Nerve growth factor (NGF)-R100E is a mutated form of human recombinant NGF that reduces the binding of NGF to its p75NTR receptor while retaining its affinity toward the TrkA receptor. Here, we used human wild type NGF and NGF-R100E knock-in mice to investigate the effects of this NGF mutation on inflammation-induced pain-related behaviors and bone loss. The hNGF-R100E mutation did not alter the nerve fiber density in the sciatic nerve, ankle joint synovium, and skin of naïve mice. Withdrawal responses to mechanical, thermal, and cold stimuli before and after joint inflammation induced by intra-articular injection of complete Freund adjuvant (CFA) were similar between human recombinant nerve growth factor-wild type and hNGF-R100E male and female mice while weight bearing and gait analysis revealed significant differences. Intriguingly, hNGF-R100E male and female mice showed only mild changes, indicating lower degrees of deep joint-related pain compared to their wild type counterparts. Furthermore, micro-CT analysis demonstrated that hNGF-R100E female mice, but not males, were protected from CFA-induced bone loss, and mRNA analysis showed a different gene regulation indicating a sex-dependent relationship between NGF, inflammation, and bone loss. In conclusion, our study reveals that the hNGF-R100E mutation renders mice insensitive to inflammation-induced impact on joint loading and gait while preserving the development of the peripheral nociceptive neurons and sensitivity to punctate stimulation of the skin. Notably, the mutation uncovers a sex-dependent relationship between NGF and inflammation-induced bone loss. These findings offer valuable insights into NGF as a target for pain management and the interplay between NGF and bone architecture.

中文翻译：

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靶向 NGF 突变 （R100E） 对小鼠疼痛行为、关节炎症和骨侵蚀的性别依赖性影响。


神经生长因子 （NGF）-R100E 是人重组 NGF 的一种突变形式，可降低 NGF 与其 p75NTR 受体的结合，同时保持其对 TrkA 受体的亲和力。在这里，我们使用人类野生型 NGF 和 NGF-R100E 敲入小鼠来研究这种 NGF 突变对炎症诱导的疼痛相关行为和骨质流失的影响。hNGF-R100E 突变没有改变幼稚小鼠坐骨神经、踝关节滑膜和皮肤中的神经纤维密度。关节内注射完全弗氏佐剂 （CFA） 诱导关节炎症前后对机械、热和冷刺激的戒断反应在人重组神经生长因子野生型和 hNGF-R100E 雄性和雌性小鼠之间相似，而负重和步态分析显示差异显著。有趣的是，hNGF-R100E 雄性和雌性小鼠仅表现出轻微的变化，表明与野生型小鼠相比，深部关节相关疼痛的程度较低。此外，显微 CT 分析表明，hNGF-R100E 雌性小鼠（而非雄性）受到保护，免受 CFA 诱导的骨质流失，mRNA 分析显示不同的基因调控表明 NGF、炎症和骨质流失之间存在性别依赖性关系。总之，我们的研究表明，hNGF-R100E 突变使小鼠对炎症诱导的关节负荷和步态的影响不敏感，同时保留了外周伤害性神经元的发育和对皮肤点状刺激的敏感性。值得注意的是，该突变揭示了 NGF 与炎症诱导的骨质流失之间的性别依赖性关系。这些发现为 NGF 作为疼痛管理靶点以及 NGF 与骨骼结构之间的相互作用提供了有价值的见解。