Trends in Endocrinology & Metabolism
Parathyroid hormone: a double-edged sword for bone metabolism
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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