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.

中文翻译：

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hPTH(3-34)(29-34) 选择性激活 PKC 并模拟 hPTH(1-34) 的骨合成代谢作用

Teriparatide (hPTH(1-34)) 具有骨合成代谢和骨分解代谢的作用。我们通过将 PTH(29-34) 域复制到 hPTH(3-34)（命名为 MY-1）来生成一种新型 PTH 类似物，它被确定为激活 PKC，但不激活 PLC 和 cAMP/PKA 信号。它增加了骨分化，但不影响原代成骨细胞或骨髓细胞中的破骨细胞生成和 RANKL 表达。MY-1 和 hPTH(1-34) 增加了成骨细胞中 β-catenin 蛋白的合成并减少了降解，而 PKC 抑制剂减弱了这种作用。体内结果表明，间歇性 MY-1 和 hPTH(1-34) 可防止去卵巢小鼠的骨质流失，而输注 MY-1 可增加正常小鼠的骨量。组织学分析观察到 hPTH(1-34) 的松质骨表面周围有更多的破骨细胞，但 MY-1 处理的小鼠没有。我们得出结论，MY-1 模拟了与 PKC 和 β-连环蛋白信号传导有关的 hPTH(1-34) 的骨合成代谢作用，但不是骨分解代谢作用。这种仅合成代谢的类似物为研究 PTH 的多功能功能和设计治疗骨质疏松症和骨缺损的新药提供了一种新策略。