Bone collagen synthesis in vitro: structure/activity relations among parathyroid hormone fragments and analogs.
The structural requirements for the inhibition of net bone collagen synthesis by parathyroid hormone (PTH) in vitro have been examined by study of the effects of selected fragments and analogs of bovine PTH (bPTH) upon the incorporation of [3H]proline into collagenase-digestible and -nondigestible proteins by neonatal mouse calvarial bone in organ culture. At concentrations of 10(-10)-10(-7) M, the amino-terminal fragment bPTH-(1-34) was found to be as potent as intact bPTH in the specific suppression of net bone collagen synthesis after 24 h in culture. The synthetic fragments bPTH-(1-30), bPTH-(1-28), and bPTH-(3-34) were approximately 3%, 1%, and 0.2% as active, respectively, as bPTH-(1-34), in good agreement with previous estimates of the relative potencies of these hormonal fragments on bone resorption in vitro and in vivo and on adenylate cyclase activation in and receptor binding to isolated renal membranes. The amino-terminal analog [Ser1]bPTH-(1-34) displayed no reduction in biological activity compared with bPTH-(1-34), as previously found for bone resorption in vivo. The overall results with this assay system indicate a minimum sequence for biological activity that extends from residues 3-28 of intact bPTH, which is consistent with similar estimates in other test systems and emphasizes the importance of the aminoterminus of the hormone in the expression of its biological effects on bone formation as well as resorption. Moreover, these findings support the potential usefulness of the mouse calvarial culture system in predicting the skeletal activity in vivo of new synthetic analogs of PTH.
D000818:Animals; D000831:Animals, Newborn / Q000378:metabolism; D001842:Bone and Bones / Q000378:metabolism*; D003094:Collagen / Q000096:biosynthesis*; D066298:In Vitro Techniques; D051379:Mice; D003012:Microbial Collagenase / Q000378:metabolism; D010281:Parathyroid Hormone / Q000031:analogs & derivatives / Q000494:pharmacology*; D010446:Peptide Fragments / Q000494:pharmacology; D013329:Structure-Activity Relationship
D010281:Parathyroid Hormone; D010446:Peptide Fragments; D003094:Collagen; D003012:Microbial Collagenase