FAT-SECRETED COMPLEMENT FACTOR D (ADIPSIN) MEDIATES KNEE PAIN POST INJURY

While discordance between pain and cartilage damage in Osteoarthritis (OA) exists clinically, it is poorly understood. We previously identified that deletion of complement factor D (CFD) results in increased pain, but protection from cartilage damage, using destabilization of the medial meniscus (DMM) surgery in mice. CFD is secreted by adipose tissue, which we demonstrated plays a key role in OA pathogenesis and pain. However, how and when CFD drives pain and cartilage damage with DMM is unknown. We hypothesized that loss of Cfd (Cfd -/- ) will protect cartilage but increase pressure-pain hyperalgesia and dysregulation of known bioactive lipid mediators involved in pain, called eicosanoids. Male and female Cfd -/- and wild-type (WT) mice were challenged with unilateral DMM or no surgery (naïve, n=5–11/group). Pressure-pain hyperalgesia, static incapacitance (side-to-side limb loading), and mechanical allodynia (Von Frey) were measured biweekly. Cartilage damage was scored using the Modified Mankin score. To determine changes in eicosanoid profiles, serum and synovial fluid (SF) samples were analyzed via liquid chromatography-mass spectrometry (LC-MS) using a targeted lipid panel. Statistical analysis was performed using MetaboAnalysis, two-way ANOVA with Tukey post-hoc analysis. In contrast to WT mice, male and female Cfd -/- showed no significant differences in Modified Mankin scores at 8 weeks after DMM. WT and Cfd -/- and DMM male and female mice exhibited decreases in pain-pressure threshold (p<0.0001), or increases in pain sensitivity, and decreased loading of the DMM limb (p<0.01) at all timepoints measured (Fig. 1b). Eicosanoid profiles at 2 weeks post-DMM displayed decreases in wound healing factors (12-HHT) in the serum and pain-suppression factors (14,15-EET; 10,11-EpDPA) in the SF of Cfd -/- mice when compared to WT. Decreases in pain suppression factors (PGJ2) and increases in pain-driving factors (12-HETE; 13-HODE) in the serum of Cfd -/- compared to WT were observed, but no differences in the SF at 8 weeks post DMM. The absence of CFD drives hyperalgesia and limb offloading in mice as early as 2 weeks post-DMM and persists through an 8-week observation period. We have previously demonstrated this pain phenotype can be reversed with Cfd repletion. Early changes in eicosanoid profiles in the SF suggest that the increased pain sensitivity may be initiated by CFD post DMM, which is later detectable in serum as pain persists. Altogether, these data confirm a mechanistic role for CFD as a mediator of fat-joint crosstalk, potentially via eicosanoids, resulting in joint pain with knee injury. For any figures or tables, please contact the authors directly.