Targeting sclerostin as potential treatment of osteoporosis

Abstract

In recent years, study of rare bone diseases has led to the identification of signalling pathways that regulate bone formation and provided targets for the development of novel therapeutic agents to stimulate bone formation in patients with osteoporosis. Studies of two bone sclerosing dysplasias, sclerosteosis and van Buchem disease led to the identification of sclerostin, a negative regulator of bone formation. Sclerostin binds to LRP5/6 and inhibits Wnt signalling, but its precise molecular mechanism of action is not yet known. Its expression is restricted in the skeleton to osteocytes and is modified by mechanical loading and parathyroid hormone treatment. Sclerostin deficiency reproduces the findings of the human diseases in mice, while sclerostin excess leads to bone loss and reduced bone strength. An antibody to sclerostin increased bone formation dramatically at all bone envelopes in ovariectomised rats and intact monkeys, without affecting bone resorption and improved bone strength. In initial human studies, a single injection of the antibody to postmenopausal women increased serum P1NP and transiently decreased serum CTX. Clinical phase II studies with this antibody are currently underway.

New understanding and treatments for osteoporosis

“…In humans, mutations of SOST lead to sclerosteosis and van Buchem disease, which are characterized by increased bone mass. Sclerostin deficiency reproduces the findings of the human diseases in mice while sclerostin excess leads to bone loss and reduced bone strength [79]. In a rat model of post-menopausal osteoporosis due to ovariectomy, treatment with a sclerostin antibodies increased bone mass at all skeletal sites and prevented the bone loss associated with estrogen deficiency [80].…”

Evaluation of serum myostatin and sclerostin levels in chronic spinal cord injured patients

“…However, even though the differences found in our study could lie in the younger age of patients enrolled (both SCI and healthy controls), the results showed no correlation between serum sclerostin and age. Nevertheless, our data could have important therapeutic implications, suggesting that antisclerostin antibodies [35][36][37] could be a valid option even in chronic phase after SCI, as serum sclerostin levels are still elevated during this phase.…”

Zinc finger protein 467 regulates Wnt signaling by modulating the expression of sclerostin in adipose derived stem cells

“…Sost is a negative regulator of bone formation associated with the development of sclerostosis and van Buchem disease whose expression is restricted to osteocytes and its mechanism of action is mediated by the binding to LRP5/6 and inhibition of Wnt signaling [7]. Sclerostin has therefore been studied as a potential target for the treatment of osteoporosis and other skeletal diseases based on the hypothesis that inhibition of sclerostin would enhance Wnt signaling and stimulate osteoblastic bone formation [33].…”

“…Therapies for skeletal disorders such as osteoporosis need to be capable of stimulating bone formation without increasing bone resorption [7] and modify the expression of specific target molecules without affecting other organs. Secreted molecules expressed predominantly in bone tissue meet these requirements.…”