Chapter 12Chapter 12

Parathyroid Hormone and Parathyroid Hormone-Related Protein

Copyright © 2013 Elsevier Inc. All rights reserved.

Copyright © 2013 Elsevier Inc. All rights reserved.

FIGURE 12.1 Relationship between plasma levels of ionized calcium and the release of parathyroid hormone (PTH)(1-84) in normal humans. Variations in plasma ionized calcium were achieved by the infusion of calcium or ethylenediaminetetraacetic acid (EDTA). Note the sigmoidal relationship, ensuring significant changes in PTH secretion with small variations in ionized calcium. Source: reproduced from Brown (1991) [4], with permission.

2

Copyright © 2013 Elsevier Inc. All rights reserved.

FIGURE 12.2 Metabolism and clearance of parathyroid hormone (PTH). PTH is subject to proteolytic cleavage in the parathyroid gland, as well as in liver and kidney, resulting in the presence of inactive mid-region and C-terminal PTH fragments in the circulation. N-terminal PTH fragments are apparently rapidly degraded and do not accumulate in the circulation. Intact PTH has a short half-life in the circulation (2–4 minutes) due to hepatic and renal metabolism. Mid-region and C-terminal PTH fragments are cleared by glomerular filtration. They have a much longer half-life that is dependent on the level of renal function. A large C-terminal fragment, PTH(7-34), that could serve as a PTH/ parathyroid hormone-related protein (PTHrP) receptor antagonist has been identified in the circulation. Source: reproduced from Endres et al. (1989) [34], with permission.

3

Copyright © 2013 Elsevier Inc. All rights reserved.

FIGURE 12.3 Regulation of osteoclast differentiation and activation by parathyroid hormone (PTH). Binding of PTH to receptors on osteoblast-lineage cells (likely osteocytes) results in increased expression of receptor activator of nuclear factor kappaB ligand (RANKL) on the cell surface. Activation of PTH receptors also reduces the secretion of the RANKL inhibitor osteoprotegerin (OPG) which is produced by cells in the bone microenvironment. These effects of PTH promote the action of RANKL on its receptor (RANK) on the surface of osteoclast precursors and mature osteoclasts. RANK signaling, together with the action of macrophage colony-stimulating factor (mCSF), stimulate the differentiation of osteoclast precursors and promote the activation of mature osteoclasts.

4

Copyright © 2013 Elsevier Inc. All rights reserved.

FIGURE 12.4 Possible mechanisms contributing to the anabolic skeletal effect of intermittent parathyroid hormone (PTH) administration. PTH may act on bone marrow stromal cell precursors to promote their differentiation to functional osteoblasts. PTH could also act directly on osteoblasts to increase their number or their functional activity. Finally, PTH could increase the lifespan of mature osteoblasts by inhibiting their death via apoptosis. There is evidence that intermittent treatment with PTH utilizes multiple anabolic mechanisms.

5

Copyright © 2013 Elsevier Inc. All rights reserved.

FIGURE 12.5 Signal transduction by the parathyroid hormone (PTH)/parathyroid hormone-related protein (PTHrP) receptor. PTH and PTHrP bind to determinants in the extracellular domain and in the body of the receptor. This leads to conformational changes in the transmembrane helices and consequent structural changes in the cytoplasmic domain. The latter permit productive interaction between the receptor and the G proteins Gs and Gq, activating the adenylyl cyclase (AC) and phospholipase C (PLC) signaling pathways, respectively. These pathways are thought to cooperate in determining the cellular response to the receptor activation. Most available evidence supports a primary role of the cyclic adenosine monophosphate (cAMP)/protein kinase-A (PKA) pathway in mediating biological effects of PTH/PTHrP receptor activation, with the PLC pathway playing a modulatory role.

6