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

Abstract

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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Funding

U.S. Department of Health & Human Services | NIH | National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)(P01 AG066603, R01 AR079171, R01 AR079171-07S1,R21AR078919)

U.S. Department of Health & Human Services | NIH | National Institute of Dental and Craniofacial Research (NIDCR)(R01 DE031488,R01 DE031028)

Alex's Lemonade Stand Foundation for Childhood Cancer (Alex's Lemonade Stand Foundation)(22-26743)

American Cancer Society (American Cancer Society, Inc.)(DBG-23-1155131-01-IBCD)

U.S. Department of Health & Human Services | NIH | National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)