Vitamin D action and regulation of bone remodeling: suppression of osteoclastogenesis by the mature osteoblast.
Vitamin D acts through the immature osteoblast to stimulate osteoclastogenesis. Transgenic elevation of VDR in mature osteoblasts was found to inhibit osteoclastogenesis associated with an altered OPG response. This inhibition was confined to cancellous bone. This study indicates that vitamin D-mediated osteoclastogenesis is regulated locally by OPG production in the mature osteoblast.


BACKGROUND
Vitamin D stimulates osteoclastogenesis acting through its nuclear receptor (VDR) in immature osteoblast/stromal cells. This mobilization of calcium stores does not occur in a random manner, with bone preferentially removed from cancellous bone. The process whereby the systemic, humoral regulator is targeted to a particular region of the skeleton is unclear.


METHODS
Bone resorption was assessed in mice with vitamin D receptor transgenically elevated in mature osteoblasts (OSVDR). Vitamin D-mediated osteoclastogenesis was examined in vitro using OSVDR osteoblasts and osteoblastic RANKL: osteoprotegerin (OPG) examined in vivo and in vitro after vitamin D treatment.


RESULTS
Vitamin D-mediated osteoclastogenesis was reduced in OSVDR mice on chow and calcium-restricted diets, with effects confined to cancellous bone. OSVDR osteoblasts had a reduced capacity to support osteoclastogenesis in culture. The vitamin D-mediated reduction in OPG expression was reduced in OSVDR osteoblasts in vivo and in vitro, resulting in a reduced RANKL/OPG ratio in OSVDR compared with wildtype, after exposure to vitamin D.


CONCLUSIONS
Mature osteoblasts play an inhibitory role in bone resorption, with active vitamin D metabolites acting through the VDR to increase OPG. This inhibition is less active in cancellous bone, effectively targeting this region for resorption after the systemic release of activated vitamin D metabolites.
Baldock
Paul A
PA
Bone Research Program, Garvan Institute of Medical Research, St Vincent's Hospital, Sydney, New South Wales, Australia.
Thomas
Gethin P
GP
Hodge
Jason M
JM
Baker
Sara Uk
SU
Dressel
Uwe
U
O'Loughlin
Peter D
PD
Nicholson
Geoffrey C
GC
Briffa
Kathy H
KH
Eisman
John A
JA
Gardiner
Edith M
EM
D000818:Animals; D016723:Bone Remodeling / Q000187:drug effects*; D001862:Bone Resorption / Q000378:metabolism*; D002136:Calcium, Dietary / Q000008:administration & dosage / Q000494:pharmacology; D018920:Coculture Techniques; D005260:Female; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D010006:Osteoblasts / Q000378:metabolism*; D053244:Osteoprotegerin / Q000378:metabolism; D053245:RANK Ligand / Q000378:metabolism; D014807:Vitamin D / Q000494:pharmacology*
D002136:Calcium, Dietary; D053244:Osteoprotegerin; D053245:RANK Ligand; D014807:Vitamin D