Sclerostin's role in bone's adaptive response to mechanical loading

Abstract

Mechanical loading is the primary functional determinant of bone mass and architecture, and osteocytes play a key role in translating mechanical signals into (re)modelling responses. Although the precise mechanisms remain unclear, Wnt signalling pathway components, and the anti-osteogenic canonical Wnt inhibitor Sost/sclerostin in particular, play an important role in regulating bone's adaptive response to loading. Increases in loading-engendered strains down-regulate osteocyte sclerostin expression, whereas reduced strains, as in disuse, are associated with increased sclerostin production and bone loss. However, while sclerostin up-regulation appears to be necessary for the loss of bone with disuse, the role of sclerostin in the osteogenic response to loading is more complex. While mice unable to down-regulate sclerostin do not gain bone with loading, Sost knockout mice have an enhanced osteogenic response to loading. The molecular mechanisms by which osteocytes sense and transduce loading-related stimuli into changes in sclerostin expression remain unclear but include several, potentially interlinked, signalling cascades involving periostin/integrin, prostaglandin, estrogen receptor, calcium/NO and Igf signalling. Deciphering the mechanisms by which changes in the mechanical environment regulate sclerostin production may lead to the development of therapeutic strategies that can reverse the skeletal structural deterioration characteristic of disuse and age-related osteoporosis and enhance bones' functional adaptation to loading. By enhancing the osteogenic potential of the context in which individual therapies such as sclerostin antibodies act it may become possible to both prevent and reverse the age-related skeletal structural deterioration characteristic of osteoporosis.

Conditional Activation of NF-κB Inducing Kinase (NIK) in the Osteolineage Enhances Both Basal and Loading-Induced Bone Formation

“…Wnt7b is upregulated by loading, as well as by the NT3 transgene, and has multiple κB‐RE, whereas Wnt1 is upregulated by loading in both genotypes and has a single κB‐RE. Expression of Sost, an inhibitor of Wnt signaling, is well‐documented to decrease in response to mechanical loading . In our study, Sost expression was trending downward, but did not reach statistical significance in control animals.…”

“…Sost was downregulated in both the NL and loaded NT3‐Cre + limbs compared with Ctrl NL tibias, whereas Dkk1 was significantly downregulated only with loading. Although others have described suppression of Sost with loading in WT mice, its expression trended downwards in Ctrl loaded samples but it did not reach statistical significance at the timepoint we evaluated. Taking all these factors together, the Wnt‐mediated response to loading appears to be enhanced in NT3‐Cre + limbs.…”

“…Bone formation in response to mechanical loading requires the coordinated action of osteocytes, which sense the load, and osteoblasts (OBs), which are directed to form bone by osteocytes. Net accrual of bone mass also requires that the bone‐degrading activity of osteoclasts be limited, which is largely accomplished at the level of the osteocyte via expression of osteoprotegerin (OPG) …”

“…Mechanical strain increases OB differentiation, via Wnt/β‐catenin signaling, a pathway that also enhances matrix production and mineralization . Osteocytes control Wnt activation in OBs via controlled secretion of sclerostin (Sost), a soluble Wnt inhibitor, and mechanical loading downregulates Sost in a strain‐dependent manner . However, Sost‐independent bone formation after loading has been documented .…”

Osteocyte Death and Bone Overgrowth in Mice Lacking Fibroblast Growth Factor Receptors 1 and 2 in Mature Osteoblasts and Osteocytes

“…Osteocytes express Sclerostin ( Sost ) and Dickkopf 1 ( Dkk1 ) and osteoblasts express Dkk2 , all potent inhibitors of Wnt signaling . In response to mechanical loading, expression of Sost and Dkk1 is suppressed, at least in part through osteocyte production of prostaglandin E2 . Interestingly, Dkk1 and Sost reciprocally regulate each other's expression; however, the anabolic activity of Dkk1 is only revealed in the absence of Sost .…”