Abstract：
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 β2-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.
摘要：
创伤性脑损伤（TBI）导致骨骼变化，包括未骨折的骨骼的骨质流失，矛盾的是加速骨折的愈合；然而，机制尚不清楚。TBI与以去甲肾上腺素释放增加为特征的高肾上腺素能状态相关。这里,我们确定β2-肾上腺素能受体(ADRB2)是对去甲肾上腺素增加的骨骼变化的介质.在小鼠股骨截骨术合并皮质撞击脑损伤模型中，与单独截骨相比，TBI与ADRB2依赖性骨折愈合增强相关。在没有骨折的12周大的老鼠骨架中，TBI诱导的骨形成减少和骨吸收增加需要ADRB2。成年30周龄小鼠的去甲肾上腺素骨浓度较高，ADRB2的表达与未骨折骨骼的骨体积减少和受伤骨骼的骨折愈合有关。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,促进骨折骨痂成骨H型血管的形成。TBI对骨修复的有益作用需要ADRB2和αCGRP两者。缺乏ADRB2而没有TBI的成年小鼠出现骨折不愈合，尽管未受伤的骨骼中的骨骼形成很高。用普萘洛尔阻断ADRB2损害小鼠骨折愈合，而ADRB2激动剂福莫特罗则通过调节骨痂新生血管形成促进骨折愈合。对72例长骨骨折患者进行的回顾性队列分析显示，静脉注射去甲肾上腺素治疗的36例患者骨痂形成改善。这些发现表明ADRB2是促进骨愈合的潜在治疗靶标。
