Parathyroid hormone (PTH) regulation of metabolic homeostasis: An old dog teaches us new tricks

Abstract

Background: Late in the nineteenth century, it was theorized that a circulating product produced by the parathyroid glands could negatively impact skeletal homeostasis. A century later, intermittent administration of that protein, namely parathyroid hormone (PTH), was approved by the FDA and EMA as the first anabolic agent to treat osteoporosis. Yet, several unanswered but important questions remain about the skeletal actions of PTH.

Scope of review: Current research efforts have focused on improving the efficacy of PTH treatment by designing structural analogs and identifying other targets (e.g., the PTH or the calcium sensing receptor). A unique but only recently described aspect of PTH action is its regulation of cellular bioenergetics and metabolism, namely in bone and adipose tissue but also in other tissues. The current review aims to provide a brief background on PTH's previously described actions on bone and highlights how PTH regulates osteoblast bioenergetics, contributing to greater bone formation. It will also shed light on how PTH could alter metabolic homeostasis through its actions in other cells and tissues, thereby impacting the skeleton in a cell non-autonomous manner.

Major conclusions: PTH administration enhances bone formation by targeting the osteoblast through transcriptional changes in several pathways; the most prominent is via adenyl cyclase and PKA. PTH and its related protein, PTHrP, also induce glycolysis and fatty acid oxidation in bone cells and drive lipolysis and thermogenic programming in adipocytes; the latter may indirectly but positively influence skeletal metabolism. While much work remains, alterations in cellular metabolism may also provide a novel mechanism related to PTH's temporal actions. Thus, the bioenergetic impact of PTH can be considered another of the myriad anabolic effects of PTH on the skeleton. Just as importantly from a translational perspective, the non-skeletal metabolic effects may lead to a better understanding of whole-body homeostasis along with new and improved therapies to treat musculoskeletal conditions.

Keywords: Adipocytes; Anabolic; Bioenergetics; Bone; Fat; Mitochondria; Osteoblasts.

Figure 1

Parathyroid hormone (PTH)'s Primary Signaling Pathways in Osteoblastic Cells. PTH is a polypeptide containing 84 amino acids (AA). The peptide fragment essential for signaling (1–34 AA) are demonstrated in blue circles. PTH binds to PTH receptor (PTH1R), a G-protein coupled receptor, and activates adenylyl cyclase and phospholipase C (PLC). Adenyl cyclase activation then converts adenosine triphosphate (ATP) to cyclic adenosine monophosphate (cAMP), which now acts as a secondary messenger to activate protein kinase A (PKA). PKA can directly interact with proteins on the lipid droplet membrane to trigger the breakdown of triglycerides to free fatty acids, or lipolysis. In addition to the cAMP/PKA pathway, PTH-PTH1R signaling triggers PLC hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP₂) to inositol triphosphate (IP₃). IP₃ is now capable of signaling within the endoplasmic reticulum to release calcium stores, thereby altering the intracellular calcium flux that is critical for regulating mitochondrial function. Upon IP₃ formation, diacylglycerol (DAG) is also formed and can act as secondary messengers, regulating protein kinase C (PKC) and protein kinase D (PKD), both of which are important for glucose and lipid metabolism. Although both pathways have been demonstrated in osteoblastic cells, it is likely that these pathways are also stimulated within other cell types which express PTH1R.

Figure 2

Parathyroid hormone (PTH)'s Actions on Metabolic Process in Various Tissues. PTH has been shown to modulate cellular metabolic processes within the bone, as in osteoblasts and bone marrow adipocytes (BMAdipo), and within classic adipocyte populations, including subcutaneous and epididymal fat. Additionally, as a primary target of PTH, the kidney is expected to experience some of the effects as well. To a lesser extent, data does exist describing alterations occurring in skeletal and cardiac muscles following PTH treatment.