RANK is the intrinsic hematopoietic cell surface receptor that controls osteoclastogenesis and regulation of bone mass and calcium metabolism

We have generated RANK (receptor activator of NF-kappa B) nullizygous mice to determine the molecular genetic interactions between osteoprotegerin, os teoprotegerin ligand, and RANK during bone resorption and remodeling proces ses. RANK(-/-) mice lack osteoclasts and have a profound defect in bone res orption and remodeling and in the development of the cartilaginous growth p lates of endochondral bone. The osteopetrosis observed in these mice can be reversed by transplantation of bone marrow from rag1(-/-) (recombinase act ivating gene 1) mice, indicating that RANK(-/-) mice have an intrinsic defe ct in osteoclast function. Calciotropic hormones and proresorptive cytokine s that are known to induce bone resorption in mice and human were administe red to RANK(-/-) mice without inducing hypercalcemia, although tumor necros is factor alpha treatment leads to the rare appearance of osteoclast-like c ells near the site of injection. Osteoclastogenesis can he initiated in RAN K(-/-) mice by transfer of the RANK cDNA back into hematopoietic precursors , suggesting a means to critically evaluate RANK structural features requir ed for bone resorption. Together these data indicate that RANK is the intri nsic cell surface determinant that mediates osteoprotegerin ligand effects on bone resorption and remodeling as well as the physiological and patholog ical effects of calciotropic hormones and proresorptive cytokines.