OPG, RANKL, and RANK gene polymorphisms and the bone mineral density response to alendronate therapy in postmenopausal Chinese women with osteoporosis or osteopenia :

We have generated RANK (receptor activator of NF-kappaB) 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 alpha 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.

Tumor necrosis factor-alpha (TNF) and the ligand for receptor activator of NF-kappaB (RANKL) are abundant in sites of inflammatory bone erosion. Because these cytokines are potent osteoclastogenic factors and because their signaling pathways are considerably overlapping, we postulated that under pro-inflammatory conditions RANKL and TNF might synergistically orchestrate enhanced osteoclastogenesis via cooperative mechanisms. We found TNF, via TNF type 1 receptor (TNFr1), prompts robust osteoclastogenesis by osteoclast precursors pretreated with RANKL, and deletion of TNFr1 abrogates this response. Enhanced osteoclastogenesis is associated with high expression of otherwise TNF and RANKL-induced mediators, including c-Src, TRAF2, TRAF6, and MEKK-1, levels of which were notably reduced in TNFr1 knockouts. Recruitment of TRAFs and MEKK1 leads to activation of downstream pathways, primarily I kappa B/NF-kappa B, ERKs, and cJun/AP-1. Consistent with impaired osteoclastogenesis and reduced expression of TRAFs and MEKK1, we found that phosphorylation and activation of I kappa B, NF-kappa B, ERKs, and cJun/AP-1 are severely reduced in RANKL-treated TNFr1-null osteoclast precursors compared with wild type counterparts. Finally, we found that TNF and RANKL synergistically up-regulate RANK expression in wild type precursors, whereas basal and stimulated levels of RANK are significantly lower in TNFr1 knockout cells. Our data suggest that exuberant TNF-induced osteoclastogensis is the result of coupling between RANK and TNFr1 and is dependent upon signals transmitted by the latter receptor.

The relative importance of genetic factors in determining bone mass in different parts of the skeleton is poorly understood. Lumbar spine and proximal femur bone mineral density and forearm bone mineral content were measured by photon absorptiometry in 38 monozygotic and 27 dizygotic twin pairs. Bone mineral density was significantly more highly correlated in monozygotic than in dizygotic twins for the spine and proximal femur and in the forearm of premenopausal twin pairs, which is consistent with significant genetic contributions to bone mass at all these sites. The lesser genetic contribution to proximal femur and distal forearm bone mass compared with the spine suggests that environmental factors are of greater importance in the aetiology of osteopenia of the hip and wrist. This is the first demonstration of a genetic contribution to bone mass of the spine and proximal femur in adults and confirms similar findings of the forearm. Furthermore, bivariate analysis suggested that a single gene or set of genes determines bone mass at all sites.