Parathyroid hormone: a double-edged sword for bone metabolism

https://doi.org/10.1016/j.tem.2004.01.006Get rights and content

Abstract

Parathyroid hormone (PTH) is the major hormone regulating calcium metabolism. It is also the only FDA-approved drug for osteoporosis treatment that stimulates bone formation when injected daily. However, continuous infusion of PTH causes severe bone loss in line with its known catabolic effects. Many studies to understand the dual effects of PTH have been carried out, and in recent years a growing number of molecular and cellular mechanisms underlying these effects have emerged. Here, we outline the present knowledge and conclude that the kinetics of administration and subsequent signaling probably account for the divergent actions of the hormone.

Section snippets

PTH regulation of bone formation

The bone-forming cells, osteoblasts, originate from bone marrow stromal stem cells. These precursors undergo proliferation and differentiate into preosteoblasts and then into mature osteoblasts. All these cells are the primary PTH-responsive cells in bone. The first observations of the anabolic properties of PTH were made in the 1930s; however, it was not until 50 years later that Tam et al. identified the differential effects of pulsatile and continuous administration of PTH on net bone

PTH regulation of bone resorption

PTH exerts its effects on bone resorption indirectly through the osteoblast. Direct interaction between receptor activator of nuclear factor κB ligand (RANKL) on osteoblasts and its receptor RANK on the hemopoietically derived pre-osteoclast is essential for osteoclast recruitment, differentiation and activation. The interaction between RANK and RANKL can be inhibited by the decoy receptor OPG and thus, ultimately, the RANKL:OPG ratio will determine the degree of osteoclast differentiation and

The coupling of bone formation and bone resorption in the anabolic actions of PTH

In normal bone remodeling, both bone formation and bone resorption are tightly coupled. Osteoclast activation and formation, which result in bone resorption, precede the recruitment, proliferation and differentiation of osteoblasts, which result in bone formation. Because antiresorptive agents are currently the drugs of choice to treat osteoporotic patients, and because some of those agents can accumulate in the matrix and remain biologically active for extended periods of time, pretreatment

PTH signaling in the osteoblast

Binding of PTH to its membrane receptor PTH1R, a G-protein-coupled receptor (GPCR), activates two well defined signal transduction pathways in osteoblasts. One is the protein kinase A (PKA) pathway, in which Gαs stimulates production of cAMP and activation of PKA. PKA subsequently phosphorylates transcription factors, such as Cbfa1 and cAMP-response element-binding protein (CREB), regulating the transcription of more genes. The other is the protein kinase C (PKC) pathway, where Gαq activates

Proteins that are essential for mediating the anabolic functions of PTH

Recent studies have identified several proteins that play important roles in the anabolic actions of PTH. Binding to the PTH1R transforms the C-terminal tail of the receptor to a phosphorylation target for GPCR kinase-2 (GRK2) and results in rapid internalization of the PTH–receptor complex 37, 38. Expression of a dominant-negative form of GRK2 enhances adenylyl cyclase signaling in response to PTH in osteoblasts. Transgenic mice bearing this GRK2 inhibitor exhibit high bone remodeling, with

Anabolic versus catabolic model

In the osteoblast, PTH initiates a complicated signaling network with two outputs: bone formation and bone resorption. How the input PTH signal is applied (pulsatile or continuous), but apparently not the amount of PTH, determines the ratio of these two outputs and subsequently determines the net result (bone gain or bone loss, anabolic or catabolic effects). The PTH signaling network must interact with other signaling networks, and the components of this network vary according to the status of

Perspective

A recent report has identified ∼14% of a total of 5531 genes on a gene chip to be differentially expressed in rat tibiae after continuous versus intermittent PTH treatments [48], which could lead to a breakthrough in understanding the dual functions of PTH. However, because of the complexity of bone structure, it is difficult to do further mechanistic studies in vivo. In fact, platelet-derived growth factor-A, the subject of that report, was found to be produced in mast cells rather than in

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