hPTH(3-34)(29-34) selectively activated PKC and mimicked osteoanabolic effects of hPTH(1-34)

Teriparatide (hPTH(1-34)) exhibits both osteoanabolic and osteocatabolic effects. We generated a novel PTH analog by duplicating the PTH(29-34) domain to hPTH(3-34) (named MY-1), which was identified to activate PKC but not PLC and cAMP/PKA signaling. It increased osteo-differentiation but did not affect osteoclastogenesis and RANKL expression in primary osteoblasts or bone marrow cells. MY-1 and hPTH(1-34) increased the synthesis and decreased the degradation οf β-catenin protein in osteoblasts, while PKC Inhibitor blunted such effects. In vivo results indicated that intermittent MY-1 and hPTH(1-34) prevented bone loss in ovariectomized mice, and that MY-1 infusion increased bone volume in normal mice. Histological analysis observed more osteoclasts surrounding the cancellous bone surface in hPTH(1-34), but not MY-1 treated mice. We conclude that MY-1 mimicked the osteoanabolic but not the osteocatabolic effects of hPTH(1-34), which is related to PKC and β-catenin signaling. Such anabolic-only analog provides a new strategy to study PTH's versatile functions and design new medicines to treat osteoporosis and bone defects.