Leptin drives osteoarthritis pain through sensory neuron reprogramming independent of cartilage signaling

Pain in osteoarthritis (OA) is often discordant with structural joint damage, particularly in obesity, where adipose-derived signals may drive nociception independently of cartilage pathology. Leptin has been demonstrated to be necessary, but not sufficient, to drive obesity-associated OA. Here, we tested the hypothesis that leptin mediates OA-associated pain through sensory neuron reprogramming rather than chondrocyte-intrinsic signaling, suggesting a fat-sensory nerve axis.

Male and female chondrocyte-specific leptin receptor knockout mice (Aggrecan-CreERT2;LepRfl/fl) and constitutive leptin-deficient (Ob/Ob), heterozygous (Ob/+), and wild-type (WT) mice were challenged with destabilization of the medial meniscus (DMM) to induce OA. Pain-related behaviors, joint pathology, serum cytokines, and lumbar dorsal root ganglia (DRG) transcriptomes were assessed. Human DRG cultures treated with leptin underwent transcriptomic profiling. Leptin and leptin receptor expression was investigated in human infrapatellar fat pad and synovium single-cell datasets.

Chondrocyte-specific deletion of the leptin receptor did not alter structural joint pathology or pain. In contrast, complete leptin deficiency (Ob/Ob) produced more severe structural damage following DMM while markedly reducing pain sensitivity. Comparing DMM limbs of Ob/+ animals to those of Ob/Ob animals, Modified Mankin score was 24.95% higher (95% CI 2.02-11.49) indicating greater structural damage, while pressure-pain thresholds were 37.5% higher (95% CI, 23.92-54.46g), indicating attenuated pain, together demonstrating dissociation between structural pathology and nociception. Circulating cytokines did not differ by genotype between Ob/+ and Ob/Ob mice, providing no systemic inflammatory signature corresponding to their divergent pain phenotypes. Mouse DRGs exhibited genotype-associated transcriptional differences, with Ob/+ DRGs enriched for lipid metabolism, eicosanoid, and inflammatory programs, whereas Ob/Ob DRGs were characterized by cytoskeletal remodeling and altered neuronal signaling. In human DRG cultures, acute leptin exposure was associated with enrichment of neuronal and nociceptor-associated transcriptional programs, whereas vehicle-treated cultures were enriched for inflammatory signaling. Human infrapatellar fat pad and synovium transcriptomic data demonstrated adipocyte-enriched leptin expression and broad leptin receptor distribution across stromal, vascular, immune, and adipocyte populations.

In mice, leptin contributes to OA pain independently of chondrocyte-intrinsic signaling and structural disease severity. These findings identify leptin-associated neuronal programs linked to nociceptor sensitization and support further investigation of adipose-joint-sensory neuron signaling as a mediator of obesity-associated OA pain.