Osteocytes and Skeletal Pathophysiology

Abstract

For many years, osteocytes have been the forgotten bone cells and considered as inactive spectators buried in the bone matrix. We now know that osteocytes detect and respond to mechanical and hormonal stimuli to coordinate bone resorption and bone formation. Osteocytes are currently considered a major source of molecules that regulate the activity of osteoclasts and osteoblasts, such as RANKL and sclerostin; and genetic and pharmacological manipulations of either molecule markedly affect bone homeostasis. Besides playing a role in physiological bone homeostasis, accumulating evidence supports the notion that dysregulation of osteocyte function and alteration of osteocyte life-span underlies the pathophysiology of skeletal disorders characterized by loss bone mass and increased bone fragility, as well as the damaging effects of cancer in bone. In this review, we highlight some of these investigations and discuss novel observations that demonstrate that osteocytes, far from being passive cells entombed in the bone, are critical for bone function and maintenance.

Keywords: SOST; Wnt signaling; bone remodeling; osteoblast; osteoclast; osteocyte.

Figure 1. Activation of Wnt-βcatenin signaling in osteocytes has an anabolic effect in bone

(A) Activation of Wnt/βcatenin in osteoblasts/osteoblast precursors increases bone mass by increasing OPG production, which reduces bone resorption, without apparent effect on osteoblast production. (B) Activation of Wnt/βcatenin signaling in osteocytes increases both bone formation and bone resorption, with a positive balance that results in bone gain. (C) Activation of Wnt signaling in all osteoblastic cells induced by neutralizing antibodies to sclerostin increases bone formation and initially decreases the serum levels of the bone-resorption marker CTX in both mouse and clinical models, that eventually come back to control levels. These findings suggest that osteocytes, rather than less-differentiated cells in the osteoblastic lineage, might mediate anabolism induced by systemic activation of the Wnt/βcatenin pathway, with neutralizing antibodies of sclerostin.

Figure 2. Osteocytes and therapies of common skeletal disorders

All current therapies for osteoporosis act on osteocytes. Anti-sclerostin antibodies increase bone formation and might reduce resorption by increasing OPG expression. The anabolic effect of intermittent PTH might be explained in part by downregulation of the SOST gene and therefore decreasing sclerostin levels. Part of the anti-fracture efficacy of intermittent PTH administration and bisphosphonates, might be due to inhibition of osteocyte apoptosis, and thus preservation of the osteocytic lacunar-canalicular network. The anti-resorptive activity of RANKL neutralizing antibodies is likely due to the inhibition of osteocytic RANKL, which is considered the major source of RANKL in adult skeleton.