Strengthening brittle bones

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Science Translational Medicine  28 Jun 2017:
Vol. 9, Issue 396, eaan6730
DOI: 10.1126/scitranslmed.aan6730


Decreased WNT1 signaling weakens bones but is partially reversed by blocking the WNT1 inhibitory regulator sclerostin.

Despite an inert appearance, bone is constantly remodeling. Osteocytes, cells embedded in mineralized bone matrix, monitor mechanical stress and communicate with cells on the bone surface. The surface cells include osteoblasts, the builders of bone, and osteoclasts, which resorb bone. Imbalances in this tightly controlled system can lead to brittle bones and increased fracture risk. An extreme example is osteogenesis imperfecta, a rare genetic disorder in which patients may suffer fractures during normal daily activities. One form of severe osteogenesis imperfecta is caused by homozygous loss of function mutations in WNT1. Heterozygous mutations in WNT1 cause a milder phenotype, early-onset osteoporosis. WNT1 is expressed in numerous tissues, and expression in osteocytes is low; therefore, it is not clear how WNT1 controls bone mass.

Joeng et al. investigated Wnt1 signaling in osteoclasts and identified therapeutic targets that ameliorate the decreased bone mass found in Wnt1-deficient mice. The investigators used mice harboring a naturally occurring Wnt1 mutation, known as the swaying mouse, and conditional Wnt1 knockdown and overexpression with a bone specific Cre-Lox system. Deletion of Wnt1 in late osteoblasts and osteocytes resulted in spontaneous fractures, decreased osteoblast activity, and decreased bone mass. In contrast, overexpression of Wnt1 both in vitro and in vivo resulted in increased osteoblast activity and increased bone mineralization. Additional experiments implicated mTOR complex 1 as a mediator of Wnt1-induced osteoblast differentiation and mineralization. These data confirmed that loss of Wnt1 signaling in osteocytes could cause the bone phenotype of osteogenesis imperfecta.

Sclerostin is an osteocyte-secreted protein that prevents binding of WNT ligands to their receptors on the osteoblast. Administering anti-sclerostin antibodies to Wnt1-deficient swaying mice partially restored bone mineralization and strength, decreasing the spontaneous fracture rate from 90% to 12.5%. Anti-sclerostin antibodies, or other drugs that decrease sclerostin, may prove to be an effective treatment for osteogenesis imperfecta caused by WNT1 mutations.

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