For whom the bell tolls: distress signals from long-lived osteocytes and the pathogenesis of metabolic bone diseases

Abstract

Osteocytes are long-lived and far more numerous than the short-lived osteoblasts and osteoclasts. Immured within the lacunar-canalicular system and mineralized matrix, osteocytes are ideally located throughout the bone to detect the need for, and accordingly choreograph, the bone regeneration process by independently controlling rate limiting steps of bone resorption and formation. Consistent with this role, emerging evidence indicates that signals arising from apoptotic and old/or dysfunctional osteocytes are seminal culprits in the pathogenesis of involutional, post-menopausal, steroid-, and immobilization-induced osteoporosis. Osteocyte-originated signals may also contribute to the increased bone fragility associated with bone matrix disorders like osteogenesis imperfecta, and perhaps the rapid reversal of bone turnover above baseline following discontinuation of anti-resorptive treatments, like denosumab.

Figure 1

Model depicting mechanisms by which osteocytes may independently control bone resorption and bone formation. Osteoclasts (OCs) and osteoblasts (OBs) within a cancellous bone BMU are shown as being derived from precursors (pOC and pOB). Osteocytes alter the rate of bone remodeling by controlling osteoclast formation via production of RANKL. Osteocytes also control the balance between formation and resorption by regulating osteoblast formation via production of sclerostin. (Reproduced from Jinhu Xiong and Charles A. O’Brien J Bone Miner Res. 2012;27:499–505)

Figure 2

Illustration of the concept that the neighbors of apoptotic osteocytes (caused by microcracks in the particular instance depicted in the model) receive and propagate distress signals (red arrow) that trigger the process of the removal of dead osteocytes and the abnormal matrix that surrounds them. Red arrows connecting osteocytes imply that such signals travel through the lacunocanalicular system to reach the bone surface and thereby target the area in need of damage repair. RANKL is shown as a representative of probably several additional mediators of the repair process. (Modified from Seeman, E. and Delmas, D.P. NEJM 2006;354:2250–2261)