Department of Pharmacology and Toxicology, University of Toronto, Toronto, Canada.
Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Canada.
Connect Tissue Res. 2023 Jul;64(4):350-361. doi: 10.1080/03008207.2023.2199086. Epub 2023 Apr 12.
β-Arrestin 2 (β-arr2) binds activated parathyroid hormone (PTH) receptors stimulating internalization. PTH stimulates both anabolic and catabolic effect on bone depending on the way it is administered. Intermittent PTH stimulation increases trabecular bone formation in mice, but this is decreased in mice lacking β-arr 2, suggesting a role for β-arr 2 in the anabolic effects of PTH. The role of β-arr 2 in the catabolic effects of continuous PTH (cPTH) treatment is not known.
To assess the effects of cPTH administration on bone in mice lacking β-arr 2 compared to wild-type (WT).
Groups of male and female WT or β-arr2 knockout (KO) mice were administered either PTH or phosphate-buffered saline by osmotic pumps for 2 weeks. Following treatment, serum calcium and phosphate levels were measured, bone structure and mineral density were measured by microcomputed tomography, and bone cells measured by static and dynamic histomorphometry.
β-arr2 KO had no effects on skeletal development in mice of either sex. PTH treatment caused hypercalcemia and hypophosphatemia and decreased trabecular and cortical bone only in male WT mice. β-arr2 KO in male mice completely abrogated the effects of PTH on bone, while in female β-arr2 KO mice, PTH treatment increased trabecular bone with no effects on cortical bone.
These results demonstrate a profound sex effect on skeletal responses to cPTH treatment, suggesting a protective effect of estrogen on bone loss. β-arr2 plays a role in restraining the anabolic effects of PTH in both male and female mice.
β-arrestin 2（β-arr2）与激活的甲状旁腺激素（PTH）受体结合，刺激其内化。PTH 对骨骼具有合成代谢和分解代谢双重作用，这取决于其给药方式。间歇性 PTH 刺激可增加小鼠的小梁骨形成，但在缺乏β-arr2 的小鼠中则减少，这表明β-arr2 在 PTH 的合成代谢作用中发挥作用。β-arr2 在持续 PTH（cPTH）治疗的分解代谢作用中的作用尚不清楚。
评估 cPTH 给药对缺乏β-arr2 的小鼠与野生型（WT）小鼠的骨骼的影响。
雄性和雌性 WT 或β-arr2 敲除（KO）小鼠分别通过渗透泵给予 PTH 或磷酸盐缓冲盐水 2 周。治疗后，测量血清钙和磷水平，通过微计算机断层扫描测量骨结构和骨密度，并通过静态和动态组织形态计量学测量骨细胞。
β-arr2 KO 对雌雄小鼠的骨骼发育没有影响。PTH 治疗导致雄性 WT 小鼠出现高钙血症和低磷血症，并仅降低小梁骨和皮质骨。雄性β-arr2 KO 小鼠中 PTH 对骨骼的作用完全被阻断，而在雌性β-arr2 KO 小鼠中，PTH 治疗增加了小梁骨，而对皮质骨没有影响。
这些结果表明，cPTH 治疗对骨骼的反应存在明显的性别差异，提示雌激素对骨丢失具有保护作用。β-arr2 在雌雄小鼠中均发挥作用，可抑制 PTH 的合成代谢作用。
