Parathyroid Hormone

PARATHYROID HORMONE

PTH is secreted from the parathyroid glands in response to a low plasma concentration of ionized (free) calcium. PTH immediately causes the transfer of labile calcium stores from bone into the bloodstream. PTH increases rates of dietary calcium absorption by the intestine indi-rectly via the vitamin D₃ system activation of enterocyte activity. Within the kidney, PTH directly stimulates cal-cium reabsorption and a phosphate diuresis.

Chemistry

PTH is a single-chain polypeptide composed of 84 amino acid residues that is devoid of disulfide bonds and has a molecular weight of 9500. Biological activity of the human hormone resides primarily in the amino terminal end of the protein (i.e., amino acids 1–34). This portion of PTH has full biological activity both in vivo and in vitro. Synthetic fragments of the 1-34 portion of the PTH molecule have been synthesized. A paraneo-plastic hormone, PTH related peptide (PTHrP) has been identified, isolated, and synthesized. PTHrP is structurally homologous to the amino terminal portion of PTH and interacts with the PTH receptor in bone and kidney. This hormone is responsible for hypercal-cemia in certain forms of malignancy. It has been used as a therapeutic agent in osteoporosis in some clinical trials.

Synthesis and Secretion

Plasma calcium concentration is the principal factor reg-ulating PTH synthesis and release. The increase in PTH synthesis and secretion induced by hypocalcemia is be-lieved to be mediated through activation of parathyroid gland adenylyl cyclase and a subsequent increase in in-tracellular cyclic adenosine monophosphate (cAMP).

Formation of PTH begins with the synthesis of sev-eral precursor molecules. PreproPTH is the initial pep-tide that is synthesized within the parathyroid gland, and it serves as a precursor to both proPTH and PTH. PreproPTH is formed within the rough endoplasmic reticulum, transported into the cisternal space, and then cleaved to form proPTH. The proPTH polypeptide is transported into the cisternal space, where another pro-teolytic cleavage occurs, forming PTH.

PTH in Target Tissues

PTH has two levels of action in bone. First, in response to acute decreases in serum calcium, PTH stimulates surface osteocytes to increase the outward flux of cal-cium ion from bone to rapidly restore serum calcium. Thus, during brief periods of hypocalcemia, PTH re-lease results in mobilization of calcium from labile areas of bone that lie adjacent to osteoclasts. This effect is not associated with any significant increase in plasma phos-phate or bone resorption. Second, PTH induces trans-formation of osteoprogenitor cells into osteoclasts, which increase bone formation. Thus, PTH has anabolic action on bone formation at physiological levels, and it is this action that allows it to be used pharmacologically to treat osteoporosis. However, in conditions that result in chronic calcium deficiency or prolonged hypocal-cemia (e.g., renal osteodystrophy, vitamin D deficiency, or malabsorption syndromes), PTH mobilizes deep os-teocytes in perilacunar bone and can result in significant bone resorption and eventual osteopenia as it attempts to maintain normal concentrations of ionic or free plasma calcium.

In the kidney, PTH stimulates the conversion of 25-(OH)D₃ into 1,25-(OH)₂D₃. Intrarenal 1,25-(OH)₂ D₃ causes an amplification of the PTH-induced calcium re-absorption and phosphate diuresis. 1,25-(OH)₂D₃ en-hances PTH action in bone also. Once again, PTH does not directly affect intestinal calcium absorption, but it does so indirectly through induction of 1,25-(OH)₂ D₃ synthesis and enhanced enterocyte absorption.