ex-527 and Osteoporosis

Preservation of bone mass is crucial for healthy ageing and largely depends on adequate responses of matrix-embedded osteocytes. These cells control bone formation and resorption concurrently by secreting the WNT/β-catenin antagonist sclerostin (SOST). Osteocytes reside within a low oxygen microenvironment, but whether and how oxygen sensing regulates their function remains elusive. Here, we show that conditional deletion of the oxygen sensor prolyl hydroxylase (PHD) 2 in osteocytes results in a high bone mass phenotype, which is caused by increased bone formation and decreased resorption. Mechanistically, enhanced HIF-1α signalling increases Sirtuin 1-dependent deacetylation of the Sost promoter, resulting in decreased sclerostin expression and enhanced WNT/β-catenin signalling. Additionally, genetic ablation of PHD2 in osteocytes blunts osteoporotic bone loss induced by oestrogen deficiency or mechanical unloading. Thus, oxygen sensing by PHD2 in osteocytes negatively regulates bone mass through epigenetic regulation of sclerostin and targeting PHD2 elicits an osteo-anabolic response in osteoporotic models.

Topics: Acetylation; Adaptor Proteins, Signal Transducing; Animals; Bone Density; Carbazoles; Cell Line; Coculture Techniques; Disease Models, Animal; Epigenesis, Genetic; Female; Glycoproteins; Heterocyclic Compounds, 4 or More Rings; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Hypoxia-Inducible Factor-Proline Dioxygenases; Intercellular Signaling Peptides and Proteins; Male; Mice, Inbred C57BL; Mice, Transgenic; Osteocytes; Osteogenesis; Osteoporosis; Oxygen; Primary Cell Culture; Promoter Regions, Genetic; Sirtuin 1; Wnt Signaling Pathway