An essential role for the association of CD47 to SHPS-1 in skeletal remodeling.
Animals, Antigens-CD47, Biological-Markers, Body-Composition, Bone-Remodeling, Cell-Differentiation, Female, Femur, Humans, Male, Mice, Osteoblasts, Osteoclasts, Osteogenesis, Phenotype, Protein-Binding, RANK-Ligand, Receptors-Immunologic, Tomography-X-Ray-Computed
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J Bone Miner Res 2011 Sep; 26(9):2068-81.
Integrin-associated protein (IAP/CD47) has been implicated in macrophage-macrophage fusion. To understand the actions of CD47 on skeletal remodeling, we compared Cd47(-/-) mice with Cd47(+/+) controls. Cd47(-/-) mice weighed less and had decreased areal bone mineral density compared with controls. Cd47(-/-) femurs were shorter in length with thinner cortices and exhibited lower trabecular bone volume owing to decreased trabecular number and thickness. Histomorphometry revealed reduced bone-formation and mineral apposition rates, accompanied by decreased osteoblast numbers. No differences in osteoclast number were observed despite a nonsignificant but 40% decrease in eroded surface/bone surface in Cd47(-/-) mice. In vitro, the number of functional osteoclasts formed by differentiating Cd47(-/-) bone marrow cells was significantly decreased compared with wild-type cultures and was associated with a decrease in bone-resorption capacity. Furthermore, by disrupting the CD47-SHPS-1 association, we found that osteoclastogenesis was markedly impaired. Assays for markers of osteoclast maturation suggested that the defect was at the point of fusion and not differentiation and was associated with a lack of SHPS-1 phosphorylation, SHP-1 phosphatase recruitment, and subsequent dephosphorylation of non-muscle cell myosin IIA. We also demonstrated a significant decrease in osteoblastogenesis in bone marrow stromal cells derived from Cd47(-/-) mice. Our finding of cell-autonomous defects in Cd47(-/-) osteoblast and osteoclast differentiation coupled with the pronounced skeletal phenotype of Cd47(-/-) mice support the conclusion that CD47 plays an important role in regulating skeletal acquisition and maintenance through its actions on both bone formation and bone resorption.
Maile, L A.; DeMambro, V E.; Wai, C; Lotinun, S; Aday, A W.; Capps, B E.; Beamer, W G.; Rosen, C J.; and Clemmons, D R., "An essential role for the association of CD47 to SHPS-1 in skeletal remodeling." (2011). Faculty Research 2011. 102.