1790: Targeted Ablation of Knee-innervating Nociceptors Attenuates Pain and Cartilage Degeneration in Experimental Osteoarthritis

Background/Purpose: Nociceptors abundantly innervate the knee joint. In experimental osteoarthritis (OA), nociceptors sprout in the medial synovium and in subchondral bone channels. We aimed to determine the effect of selective ablation of knee-innervating nociceptors in murine OA.

Methods: Adeno-associated virus AAV.PHP.S carrying diphtheria toxin A (dtA) (AAV-dtA) or control AAV (AAV-Ctrl) was injected intra-articularly (i.a.) into the knee cavity of 7-week old male Na_V1.8-Cre mice. Destabilization of the medial meniscus (DMM) or sham surgery were performed 3 weeks later. Pain-related behaviors (weight bearing and knee hyperalgesia) were assessed up to 16 weeks after surgery. Knee joints were collected for histology, microCT, innervation analysis, and protein antibody array. Lumbar dorsal root ganglia (DRG) were collected for immunofluorescence staining or qPCR analysis.

Results: Injection of AAV-dtA effectively ablated joint nociceptors. This had no effect on knee hyperalgesia but attenuated weight bearing deficits (Fig. 1A-B), with decreased Ccl2 in DRG (Fig. 1C). AAV-dtA administration suppressed nociceptor sprouting in subchondral bone channels (Fig. 1D), but not in the medial synovium (Fig. 1E). Marked cartilage damage observed in AAV-Ctrl injected joints was attenuated in AAV-dtA injected mice (Fig. 2A), while synovitis, osteophytes, and microCT of the subchondral bone were similar in both groups. Knee joint lysates showed lower levels of calcitonin gene-related peptide (CGRP) 4 and 8 weeks after DMM in AAV-dtA injected mice (Fig. 2B), as well as decreased pro-inflammatory factors 8 weeks after DMM and increased levels of cartilage-anabolic markers 16 weeks after DMM (Fig. 2C). CGRP+ neurons were also decreased in ipsilateral lumbar DRGs, along with reduced Na_V1.8+ neurons after ablation.

Conclusion: Knee-innervating nociceptor ablation before DMM attenuated weight bearing asymmetry, subchondral bone nerve sprouting, and cartilage degeneration. Cartilage anabolic factors were increased in the joints, while CGRP levels were decreased. The neurogenic contribution to OA may result from the neuropeptides released from nerve endings in early stages of OA.