Structural requirements for parathyroid hormone action in mature bone. Effects on release of cyclic adenosine monophosphate and bone gamma-carboxyglutamic acid-containing protein from perfused rat hindquarters.
To determine the structural requirements for parathyroid hormone (PTH) activity in mature bone, we perfused the surgically isolated hindquarters of adult male rats with either native bovine PTH-(1-84) [bPTH-(1-84)] or the synthetic amino-terminal fragment, bovine PTH-(1-34) [bPTH-(1-34)]. Changes in the release of cyclic AMP (cAMP) and bone Gla protein (BGP) were monitored as evidence of bone-specific response to PTH; tissue specificity of the cAMP response was confirmed through in vitro examination on nonskeletal tissue response to PTH. Biologically active, monoiodinated 125I-bPTH-(1-84) was administered to determine if mature murine bone cleaves native hormone. We found that perfused rat bone continuously releases BGP, and that both bPTH-(1-84) and bPTH-(1-34) acutely suppress this release. In addition, both hormones stimulate cAMP release from perfused rat hindquarters. When examined on a molar basis, the magnitude of the cAMP response was dose-dependent and similar for both hormones, with doses yielding half-maximal cAMP responses. The response for bPTH-(1-34) was 0.5 nmol and for bPTH-(1-84) was 0.7 nmol. Moreover, biologically active 125I-bPTH-(1-84) was not metabolized in our hindquarter perfusion system. These findings indicate that PTH-(1-84) does not require extraskeletal or skeletal cleavage to an amino-terminal fragment in order to stimulate cAMP generation in, or suppress BGP release from, mature rat bone.
D000818:Animals; D001842:Bone and Bones / Q000187:drug effects / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism*; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D008297:Male; D009132:Muscles / Q000378:metabolism; D015675:Osteocalcin; D010281:Parathyroid Hormone / Q000494:pharmacology*; D010446:Peptide Fragments / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D019379:Teriparatide
D002135:Calcium-Binding Proteins; D010281:Parathyroid Hormone; D010446:Peptide Fragments; D015675:Osteocalcin; D019379:Teriparatide; D000242:Cyclic AMP