Regulation of Bone Remodeling by Parathyroid Hormone

Abstract

Parathyroid hormone (PTH) exerts profound effects on skeletal homeostasis through multiple cellular and molecular mechanisms. Continuous hyperparathyroidism causes net loss of bone mass, despite accelerating bone formation by osteoblasts. Intermittent treatment with PTH analogs represents the only Food and Drug Administration (FDA)-approved bone anabolic osteoporosis treatment strategy. Functional PTH receptors are present on cells of the osteoblast lineage, ranging from early skeletal stem cells to matrix-embedded osteocytes. In addition, bone remodeling by osteoclasts liberates latent growth factors present within bone matrix. Here, we will provide an overview of the multiple cellular and molecular mechanisms through which PTH influences bone homeostasis. Notably, net skeletal effects of continuous versus intermittent can differ significantly. Where possible, we will highlight mechanisms through which continuous hyperparathyroidism leads to bone loss, and through which intermittent hyperparathyroidism boosts bone mass. Given the therapeutic usage of intermittent PTH (iPTH) treatment for osteoporosis, particular attention will be paid toward mechanisms underlying the bone anabolic effects of once daily PTH administration.

Figure 1.

Model showing the intracellular signaling mechanisms used in osteocytes to regulate SOST and RANKL expression downstream from parathyroid hormone (PTH) receptor signaling. Protein kinase–mediated SIK2 phosphorylation inhibits SIK2 cellular activity, which leads to reduced phosphorylation of SIK2 substrates, including HDAC4 and CRTC2. When dephosphorylated, these proteins translocate from the cytoplasm to the nucleus where they regulate gene expression. Because PTH signaling inhibits SIK2 cellular activity, small-molecule SIK inhibitors (such as YKL-05-099) mimic many of the cellular effects of PTH. As detailed in the text, SIK2-independent protein kinase A (PKA)-dependent nodes of PTH receptor signaling are also present in osteocytes. cAMP, Cyclic adenosine monophosphate.