Mechanical Stimulation of Bone in Vivo Reduces Osteocyte Expression of Sost/Sclerostin

Abstract

Sclerostin, the protein product of the Sost gene, is a potent inhibitor of bone formation. Among bone cells, sclerostin is found nearly exclusively in the osteocytes, the cell type that historically has been implicated in sensing and initiating mechanical signaling. The recent discovery of the antagonistic effects of sclerostin on Lrp5 receptor signaling, a crucial mediator of skeletal mechanotransduction, provides a potential mechanism for the osteocytes to control mechanotransduction, by adjusting their sclerostin (Wnt inhibitory) signal output to modulate Wnt signaling in the effector cell population. We investigated the mechanoregulation of Sost and sclerostin under enhanced (ulnar loading) and reduced (hindlimb unloading) loading conditions. Sost transcripts and sclerostin protein levels were dramatically reduced by ulnar loading. Portions of the ulnar cortex receiving a greater strain stimulus were associated with a greater reduction in Sost staining intensity and sclerostin-positive osteocytes (revealed via in situ hybridization and immunohistochemistry, respectively) than were lower strain portions of the tissue. Hindlimb unloading yielded a significant increase in Sost expression in the tibia. Modulation of sclerostin levels appears to be a finely tuned mechanism by which osteocytes coordinate regional and local osteogenesis in response to increased mechanical stimulation, perhaps via releasing the local inhibition of Wnt/Lrp5 signaling.Low bone mass and poor bone structure are two major risk factors for osteoporotic fracture (1, 2). A simple yet effective means to enhance bone mass and architecture is through mechanical stimulation of the resident bone cell population (3, 4). Mechanical loading (e.g. exercise) improves bone mass and strength by stimulating the addition of new bone onto surfaces experiencing high strains, whereas surfaces that experience small strains largely remain quiescent. This phenomenon occurs both across the skeleton (limb bones adapt to locomotive loading, whereas nonbearing bones (e.g. skull) do not) and within a loaded bone (tension/compression surfaces undergo bone formation, whereas surfaces straddling the neutral bending axis do not). The cellular mechanisms involved in directing new bone formation to the high strain regions of a loaded bone are unclear, but elucidation of these mechanisms would provide an attractive target for pharmaceutical intervention aimed at mimicking the adaptive response to loading (5).Despite these gaps in our understanding, significant progress has been made in delineating some of the basic mechanisms of mechanotransduction in bone, in large part because of the creation of genetically engineered mice. A key finding in this arena is the requirement for Wnt signaling through Lrp5 (the low density lipoprotein receptor-related protein 5) in mechanically induced bone formation. We reported recently that mice engineered with a loss-of-function mutation in Lrp5 recapitulate the low bone mass phenotype observed in humans with inactivating mutations of LRP...

A sclerostin-based theory for strain-induced bone formation

“…In this context it is necessary that mechanical stimuli reduce sclerostin secretion by osteocytes, as was recently confirmed by Robling et al (2008) and Papanicolaou et al (2009). Compared to our previous stimulatory model, where strains stimulate osteocytes to stimulate osteoblasts, this model is the exact reverse: strains inhibit the inhibition of bone formation.…”

“…To reconcile this information with strain-induced bone formation, one needs to assume that sclerostin production by osteocytes decreases with mechanical loading. A recent study by Robling et al (2008) confirms this assumption: in vivo loading of rat and mice forelimbs significantly reduced sclerostin secretion by osteocytes in the loaded forelimb. A new theory for strain-induced bone formation is thus a case of 'minus times minus equals plus': mechanical loading inhibits the inhibition of bone formation.…”

“…Robling et al (2008) showed that the expression of dickkopf homolog 1 (Dkk1), another inhibitor of bone formation, also decreased with mechanical loading. Although our inhibitory model was inspired by sclerostin, the same concept could thus apply to other inhibitors of bone formation.…”

Sclerostin: A gem from the genome leads to bone-building antibodies

“…Moreover, the regions of bone that endured the greatest strain energy were those which exhibited the greatest reductions in SOST/sclerostin and that had the greatest increases in bone formation. (58) Others have subsequently replicated many of these initial results. (59) In addition to decreased SOST/sclerostin, there also was a loadinginduced significant reduction in another Wnt signaling antagonist, DKK1.…”

“…(58) Specifically, there was a significant reduction (up to about 70%) in sclerostin protein levels and in SOST transcripts in bones subjected to loading. Moreover, the regions of bone that endured the greatest strain energy were those which exhibited the greatest reductions in SOST/sclerostin and that had the greatest increases in bone formation.…”