Heterotopic ossification (HO) is a pathological process that commonly arises following severe polytrauma, characterized by the anomalous differentiation of mesenchymal progenitor cells and resulting in the formation of ectopic bone in non-skeletal tissues. This abnormal bone growth contributes to pain and reduced mobility, especially when adjacent to a joint. Our prior observations suggested an essential role of NGF (Nerve Growth Factor)-responsive TrkA (Tropomyosin Receptor Kinase A)-expressing peripheral nerves in regulating abnormal osteochondral differentiation following tendon injury. Here, we utilized a recently developed mouse model of hip arthroplasty-induced HO to further validate the role of peripheral nerve regulation of traumatic HO. Nerve ingrowth was either modulated using a knockin transgenic animals with point mutation in TrkA, or local treatment with an FDA-approved formulation of long acting Bupivacaine which prevents peripheral nerve growth. Results demonstrate exuberant sensory and sympathetic nerve growth within the peri-articular HO site, and that both methods to reduce local innervation significantly reduced heterotopic bone formation. TrkA inhibition led to a 34% reduction in bone volume, while bupivacaine treatment resulted in a 50% decrease. Mechanistically, alterations in TGFβ and FGF signaling activation accompanied both methods of local denervation, and a shift in macrophages from M1 to M2 phenotypes was observed. In sum, these studies reinforce the observations that peripheral nerves play a role in the etiopathogenesis of HO, and that targeting local nerves represents a potential therapeutic approach for disease prevention.

异位骨化（HO）是严重多发伤后常见的病理过程，其特征是间充质祖细胞的异常分化并导致非骨骼组织中异位骨的形成。这种异常的骨骼生长会导致疼痛和活动能力下降，尤其是在邻近关节时。我们之前的观察表明，NGF（神经生长因子）反应性 TrkA（原肌球蛋白受体激酶 A）表达的周围神经在调节肌腱损伤后异常骨软骨分化中发挥着重要作用。在这里，我们利用最近开发的髋关节置换术诱导 HO 的小鼠模型来进一步验证外伤性 HO 的周围神经调节作用。神经向内生长要么使用 TrkA 点突变的敲入转基因动物进行调节，要么使用 FDA 批准的长效布比卡因制剂进行局部治疗，以防止周围神经生长。结果表明，关节周围 HO 部位的感觉神经和交感神经生长旺盛，并且两种减少局部神经支配的方法都显着减少了异位骨形成。 TrkA 抑制导致骨量减少 34%，而布比卡因治疗则导致骨量减少 50%。从机制上讲，两种局部去神经方法都伴随着 TGFβ 和 FGF 信号激活的改变，并且观察到巨噬细胞从 M1 表型转变为 M2 表型。总之，这些研究强化了以下观察结果：周围神经在 HO 的发病机制中发挥作用，并且针对局部神经代表了一种潜在的疾病预防治疗方法。