to A.G.), and NIH Grants DK-25409, DK-59505, DK-58546, and AR-27032 (to R.K.).

¹ Current address: Hacettepe University School of Medicine, Department of Medicine, Division of Endocrinology and Metabolism, Ankara, Turkey.

Abbreviations: AP-1, Activator protein-1; AR, Amphiregulin; CFU-GM, colony forming unit-granulocyte/macrophage; EGF, epidermal growth factor; EGFR, EGF receptor; GM-CSF, granulocyte/macrophage colony stimulating factor; HER, human EGF receptor; IFN, interferon; IGFBP, IGF binding protein; M-CSF, macrophage colony stimulating factor; NGF, nerve growth factor; 1,25(OH)₂D₃, 1,25-dihydroxyvitamin D₃; OPG, osteoprotegerin; PDGF, platelet-derived growth factor; PKC, protein kinase C; RANK, receptor activator of nuclear factor B; RANKL, RANK ligand; RANTES, regulated on activation, normal T expressed and secreted; Smad, mothers against decapentaplegic-related protein; VDR, vitamin D receptor; VDRE, vitamin D response element; VEGF, vascular endothelial growth factor.

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Top Abstract I. Introduction II. 1{alpha},25(OH)2D3 as a... III. Effect of... IV. Impact of 1{alpha},25(OH)2D3... V. Summary and Future... References

 

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