Vitamin D receptor in chondrocytes promotes osteoclastogenesis and regulates FGF23 production in osteoblasts.
Genomic actions induced by 1alpha25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] are crucial for normal bone metabolism, mainly because they regulate active intestinal calcium transport. To evaluate whether the vitamin D receptor (VDR) has a specific role in growth-plate development and endochondral bone formation, we investigated mice with conditional inactivation of VDR in chondrocytes. Growth-plate chondrocyte development was not affected by the lack of VDR. Yet vascular invasion was impaired, and osteoclast number was reduced in juvenile mice, resulting in increased trabecular bone mass. In vitro experiments confirmed that VDR signaling in chondrocytes directly regulated osteoclastogenesis by inducing receptor activator of NF-kappaB ligand (RANKL) expression. Remarkably, mineral homeostasis was also affected in chondrocyte-specific VDR-null mice, as serum phosphate and 1,25(OH)(2)D levels were increased in young mice, in whom growth-plate activity is important. Both in vivo and in vitro analysis indicated that VDR inactivation in chondrocytes reduced the expression of FGF23 by osteoblasts and consequently led to increased renal expression of 1alpha-hydroxylase and of sodium phosphate cotransporter type IIa. Taken together, our findings provide evidence that VDR signaling in chondrocytes is required for timely osteoclast formation during bone development and for the endocrine action of bone in phosphate homeostasis.
Masuyama
Ritsuko
R
Laboratory of Experimental Medicine and Endocrinology, Katholieke Universiteit Leuven, Leuven, Belgium.
Stockmans
Ingrid
I
Torrekens
Sophie
S
Van Looveren
Riet
R
Maes
Christa
C
Carmeliet
Peter
P
Bouillon
Roger
R
Carmeliet
Geert
G
D000818:Animals; D000831:Animals, Newborn; D001846:Bone Development / Q000235:genetics / Q000502:physiology; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D019902:Chondrocytes / Q000166:cytology / Q000378:metabolism*; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000235:genetics*; D015870:Gene Expression / Q000235:genetics; D006132:Growth Plate / Q000166:cytology / Q000378:metabolism; D006706:Homeostasis / Q000502:physiology; D007150:Immunohistochemistry; D051379:Mice; D009154:Mutation / Q000235:genetics; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism*; D010010:Osteoclasts / Q000166:cytology / Q000378:metabolism; D010012:Osteogenesis / Q000235:genetics / Q000502:physiology; D010710:Phosphates / Q000378:metabolism; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000032:analysis; D053245:RANK Ligand / Q000235:genetics / Q000502:physiology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018167:Receptors, Calcitriol / Q000235:genetics / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013997:Time Factors; D014807:Vitamin D / Q000031:analogs & derivatives / Q000235:genetics / Q000502:physiology
C000717428:Fgf23 protein, mouse; D010710:Phosphates; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D053245:RANK Ligand; D012333:RNA, Messenger; D018167:Receptors, Calcitriol; C118756:dihydroxy-vitamin D3; D014807:Vitamin D; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23