Osteocytes orchestrate bone modeling and remodeling in response to mechanical loading, parathyroid hormone (PTH) and microdamage. These actions are primarily mediated by sclerostin (Sost) and RANKL/osteoprotegerin (OPG), respectively. Moreover osteocytes may be capable of directly resorbing bone, i.e osteocytic osteolysis, and therefore to express cathepsin K (CatK) and other collagenases. During the last SNF grant cycle, we discovered that the matricellular protein periostin (Postn) expressed by osteocytes is an essential mediator of the cortical bone response to mechanical loading in both exercise regimen (Bonnet et al., J Biol Chem 2009) and fatigue, as well as to intermittent PTH administration (Bonnet, Conway, Ferrari, PNAS 2012). Indeed, axial compression and PTH increase periostin expression, which in turn inhibits sclerostin, stimulates Wnt-beta-catenin signaling, and regulates osteoblastic gene expression (ibidem). Moreover, we observed an increased expression of RANKL in osteocytes from Postn KO mice, whereas periostin expression was increased in CatK KO mice. We also reported that inhibition of RANKL markedly decreases the anabolic effects of intermittent PTH on bone remodeling surfaces, but not on modeling surfaces (Pierroz et al., J Biol Chem 2010), -where periostin is expressed-. Hence we hypothesize that periostin plays a central role in the osteocytic control of bone modeling and remodeling. We further hypothesize that RANKL is not required for a modeling response to mechanical loading.

Nephrology