Transgenic mice with OIP-1/hSca overexpression targeted to the osteoclast lineage develop an osteopetrosis bone phenotype.

Regulatory mechanisms operative in bone-resorbing osteoclasts are complex. We previously defined the Ly-6 gene family member OIP-1/hSca as an inhibitor of osteoclastogenesis in vitro; however, a role in skeletal development is unknown. In this study, we developed transgenic mice with OIP-1/hSca expression targeted to the osteoclast lineage that develop an osteopetrotic bone phenotype. Humeri from OIP-1 mice showed a significant increase in bone mineral density and bone mineral content. microCT analysis showed increased trabecular thickness and bone volume. OIP-1 mice have dense sclerotic cortical bone with absence of spongiosa and inadequate formation of marrow spaces compared to wild-type mice. Moreover, complete inhibition of osteoclasts and marrow cavities in calvaria suggests defective bone resorption in these mice. OIP-1 mouse bone marrow cultures demonstrated a significant decrease (41%) in osteoclast progenitors and inhibition (39%) of osteoclast differentiation/bone resorption. Western blot analysis further demonstrated suppression of TRAF-2, c-Fos, p-c-Jun, and NFATc1 levels in RANKL-stimulated osteoclast precursors derived from OIP-1 mice. Therefore, OIP-1 is an important physiological inhibitor of osteoclastogenesis and may have therapeutic value against bone loss in vivo.