PTH receptor signalling, osteocytes and bone disease induced by diabetes mellitus

Basic, translational and clinical research over the past few decades has provided new understanding on the mechanisms by which activation of the receptor of parathyroid hormone (parathyroid hormone 1 receptor (PTH1R)) regulates bone physiology and pathophysiology. A fundamental change in the field emerged upon the recognition that osteocytes, which are permanent residents of bone and the most abundant cells in bone, are targets of the actions of natural and synthetic ligands of PTH1R (parathyroid hormone and abaloparatide, respectively), and that these cells drive essential actions related to bone remodelling. Among the numerous genes regulated by PTH1R in osteocytes, SOST (which encodes sclerostin, the WNT signalling antagonist and inhibitor of bone formation) has a critical role in bone homeostasis and changes in its expression are associated with several bone pathologies. The bone fragility syndrome induced by diabetes mellitus is accompanied by increased osteocyte apoptosis and changes in the expression of osteocytic genes, including SOST. This Review will discuss advances in our knowledge of the role of osteocytes in PTH1R signalling and the new opportunities to restore bone health in diabetes mellitus by targeting the osteocytic PTH1R–sclerostin axis. This article reviews the role of the parathyroid hormone 1 receptor (PTH1R) pathway in bone homeostasis and of osteocytes as mechanosensors and drivers of bone remodelling. It will also discuss how the PTH1R–sclerostin axis can be harnessed for the treatment of bone disease induced by diabetes mellitus.