Increased formation and decreased resorption of bone in mice with elevated vitamin D receptor in mature cells of the osteoblastic lineage.
The microarchitecture of bone is regulated by complex interactions between the bone-forming and resorbing cells, and several compounds regulate both actions. For example, vitamin D, which is required for bone mineralization, also stimulates bone resorption. Transgenic mice overexpressing the vitamin D receptor solely in mature cells of the osteoblastic bone-forming lineage were generated to test the potential therapeutic value of shifting the balance of vitamin D activity in favor of bone formation. Cortical bone was 5% wider and 15% stronger in these mice due to a doubling of periosteal mineral apposition rate without altered body weight or calcium homeostatic hormone levels. A 20% increase in trabecular bone volume in transgenic vertebrae was also observed, unexpectedly associated with a 30% reduction in resorption surface rather than greater bone formation. These findings indicate anabolic vitamin D activity in bone and identify a previously unknown pathway from mature osteoblastic cells to inhibit osteoclastic bone resorption, counterbalancing the known stimulatory action through immature osteoblastic cells. A therapeutic approach that both stimulates cortical anabolic and inhibits trabecular resorptive pathways would be ideal for treatment of osteoporosis and other osteopenic disorders.
Gardiner
E M
EM
*Bone and Mineral Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia. e.gardiner@garvan.unsw.edu.au
Baldock
P A
PA
Thomas
G P
GP
Sims
N A
NA
Henderson
N K
NK
Hollis
B
B
White
C P
CP
Sunn
K L
KL
Morrison
N A
NA
Walsh
W R
WR
Eisman
J A
JA
D000818:Animals; D001696:Biomechanical Phenomena; D001862:Bone Resorption / Q000235:genetics*; D019070:Cell Lineage; D005260:Female; D051379:Mice; D008822:Mice, Transgenic; D010006:Osteoblasts / Q000378:metabolism*; D010012:Osteogenesis / Q000235:genetics*; D018167:Receptors, Calcitriol / Q000235:genetics*; D013977:Tibia / Q000033:anatomy & histology; D014018:Tissue Distribution; D014807:Vitamin D / Q000031:analogs & derivatives / Q000378:metabolism
D018167:Receptors, Calcitriol; D014807:Vitamin D; C097949:1,25-dihydroxyvitamin D