Traumatic brain injury (TBI) leads to skeletal changes, including bone loss in the unfractured skeleton, and paradoxically accelerates healing of bone fractures; however, the mechanisms remain unclear. TBI is associated with a hyperadrenergic state characterized by increased norepinephrine release. Here, we identified the β 2 -adrenergic receptor (ADRB2) as a mediator of skeletal changes in response to increased norepinephrine. In a murine model of femoral osteotomy combined with cortical impact brain injury, TBI was associated with ADRB2-dependent enhanced fracture healing compared with osteotomy alone. In the unfractured 12-week-old mouse skeleton, ADRB2 was required for TBI-induced decrease in bone formation and increased bone resorption. Adult 30-week-old mice had higher bone concentrations of norepinephrine, and ADRB2 expression was associated with decreased bone volume in the unfractured skeleton and better fracture healing in the injured skeleton. Norepinephrine stimulated expression of vascular endothelial growth factor A and calcitonin gene–related peptide-α (αCGRP) in periosteal cells through ADRB2, promoting formation of osteogenic type-H vessels in the fracture callus. Both ADRB2 and αCGRP were required for the beneficial effect of TBI on bone repair. Adult mice deficient in ADRB2 without TBI developed fracture nonunion despite high bone formation in uninjured bone. Blocking ADRB2 with propranolol impaired fracture healing in mice, whereas the ADRB2 agonist formoterol promoted fracture healing by regulating callus neovascularization. A retrospective cohort analysis of 72 patients with long bone fractures indicated improved callus formation in 36 patients treated with intravenous norepinephrine. These findings suggest that ADRB2 is a potential therapeutic target for promoting bone healing.

中文翻译：

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β2-肾上腺素信号传导增强通过小鼠愈伤组织新生血管促进骨折愈合

创伤性脑损伤 (TBI) 会导致骨骼变化，包括未骨折骨骼的骨质流失，并反而加速骨折的愈合；然而，其机制仍不清楚。 TBI 与以去甲肾上腺素释放增加为特征的高肾上腺素状态有关。在这里，我们确定了 β2-肾上腺素能受体（ADRB2）作为骨骼变化的介质，以响应去甲肾上腺素增加。在股骨截骨术联合皮质撞击性脑损伤的小鼠模型中，与单独截骨术相比，TBI 与 ADRB2 依赖性增强骨折愈合相关。在未骨折的 12 周龄小鼠骨骼中，ADRB2 是 TBI 诱导的骨形成减少和骨吸收增加所必需的。 30周龄成年小鼠的骨中去甲肾上腺素浓度较高，ADRB2的表达与未骨折骨骼中骨量的减少以及受伤骨骼中更好的骨折愈合有关。去甲肾上腺素通过ADRB2刺激骨膜细胞中血管内皮生长因子A和降钙素基因相关肽-α（αCGRP）的表达，促进骨折骨痂中成骨H型血管的形成。 ADRB2 和 αCGRP 都是 TBI 对骨修复产生有益作用所必需的。成年小鼠缺乏尽管未受伤骨的骨形成率很高，但没有 TBI 的 ADRB2 仍出现骨折不愈合。用普萘洛尔阻断 ADRB2 会损害小鼠的骨折愈合，而 ADRB2 激动剂福莫特罗则通过调节愈伤组织新生血管形成来促进骨折愈合。对 72 名长骨骨折患者的回顾性队列分析表明，静脉注射去甲肾上腺素治疗的 36 名患者骨痂形成得到改善。这些发现表明 ADRB2 是促进骨愈合的潜在治疗靶点。