Circulating PTH molecular forms: What we know and what we don't

Circulating parathyroid hormone (PTH) molecular forms have been identified by three generations of PTH assays after gel chromatography or high-performance liquid chromatography fractionation of serum. Carboxyl-terminal (C) fragments missing the amino-terminal (N) structure of PTH(1-84) were identified first. They represent 80% of circulating PTH in normal individuals and up to 95% in renal failure patients. They are regulated by calcium (Ca) slightly differently than PTH(1-84), occurring in a relatively smaller proportion relative to the latter in hypocalcemia but in a much larger proportion in hypercalcemia. Synthetic C-PTH fragments do not bind to the PTH/PTHrP type I receptor and are not implicated in the classical biological effect of PTH(1-84). They bind to a different C-PTH receptor and exert biological actions on bone that are opposite to those of PTH(1-84). The integrity of the distal C-structure appears to be important for these biological effects, and it is uncertain if all C-PTH fragments are intact up to position 84. A second category of C-PTH fragment has a partially preserved N-structure. They are called non-(1-84) PTH or N-truncated fragments. They react in Intact (I)-PTH assays but not in PTH assays with a 1-4 epitope. They are acutely regulated by Ca2+ concentration. They also exert similar hypocalcemic and antiresorptive effects but have 10-fold greater affinity for the C-PTH receptor compared to other C-PTH fragments. Even if they represent only 10% of all C-PTH fragments, they could be as relevant biologically. An N form of PTH other than PTH(1-84) has been identified in the circulation. It reacts very well in PTH assays with a 1-4 epitope but poorly in I-PTH assay with a 12-18 epitope. It is oversecreted in severe primary and secondary hyperparathyroidism and in parathyroid cancers. Its biological activity is still unknown. Overall, these studies suggest that PTH(1-84) and C-PTH fragments are regulated differently to exert opposite biological effects on bone via two different receptors. This may serve to control bone turnover and Ca concentration more efficiently.