NDLI: c-Fos protein as a target of anti-osteoclastogenic action of vitamin D, and synthesis of new analogs

Content Provider	PubMed Central
Author	Takasu, Hisashi Sugita, Atsuko Uchiyama, Yasushi Katagiri, Nobuyoshi Okazaki, Makoto Ogata, Etsuro Ikeda, Kyoji
Copyright Year	2006
Abstract	Although active vitamin D drugs have been used for the treatment of osteoporosis, how the vitamin D receptor (VDR) regulates bone cell function remains largely unknown. Using osteoprotegerin-deficient mice, which exhibit severe osteoporosis due to excessive receptor activator of NF-κB ligand/receptor activator of NF-κB (RANKL/RANK) stimulation, we show herein that oral treatment of these mice with 1α,25-dihydroxyvitamin D3 [1α,25(OH)2D3] inhibited bone resorption and prevented bone loss, suggesting that VDR counters RANKL/RANK signaling. In M-CSF–dependent osteoclast precursor cells isolated from mouse bone marrow, 1α,25(OH)2D3 potently and dose-dependently inhibited their differentiation into multinucleate osteoclasts induced by RANKL. Among signaling molecules downstream of RANK, 1α,25(OH)2D3 inhibited the induction of c-Fos protein after RANKL stimulation, and retroviral expression of c-Fos protein abrogated the suppressive effect of 1α,25(OH)2D3 on osteoclast development. By screening vitamin D analogs based on their c-Fos–suppressing activity, we identified a new analog, named DD281, that inhibited bone resorption and prevented bone loss in ovariectomized mice, more potently than 1α,25(OH)2D3, with similar levels of calcium absorption. Thus, c-Fos protein is an important target of the skeletal action of VDR-based drugs, and DD281 is a bone-selective analog that may be useful for the treatment of bone diseases with excessive osteoclastic activity.
Related Links	http://dx.doi.org/10.1172/JCI24742
Starting Page	528
File Format	PDF
ISSN	00219738
Journal	Journal of Clinical Investigation
Issue Number	2
Volume Number	116
Language	English
Publisher	American Society for Clinical Investigation
Publisher Date	2006-02-01
Access Restriction	Open
Rights Holder	American Society for Clinical Investigation
Subject Keyword	Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Medicine

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