Review Question - QID 4491

Sclerostin inhibits the Wnt pathway, making answer choice 4 the correct answer.

Sclerostin is an osteocyte-derived negative regulator of Wnt signaling in osteoblasts. Amongst other things, the Wnt pathway and the Wnt proteins are important regulators of bone mass. They are thought to work by stimulating the production of osteoblasts. By inhibiting the Wnt pathway, sclerostin leads to decreased bone mass.

Dijke et al. discuss the role of the SOST gene in the conditions sclerosteosis and Van Buchem disease. They describe the SOST as a gene that encodes sclerostin, which is a negative regulator of Wnt signaling in osteoblasts. The authors argue that the high bone mass seen in sclerosteosis and Van Buchem disease may be caused by increased Wnt signaling.

Day et al. review the Wnt and hedgehog signaling pathways. The Wnt and hedgehog pathways, they describe, control the differentiation of progenitor cells into osteoblasts or chondrocytes. They found that up-regulation of Wnt signaling leads to suppression of chondrocyte formation and enhanced ossification, which may be important in fracture healing.

Illustration A shows the pathway by which Wnt promotes osteoblast formation. In addition to increasing osteoblast formation, the pathway upregulates OPG, which blocks osteoclastogenesis. Illustration B shows how sclerostin inhibits the Wnt pathway, resulting in a net decrease in bone mass. Illustration C shows an example of Van Buchem disease, an autosomal recessive disorder characterized by hyperostosis of the skull, mandible, clavicles, ribs, and diaphyseal cortices of the long bone.

Incorrect Answers:
Answers 1, 2, 3, 5: These statements are all correct regarding sclerostin.