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Bone remodelling and bone loss are controlled by a balance between the tumour necrosis factor family molecule osteoprotegerin ligand (OPGL) and its decoy receptor osteoprotegerin (OPG). In addition, OPGL regulates lymph node organogenesis, lymphocyte development and interactions between T cells and dendritic cells in the immune system. The OPGL receptor, RANK, is expressed on chondrocytes, osteoclast precursors and mature osteoclasts. OPGL expression in T cells is induced by antigen receptor engagement, which suggests that activated T cells may influence bone metabolism through OPGL and RANK. Here we report that activated T cells can directly trigger osteoclastogenesis through OPGL. Systemic activation of T cells in vivo leads to an OPGL-mediated increase in osteoclastogenesis and bone loss. In a T-cell-dependent model of rat adjuvant arthritis characterized by severe joint inflammation, bone and cartilage destruction and crippling, blocking of OPGL through osteoprotegerin treatment at the onset of disease prevents bone and cartilage destruction but not inflammation. These results show that both systemic and local T-cell activation can lead to OPGL production and subsequent bone loss, and they provide a novel paradigm for T cells as regulators of bone physiology.

We have generated RANK (receptor activator of NF-B) nullizygous mice to determine the molecular genetic interactions between osteoprotegerin, osteoprotegerin ligand, and RANK during bone resorption and remodeling processes. RANK ؊/؊ mice lack osteoclasts and have a profound defect in bone resorption and remodeling and in the development of the cartilaginous growth plates of endochondral bone. The osteopetrosis observed in these mice can be reversed by transplantation of bone marrow from rag1 ؊/؊ (recombinase activating gene 1) mice, indicating that RANK ؊/؊ mice have an intrinsic defect in osteoclast function. Calciotropic hormones and proresorptive cytokines that are known to induce bone resorption in mice and human were administered to RANK ؊/؊ mice without inducing hypercalcemia, although tumor necrosis factor ␣ treatment leads to the rare appearance of osteoclast-like cells near the site of injection. Osteoclastogenesis can be initiated in RANK ؊/؊ mice by transfer of the RANK cDNA back into hematopoietic precursors, suggesting a means to critically evaluate RANK structural features required for bone resorption. Together these data indicate that RANK is the intrinsic cell surface determinant that mediates osteoprotegerin ligand effects on bone resorption and remodeling as well as the physiological and pathological effects of calciotropic hormones and proresorptive cytokines.B one remodeling and homeostasis is an essential function that regulates skeletal integrity throughout adult life in higher vertebrates and mammals. The maintenance of skeletal mass is controlled by the activities of specialized cells within the bone that have seemingly antagonistic activities: bone synthesis and bone resorption. Osteoblastic cells of mesenchymal origin synthesize and deposit bone matrix and increase bone mass. Osteoclastic cells are large, multinucleated phagocytes of hematopoietic origin that resorb both mature and newly synthesized bone upon activation. Bone synthesis and resorption processes are highly coordinated and are regulated by osteotropic and calciotropic hormones during physiological and pathological conditions (1, 2). Increased bone resorption and turnover mediated by activated osteoclasts is known to occur in various crippling diseases, such as osteoporosis and arthritis, and can lead to pathological decreases in bone mass and skeletal integrity.Recently, two critical extracellular regulators of osteoclast differentiation and activation have been identified: osteoprotegerin (OPG) (3) and OPG ligand (OPGL) (4). OPGL is a tumor necrosis factor (TNF)-related cytokine that stimulates osteoclast differentiation from hematopoietic precursor cells and activation of mature osteoclasts in vitro and in vivo. Mice lacking OPGL also lack osteoclasts and have defects in bone remodeling processes that leads to severe osteopetrosis (5). OPG is a secreted TNF receptor (TNFR)-related protein that binds to and neutralizes OPGL bioactivity. Transgenic mice that overexpress OPG also have defects in osteoclastogenesis similar t...

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Osteoprotegerin-ligand (OPGL) is a key osteoclast differentiation/activation factor essential for bone remodeling. We report that mice lacking OPGL or its receptor RANK fail to form lobulo-alveolar mammary structures during pregnancy, resulting in death of newborns. Transplantation and OPGL-rescue experiments in opgl-/- and rank-/- pregnant females showed that OPGL acts directly on RANK-expressing mammary epithelial cells. The effects of OPGL are autonomous to epithelial cells. The mammary gland defect in female opgl-/- mice is characterized by enhanced apoptosis and failures in proliferation and PKB activation in lobulo-alveolar buds that can be reversed by recombinant OPGL treatment. These data provide a novel paradigm in mammary gland development and an evolutionary rationale for hormonal regulation and gender bias of osteoporosis in females.