Osteocyte control of bone remodeling: is sclerostin a key molecular coordinator of the balanced bone resorption–formation cycles?

Abstract

Osteocytes, entrapped within a newly mineralized bone matrix, possess a unique cellular identity due to a specialized morphology and a molecular signature. These features endow them to serve as a bone response mechanism for mechanical stress in their microenvironment. Sclerostin, a primarily osteocyte product, is widely considered as a mechanotranduction key molecule whose expression is suppressed by mechanical loading, or it is induced by unloading. This review presents a model suggesting that sclerostin is major mediator for integrating mechanical, local, and hormonal signals, sensed by the osteocytes, in controlling the remodeling apparatus. This central role is achieved through interplay between two opposing mechanisms: (1) unloading-induced high sclerostin levels, which antagonize Wnt-canonical-β-catenin signaling in osteocytes and osteoblasts, permitting simultaneously Wnt-noncanonical and/or other pathways in osteocytes and osteoclasts, directed at bone resorption; (2) mechanical loading results in low sclerostin levels, activation of Wnt-canonical signaling, and bone formation. Therefore, adaptive bone remodeling occurring at a distinct bone compartment is orchestrated by altered sclerostin levels, which regulate the expression of the other osteocyte-specific proteins, such as RANKL, OPG, and proteins encoded by "mineralization-related genes" (DMP1, PHEX, and probably FGF23). For example, under specific terms, sclerostin regulates differential RANKL and OPG production, and creates a dynamic RANKL/OPG ratio, leading either to bone formation or resorption. It also controls the expression of PHEX, DMP1, and most likely FGF23, leading to either bone matrix mineralization or its inhibition. Such opposing up- or down-regulation of remodeling phases allows osteocytes to function as an "external unit", ensuring transition from bone resorption to bone formation.Mini Abstract: The osteocyte network plays a central role in directing bone response either to mechanical loading, or to unloading, leading correspondingly to bone formation or resorption. This review shows a key role of the osteocyte-produced sclerostin as a major mediator of the molecular mechanisms involved in the process of adaptive bone remodeling.

Ibandronate Increases Sclerostin Levels and Bone Strength in Male Patients with Idiopathic Osteoporosis

“…Bone remodeling is mediated by altered sclerostin levels through different expressions of RANKL, OPG, and likely FGF23, which are also secreted by osteocytes. Antiresorptive treatment may be responsible for dynamic RANKL/OPG ratios, leading either to osteocyte-mediated early bone formation or prolonged resorption at a later point [31].…”

Circulating sclerostin and Dickkopf-1 levels in patients with nonalcoholic fatty liver disease

“…A pathogenetic hypothesis could be "insulin-based": sclerostin is exclusively produced from the osteocytes [22], which express insulin-like growth factor (IGF)-1 receptors in their cell membrane [23]. Furthermore, osteocyte-derived IGF-1 has been proposed to suppress sclerostin production in association with mechanical loading [24].…”

Bone turnover markers in serum and urine as diagnostic, prognostic and monitoring biomarkers of bone metastasis

“…The relationship to the really observed bone mass and other circulating bone turnover markers has often been found contrary to their assumed regulative effect on osteoblasts [43][44][45][46]. Thus, the influence of biological factors (age, menopausal and hormonal status, renal function) on the concentration of both analytes in serum/plasma [47,48], the still not fully understood molecular processes in the bone [49,50], but also simply unresolved analytical problems [51] may currently be reasons for these substantial interpretation difficulties of the two analytes in serum/plasma. For example, the three commercially available sclerostin ELISAs (Mesa Scale discovery, Rockville, Maryland, USA; TECOmedical, Sissach, Switzerland; Biomedica, Wien, Austria) resulted, despite a reasonable correlation of data, in up to 10-to 30-fold different mean concentrations [44].…”