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Vitamin D, Osteoclastogenesis and Bone Resorption: from Mechanistic Insight to the Development of New Analogs

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Vitamin D, Osteoclastogenesis and Bone Resorption: from Mechanistic Insight to the Development of New Analogs Endocrine Journal 2007, 54 (1), 1–6 REVIEW Vitamin D, Osteoclastogenesis and Bone Resorption: from Mechanistic Insight to the Development of New Analogs KYOJI IKEDA Department of Bone and Joint Disease, Research Institute, National Center for Geriatrics and Gerontology (NCGG), Obu, Aichi 474-8522, Japan (Endocrine Journal 54: 1–6, 2007) Prologue: 1α,25(OH)2D3 as factor (OCIF) or osteoprotegerin (OPG), was dis- a bone-resorbing hormone covered to protect bone by negatively regulating osteoclast formation. This work was reported by THE vitamin D hormone 1α,25-dihydroxyvitamin D3 Yukijirushi [6] and Amgen [7]. In the following year, (1α,25(OH)2D3) is a pleiotropic hormone which exerts its ligand, OPGL, or currently under the prevailing its effects through the nuclear vitamin D receptor name of “receptor activator of nuclear factor-κB (VDR) [1]. Among these effects, the physiological ligand” (RANKL), was identified by the 2 companies importance of VDR in maintaining the integrity of as the long-sought osteoclast differentiation factor mineral and skeletal systems is underscored by the se- (ODF) that is presented on osteoblastic/stromal cells, vere hypocalcemia and rickets/osteomalacia observed thereby promoting the terminal differentiation into in VDR gene knockout mice as well as patients with osteoclasts [8, 9]. Yasuda et al. elegantly showed that –8 –7 vitamin D deficiency [2]. The connection between vi- 1α,25(OH)2D3 at relatively high doses of 10 –10 M, tamin D and bone resorption was first made in 1972, induces the expression of RANKL in the ST2 stromal when it was reported that in a classic experiment using cell line [8], providing the final molecular proof that bone organ cultures, the so-called “Raisz assay”, 1α,25(OH)2D3 is a pro-osteoclastogenic hormone [4]. 1α,25(OH)2D3 stimulates bone resorption, as deter- It then became widely recognized that in addition to 45 mined by the release of Ca from pre-labeled fetal 1α,25(OH)2D3, many other bone-resorbing hormones long bones [3]. This paper formed the basis of the cur- and cytokines, such as PTH, prostaglandins, TNF and rently prevailing belief that 1α,25(OH)2D3 is a bone- IL-1, stimulate osteoclastogenesis indirectly by induc- resorbing hormone [4]. In the 1980’s, the now well- ing RANKL in stromal/osteoblastic cells. known co-culture system of hematopoietic cells with Contrary to this prevailing view, however, we in osteoblast/stromal cells for generating osteoclasts was fact observed in various models of accelerated bone re- developed [5], and together with the demonstration of sorption that pharmacological doses of active vitamin 1α,25(OH)2D3 as a differentiation-inducing agent, the D drugs unexpectedly inhibit bone resorption in vivo dogma that 1α,25(OH)2D3 is essential for osteoclast [10–12]. I herein summarize what has been learned differentiation became firmly established [4]. from these pharmacological experiments, and discuss 1997 was a landmark year in the research history the role of VDR-based drugs in the treatment of bone of bone biology, especially in terms of the osteoclast. disease, especially osteoporosis. A novel cytokine, named osteoclastogenesis inhibitory Correspondence to: Kyoji IKEDA, M.D., Department of Bone Osteoclasts in osteoporosis and Joint Disease, Research Institute, National Center for Geriatrics and Gerontology (NCGG), 36-3 Gengo, Morioka, Obu, Osteoclast-mediated bone resorption plays a central Aichi 474-8522, Japan pathogenetic role in the development and progression 2 IKEDA of osteoporosis [13]. Bisphosphonates, which potently We compared the pharmacological effects of vari- inhibit the bone-resorbing activity of mature osteo- ous doses of native vitamin D versus 1α(OH)D3 as a clasts, are currently the most widely used treatment for prodrug converted to the active form, in ovariecto- osteoporosis [14, 15]. Multinucleated osteoclasts are mized rats. The animals were supplemented with derived from hematopoietic precursor cells through the calcium and native vitamin D [24]. The results indi- concerted action of 2 cytokines, macrophage-colony- cate that active vitamin D increases BMD and bone stimulating factor (M-CSF) and RANKL [16, 17]. strength more potently than native vitamin D with These cytokines are produced by osteoclastogenesis- comparable effects on calcium metabolism, pointing to supporting marrow stromal cells, and act on osteoclast an advantage of the hormonal over the native form. precursor cells through their cognate receptors, c-fms and RANK, respectively. These cell-surface receptors transmit osteoclastogenic signals through intracellular Anti-osteoclastogenic action of VDR kinase cascades, which eventually lead to the activa- tion of the transcription factors c-Fos/AP-1 and NF-κB The first hint that active vitamin D may actually be in the nucleus. Accordingly, mice deficient in c-Fos, an inhibitor of bone resorption was obtained unex- NF-κB, RANK, RANKL or M-CSF fail to generate pectedly with experiments examining the effects of a osteoclasts and exhibit osteopetrosis [16, 17]. vitamin D analog, OCT, on cancer-induced hyper- Menopause and aging are thought to cause aberrant- calcemia. To carry out that investigation we had ly elevated generation of osteoclasts, which elevation established parathyroidectomized rats rendered hyper- involves diverse mechanisms, including the produc- calcemic with constant PTHrP infusion so the endo- tion of bone-resorbing cytokines in response to estro- genous PTH levels would be constant. Under these gen deficiency [14, 18]. In addition to estrogen “PTH clamp” conditions, we observed that not only deficiency, a recent report suggests that the pituitary OCT but, surprisingly, 1α,25(OH)2D3, ameliorated hy- hormone FSH also contributes to the high bone turn- percalcemia with concomitant inhibition of bone re- over which characteristically follows menopause [19]. sorption [25]. This prompted us to hypothesize that 1α,25(OH)2D3 has the potential to inhibit bone resorp- tion independently of its effect on PTH. We further Native versus active vitamin D studied the pharmacological action of active vitamin D in ovariectomized (OVX) rats, which comprise an The importance of simple vitamin D as a nutrient for established model of high bone turnover osteoporosis the prevention of osteoporosis is widely recognized, due to estrogen deficiency. Using deoxypyridinoline especially in the elderly population, in which simple (DPD) as a biochemical marker of bone resorption vitamin D deficiency is often prevalent [20, 21]. Vita- combined with histomorphometric techniques, we min D, which is both synthesized in the skin and taken demonstrated that the administration of alfacalcidol, a up from food, is activated into the hormonal form, prodrug metabolized to the natural vitamin D hormone 1α,25(OH)2D3, through sequential hydroxylation in 1α,25(OH)2D3, suppresses the bone resorption elevat- the liver and then in the kidney. Although it is gener- ed by OVX [10]. In the bones of treated rats, the ally believed that vitamin D deficiency is a risk factor number of osteoclasts was substantially reduced, sug- for osteoporosis and fragile skeleton fractures, precise- gesting that VDR inhibits the differentiation/recruit- ly how native vitamin D and vitamin D hormone differ ment of osteoclasts [10]. The anti-osteoclastogenic in skeletal action, and whether or not vitamin D hor- action of active vitamin D was confirmed by another mone has any therapeutic advantage over plain vitamin analog, ED-71 (Fig. 1) [11]. D, especially in patients without vitamin D deficiency ED-71 has recently been demonstrated in a clinical or supplemented with native vitamin D, have been and trial in Japan to reduce a bone resorption marker and continue to be controversial [22, 23]. In a recent meta increase BMD in osteoporotic patients provided native analysis, it is concluded that native and/or active vita- vitamin D3 supplementation [26]. min D are effective in reducing vertebral fracture, while the evidence for an effect on non-vertebral frac- ture is currently lacking [23]. VITAMIN D AND OSTEOCLASTS 3 Fig. 1. Chemical structure of 1α,25(OH)2D3 and its analogs. ED-71: 2β-(3-hydroxypropoxy)-1α,25(OH)2D3 DD281: (1R,3S,5Z)-5-[(2E)-[(3aS,7aS)-1-[(1R)-1-[(2- ethyl-2-hydroxybutyl)thio] ethyl]-3,3a,5,6,7,7a-hexahydro- 7a-methyl-4H-inden-4-ylidene]ethylidene]-4-methylene- 1,3-cyclohexanediol Pharmacological properties of ED-71 and DD281 have Fig. 2. VDR-based drugs inhibit the differentiation into mature been described in ref. [11] and [12], respectively. A clin- osteoclasts by suppressing c-Fos protein in bone ical trial of ED-71 is now in phase III in Japan [26]. marrow macrophages. BMM: bone marrow macrophage Bone marrow macrophages as a target of VDR stage was confirmed by the result that treatment of the The findings that vitamin D hormone, acting through cultures with 1α,25(OH)2D3 was sufficient only during VDR, has the potential to suppress osteoclast develop- the latter differentiation stage to inhibit osteoclast for- ment prompted us to explore both the “seeds” and mation, whereas such treatment in the former period of “soil” of osteoclastogenesis in the bone microenviron- M-CSF-dependent growth had no effect. Importantly, ment of vitamin D-treated animals. With respect to this action was shown to be mediated through VDR, “soil”, the expression of RANKL in bone did not in- since in VDR-deficient osteoclast precursor cells crease following 1α,25(OH)2D3 administration in vivo, isolated from KO mice, the suppressive effect of even at the high doses that induce hypercalcemia [27]. 1α,25(OH)2D3 on osteoclastogenesis was not observed In contrast, when the “seeds” for osteoclasts were at all. These data indicate that 1α,25(OH)2D3 acts evaluated by a limiting dilution technique, we found directly on osteoclast precursors and inhibits their dif- that the number of osteoclast progenitors present in the ferentiation into mature osteoclasts through the VDR bone marrow had been increased by the estrogen defi- (Fig.
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