Application of anti-Sclerostin therapy in non-osteoporosis disease models

Abstract

Sclerostin, a known inhibitor of the low density lipoprotein related protein 5 and 6 (LRP5 and LRP6) cell surface signaling receptors, is integral in the maintenance of normal bone mass and strength. Patients with loss of function mutations in SOST or missense mutations in LRP5 that prevent Sclerostin from binding and inhibiting the receptor, have significantly increased bone mass. This observation lead to the development of Sclerostin neutralizing therapies to increase bone mass and strength. Anti-Sclerostin therapy has been shown to be effective at increasing bone density and strength in animal models and patients with osteoporosis. Loss of function of Sost or treatment with a Sclerostin neutralizing antibody improves bone properties in animal models of Osteoporosis Pseudoglioma syndrome (OPPG), likely due to action through the LRP6 receptor, which suggests patients may benefit from these therapies. Sclerostin antibody is effective at improving bone properties in mouse models of Osteogenesis Imperfecta, a genetic disorder of low bone mass and fragility due to type I collagen mutations, in as little as two weeks after initiation of therapy. However, these improvements are due to increases in bone quantity as the quality (brittleness) of bone remains unaffected. Similarly, Sclerostin antibody treatment improves bone density in animal models of other diseases. Sclerostin neutralizing therapies are likely to benefit many patients with genetic disorders of bone, as well as other forms of metabolic bone disease.

Reduction of SOST gene promotes bone formation through the Wnt/β‐catenin signalling pathway and compensates particle‐induced osteolysis

“…Previous studies have shown that sclerostin antibodies can be used to treat osteoporosis and skeletal abnormalities, increasing bone formation, bone mass and bone strength . Additionally, sclerostin antibodies have been reported to promote fracture callus formation and increase the stability of internal fixation .…”

“…Sclerostin inhibits osteoblast differentiation and induces osteoblast apoptosis, meanwhile, stimulates osteocytes to secrete RANKL and activates osteoclasts. Some studies have shown that SOST gene and sclerostin are associated with sclerosis, fracture healing and osteoporosis . Bone volume of osteoporosis is increased, and implant fixation is improved after SOST/sclerostin blockage .…”

A novel nonosteocytic regulatory mechanism of bone modeling

“…Demonstration of SOST expression by multiple cell types and identification of SOST as an evolutionarily conserved key player in bone modeling in fishes expands the relevance of sclerostin to modeling regulation for both paracrine and autocrine signaling. Currently, a wave of new sclerostin-targeting therapies are being explored in an effort to control sclerostin’s antianabolic properties in the treatment of osteoporosis and other skeletal disorders [42–44]. Our findings suggest great potential for the massively speciose clade of fishes, with both osteocytic and anosteocytic members, as a powerful and relevant platform for research in bone physiology, as well as fracture healing and bone therapeutics.…”

SOST gene suppression stimulates osteocyte Wnt/β-catenin signaling to prevent bone resorption and attenuates particle-induced osteolysis

“…Sclerostin stimulates osteocyte secretion of RANKL and activates osteoclasts while inhibiting osteoblast differentiation and inducing osteoblast apoptosis. Several studies have shown SOST/sclerostin is involved in sclerosis, fracture repair, and osteoporosis (Jacobsen 2017). After SOST/sclerostin blockade, bone volume increases, and endophyte xation improves in osteoporosis (Virdi et al 2012).…”