Clinical Note

The importance of cyclic AMP for the action of PTH is underscored by the occurrence of a rare disease called pseudohypoparathyroidism in which patients are unresponsive to PTH. About one-half of the reported cases of unresponsive-ness to PTH are attributable to a mutation in the

GTP-binding protein (Gs) that couples the hormone receptor with adenylyl cyclase. These patients also have decreased responses to some other cyclic AMP-dependent signals, but because there are four distinct genes for Gas, not all cyclic AMP-dependent responses are affected by this mutation.

the PTH receptor and therefore produce the same biological effects as PTH. PTH and PTHrP are immu-nologically distinct and do not cross-react in immu-noassays. PTHrP is synthesized in a wide range of tissues and acts locally as a paracrine factor to regulate a variety of processes that are unrelated to regulation of calcium concentrations in extracellular fluid. Little or no PTHrP is found in blood plasma of normal individuals.

Mechanisms of PTH Actions

Binding of PTH to G-protein-coupled receptors on the surfaces of target cells increases the formation of cyclic AMP and of inositol trisphosphate (IP3) and diacylglycerol (DAG) (see Chapter 2). The PTH receptor is coupled to adenylyl cyclase through a stimulatory G protein (Gs) and to phospholipase C through Gq. Consequently, protein kinases A and C are also activated and intracellular calcium is increased. Rapid responses almost certainly result from protein phosphorylation, while delayed responses result from altered expression of genes regulated by CREB. It is likely that the two second messenger pathways activated by PTH are redundant and reinforce each other (see Clinical Note above).

Physiologic Actions of PTH

Parathyroid hormone is the principal regulator of the extracellular calcium pool. It increases the calcium concentration and decreases the phosphate concentration in blood by various direct and indirect actions on bone, kidney, and intestine. In its absence, the concentration of calcium in blood, and hence interstitial fluid, decreases dramatically over a period of several hours while the concentration of phosphate increases.

Actions on Bone

Increases in PTH concentration in blood result in mobilization of calcium phosphate from the bone matrix due to increased osteoclastic activity. The initial phase is seen within 1-2 hr and results from activation of preformed osteoclasts already present on the bone surface. A later and more pronounced phase of the response to PTH becomes evident after about 12 hr and is characterized by widespread resorption of both mineral and organic components of bone matrix, particularly in trabecular bone. Evidence of osteoclastic activity is reflected not only by calcium phosphate mobilization, but also by increased urinary excretion of hydroxy-proline and other products of collagen breakdown.

Although activity of all bone cell types is affected by PTH, only cells of osteoblastic lineage express receptors for PTH. Osteoclasts are thus not direct targets for PTH. Activation, differentiation, and recruitment of osteoclasts in response to PTH depends on increased expression of at least two cytokines by cells of osteo-blastic lineage within the bone marrow (Fig. 7). PTH induces these cells to synthesize and secrete m-CSF and to express RANKL on their surfaces (see earlier section on osteoclasts). These cytokines increase the differentiation and activity of osteoclasts and protect them from apoptosis. In addition, PTH may decrease osteoblastic expression of OPG, the competitive inhibitor of RANK

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