The hormone exerts important effects on bone and kidney and indirectly influences the gastrointestinal tract. In response to a fall in the extracellular fluid ionized calcium concentration, PTH is released from the para thyroid cell and acts directly on the kidney to enhance renal calcium reabsorption and promote the conversion of 25- hydroxyvitamin D to 1,25(OH)2D. In the cortical thick ascending limb of the loop of Henle (CTAL) PTH binds to the PTH receptor (PTHR1), and enhances Ca reabsorption., by increasing the activity of the Na/ K/ 2Cl cotransporter that drives NaCl reabsorption and stimulates paracellular Ca and Mg reabsorption. In the distal convoluted tubule (DCT) PTH, after binding to its receptor, increases luminal Ca transfer into the renal tubule cell by augmenting the epithelial apical Ca channel of the transient receptor potential vanilloid family, TRPV5, followed by translocation of Ca across the cell from apical to basolateral surface via proteins such as calbindin- D28K, and then active extrusion of Ca from the cell into the blood via a Na+/ Ca exchanger, NCX1, whose activity is stimulated by a cyclic AMP- mediated mechanism. PTH can also stimulate the 1α(OH)ase, in the proximal tubule leading to increased synthesis of 1,25(OH)2D from 25OHD. The 1,25(OH)2D increases gastro intestinal absorption of calcium and, with PTH, induces skeletal resorption, causing the restoration of extracellular fluid calcium and the neutralization of the signal initiating PTH release. In bone, PTHR1 is localized on cells of the osteoblast phenotype which are of mesenchymal origin but not on osteoclasts which are of hematogenous origin. PTH then enhances release of the cytokine, receptor activator of NFκB ligand (RANKL) which binds to its receptor, RANK, on osteoclast precursors and osteoclasts, increasing the formation of mature osteoclasts from precursors and increasing the resorptive activity of existing osteoclasts especially in cortical bone. PTH may also reduce the osteoblastic protein, osteoprotegerin, which normally binds to RANKL, forms an inactive complex, and prevents it from binding to RANK, thus reducing osteoclastic activity. It has also been suggested that PTH can acutely release mineral at the bone surface in an osteoclast- independent manner by modifying its solubility. The opposite series of homeostatic events occur in response to a rise in extracellular fluid calcium levels and a fall in PTH.
Although this scheme outlines the overall events that occur after a fall in calcium, aspects of the response may vary. Certain actions of PTH, such as renal calcium retention may predominate at relatively low circulating concentrations of PTH. Furthermore, PTH appears to be essential as a bone anabolic factor in the fetus and neonate, particularly in trabecular bone but may be predominantly resorptive, especially in the cortical compartment of bone, in older animals when the source of external calcium changes. PTH and PTHrP regulate osseous cellular differentiation, proliferation, and development, and via their actions on osteoblastic cells can function as anabolic skeletal agents when administered intermittently rather than continuously in vivo. Thus, intermittent doses of PTH(1- 34)— and PTHrP(1- 34) and related analogues— promote bone formation directly by stimulating osteoblastic activity and indirectly, both by stimulating IGF-I production and suppressing sclerostin, thereby increasing Wnt signalling. Daily injections of human PTH(1- 34), teriparatide, or a human PTHrP analogue, abaloparatide, increase hip and spine BMD, and prevent vertebral and non- vertebral fractures in osteoporosis, and each has been approved clinically for use as a bone anabolic agent to treat osteoporosis.
Besides regulating calcium homeostasis, PTH elicits various other responses. Among these responses are perturbations of other ions, the most marked of which are those involving phosphate. As a consequence of PTH- enhanced 1,25(OH)2D production, the gastrointestinal absorption of phosphate is facilitated to some extent, and with PTH- induced skeletal lysis, phosphate and calcium are released. These effects increase the extracellular fluid phosphate levels. However the predominant effect of PTH on phosphate homeostasis is to inhibit renal phosphate reabsorption in the proximal renal tubule by enhancing rapid internalization and lysosomal degradation of the type II sodium phosphate cotransporters, NPT2a (SLC34A1) and Npt2c (SLC34A3) thus decreasing luminal transport of phosphate and causing phosphaturia. Consequently, a net decrease in extracellular fluid phosphate con centration occurs which is adjunctive to the role of PTH in raising calcium levels.
