Osteocyte regulation of the function of the executive cells of bone remodeling: the Sost/sclerostin paradigm

It has been long postulated that osteocytes initiate the adaptive response of bone to mechanical stimuli. Osteoblasts and osteoclasts are present on bone only transiently, in low number, and in variable locations. Osteocytes, on the other hand, are the most abundant resident cells (compared to lining and periosteal cells) and are present in the entire bone volume. In addition, osteocytes form a syncytium among themselves and with cells on the bone surface via cytoplasmic processes that radiate from their bodies and travel along canaliculi excavated in the mineralized matrix. This network is ideally suited to sense and respond not only to mechanical but also to systemic stimuli by generating signals that affect osteoblasts, osteoclasts, and their progenitors in the bone marrow. However, in spite of significant progress in our knowledge about osteocytes in recent years, the mechanisms by which these cells control the function of osteoblasts and osteoclasts are just starting to emerge. Osteocytes perceive changes in the level of both physical stimuli as well as circulating factors as evidenced by studies on the regulation of their life span. Thus, increased prevalence of osteocyte apoptosis accompanies the bone fragility syndrome that characterizes glucocorticoid excess and estrogen withdrawal. Furthermore, inhibition of osteocyte apoptosis by bisphosphonates might explain at least part of the effects of these agents on fracture prevention, which is not accounted for by changes in BMD. Osteocyte apoptosis is also regulated by mechanical forces as evidenced by increased prevalence of apoptotic osteocytes in bones exposed to high levels of mechanical stimulation or in unloaded bones. Notably, in both cases osteocyte apoptosis precedes temporally, and is spatially associated with, increased osteoclast-mediated resorption and subsequent loss of bone mineral and strength. This evidence strongly suggests that, irrespective of the mechanism by which osteocytes are induced to die, osteocyte apoptosis might initiate a cascade of events to replace bone in the same location, namely targeted remodeling. This phenomenon represents an example of communication between osteocytes and osteoclasts; although the identity of the osteocyte-derived molecules responsible for initiating the osteoclastogenic response remains unknown. The most compelling paradigm by which osteocytes influence the function and number of the executive cells of remodeling is symbolized by Sost/sclerostin. Osteocytes, but no other cells in bone, express sclerostin – the product of the Sost gene. As expected for an osteocyte-derived secreted protein, high levels of sclerostin are detected in the lacunarcanaliculi system. Sclerostin potently antagonizes several members of the bone morphogenetic protein (BMP) family of proteins, and also binds to LRP5/LRP6 preventing canonical Wnt signaling. Both BMPs and Wnts are critical for osteoblastogenesis as they provide the initial and essential stimulus for commitment of multipotential mesenchymal progenitors to the osteoblast lineage. Loss of Sost in humans causes the high bone mass disorders Van Buchem disease and sclerosteosis. In addition, administration of an anti-sclerostin antibody increases bone formation and restores the bone lost upon ovariectomy in rodents. Conversely, transgenic mice overexpressing Sost exhibit low bone mass. Taken together, these lines of evidence have led to the conclusion that sclerostin derived from osteocytes – the ultimate progeny of the osteoblast differentiation pathway – exerts a negative feedback control at the earliest step of mesenchymal stem cell differentiation toward the osteoblast lineage. J Musculoskelet Neuronal Interact 2006; 6(4):360-363