Anti-NGF treatment worsens subchondral bone and cartilage measures while improving symptoms in floor-housed rabbits with osteoarthritis

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.

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Sex-dependent effects of the targeted nerve growth factor mutation (R100E) on pain behavior, joint inflammation, and bone erosion in mice

Morado-Urbina,

Kato,

Sandor

et al. 2024

Pain

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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.

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Anti-NGF treatment worsens subchondral bone and cartilage measures while improving symptoms in floor-housed rabbits with osteoarthritis

Cited by 4 publications

References 51 publications

Neural and immune roles in osteoarthritis pain: Mechanisms and intervention strategies

Neural and immune roles in osteoarthritis pain: Mechanisms and intervention strategies

Pharmacologic or genetic targeting of peripheral nerves prevents peri-articular traumatic heterotopic ossification

Sex-dependent effects of the targeted nerve growth factor mutation (R100E) on pain behavior, joint inflammation, and bone erosion in mice

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