TRUNCATION OF THE AMINO-TERMINUS OF PTH ALTERS ITS ANABOLIC ACTIVITY ON BONE IN-VIVO

In vitro studies of parathyroid hormone (PTH) structure and function h ave suggested that the anabolic effect of PTH on bone requires the pre sence of amino acid residues 28-34 (domains for protein kinase C activ ation and mitogenic activity), but not amino acid residues 1-7 (adenyl ate cyclase activation domain), We have tested this hypothesis with in vivo studies of human PTH (hPTH) analogs, Serum biomarkers and select ed histomorphometric parameters of bone formation and resorption were assessed in adult, female, Sprague-Dawley rats following 19 daily inje ctions of vehicle, 10 mu g/kg body weight (bw) of hPTH(1-38), or a dos e range of 10, 40, and 100 mu g/100 g bw of hPTH(2-38) or hPTH(3-38), Treatment with hPTH(1-38) increased serum osteocalcin, the percentage of osteoblast surface, percentage of osteoid surface, percentage of bo ne volume, trabecular thickness, and bone formation rate, while it dec reased the percentage of osteoclast surface, The hPTH(2-38) fragment e xhibited 10%-25% of the in vivo anabolic activity of hPTH(1-38), while it had no effect on the percentage of osteoclast surface, The hPTH(3- 38) fragment exhibited no biological activity on bone, Tn contrast, se rum INS-PTH (intact-N-terminal specific PTH) levels were similarly and significantly increased above control in rats treated with hPTH(1-38) , hPTH(2-38), or hPTH(3-38) at the same dose, This preliminary finding suggests that the differential activity of these peptides on bone is not due to differences in the circulating level of immunoreactive PTH (intact and amino-terminal fragments of PTH from endogenous and exogen ous sources) several hours after PTH injection, However, we can draw n o conclusion regarding the relative clearance rates of these peptides, Last, because hPTH(3-38) was without any detectable biological activi ty on rat bone in vivo, its mitogenic activity was confirmed in two os teoblast-like cell lines, In summary, the anabolic effect of hPTH(1-38 ) on bone in vivo was (1) diminished by removal of amino acid residue 1, and (2) abolished by the removal of amino acid residues 1 and 2, Al though these findings suggest that the therapeutic benefits of exogeno us PTH administration may depend upon activation of not only protein k inase C, but also adenylate cyclase, they do not rule out a differenti al PTH response due to other causes, e,g,, metabolic inactivation. (C) 1996 by Elsevier Science Inc.