Selective anabolic effects of muteins of mid-region PTH fragments on skeletal tissues of prepubertal rats

Abstract

We have demonstrated the net anabolic potential of a mid-region fragment of human parathyroid hormone (hPTH), and a protease resistant mutein derived from it, to stimulate growth of skeletal-derived tissues. The fragment hPTH (28–48), lacking the N-terminal amino acids necessary for stimulation of adenylate cyclase, and therefore unable to stimulate bone resorption by osteoclasts, was compared with the protease-resistant double-mutein hPTH (28–48) F34M L37T, full-length hPTH (1–84), the protease resistant form hPTH (1–84) L37T, 17β estradiol (E2), and the combination of mid-region fragments of PTH and E2. The hormones, at concentrations spanning a 100-fold range, were given by 14 injections (6/week, excluding Saturday), to 17-day-old female Wistar-derived rats. At the low concentration of 200 ng/day of PTH (1–84), or the molar equivalent of the fragment, and 50 ng E2, all the hormones increased significantly the specific activity of creatine kinase (CK; a marker of skeletal cell proliferation) in tibial diaphysis and epiphysis, the width of the cortical bone in the humeral diaphysis, and the number of cells in the proliferating zone of the humeral epiphyseal growth plate. At a 10-fold lower concentration of both PTH and E2, CK specific activity was synergistically stimulated in both diaphyseal bone and epiphyseal cartilage. However, PTH mid-region fragments at a dose of 1 μg/day did not increase trabecular bone volume.