DIFFERENTIAL-EFFECTS OF PARATHYROID-HORMONE FRAGMENTS ON COLLAGEN GENE-EXPRESSION IN CHONDROCYTES

The effect of parathyroid hormone (PTH) in vivo after secretion by the parathyroid gland is mediated by bioactive fragments of the molecule. To elucidate their possible role in the regulation of cartilage matri x metabolism, the influence of the amino-terminal (NH2-terminal), the central, and the carboxyl-terminal (COOH-terminal) portion of the PTH on collagen gene expression was studied in a serum free cell culture s ystem of fetal bovine and human chondrocytes. Expression of alpha 1 (I ), alpha 1 (II), alpha 1 (III), and alpha 1 (X) mRNA was investigated by in situ hybridization and quantified by Northern blot analysis. NH2 -terminal and mid-regional fragments containing a core sequence betwee n amino acid residues 28-34 of PTH induced a significant rise in alpha 1 (II) mRNA in proliferating chondrocytes. In addition, the COOH-term inal portion (aa 52-84) of the PTH molecule was shown to exert a stimu latory effect on alpha 1(II) and alpha 1 (X) mRNA expression in chondr ocytes from the hypertrophic zone of bovine epiphyseal cartilage. PTH peptides harboring either the functional domain in the central or COOH -terminal region of PTH can induce cAMP independent Ca2+ signaling in different subsets of chondrocytes as assessed by microfluorometry of F ura-2/AM loaded cells. These results support the hypothesis that diffe rent hormonal effects of PTH on cartilage matrix metabolism are exerte d by distinct effector domains and depend on the differentiation stage of the target cell.