TREM2 modulates CXCL9:SPP1 polarity to influence macrophage-chondrocyte crosstalk and promote osteoarthritis...

Joint injury is a major risk factor for osteoarthritis (OA), but the mechanisms driving OA progression post-injury remain unclear. CXCL9:SPP1 (CS) polarity has been discovered in recent years as a key molecular switch regulating macrophage M1/M2 polarisation, determining the pro-inflammatory or anti-inflammatory state of the joint microenvironment, and thereby affecting cartilage metabolic balance. We aimed to elucidate the polarity regulation mechanism, which is of great significance for understanding the pathogenesis of OA and developing targeted treatment strategies.

We annotated single-cell data of injured/uninjured mouse joints from GEO, identified key cell populations, and analysed pathways via GO/KEGG. OA models were established in macrophage-specific TREM2 knockout (KO) and wild-type (WT) mice via anterior cruciate ligament transection. Joint pathology was evaluated by H & E, Safranin O-Fast Green staining, and Micro-CT. Macrophage-chondrocyte co-cultures were used to detect gene/protein expression (qPCR/Western blot), macrophage polarisation (flow cytometry), chondrocyte proliferation (CCK-8/EdU), and apoptosis (TUNEL).

Bioinformatic analysis showed TREM2+Mac overexpression in injured joints, linked to CS polarity and inflammation. In vivo, TREM2 was upregulated in OA model macrophages; TREM2 KO promoted M2 polarisation, alleviated cartilage damage, and suppressed OA. In vitro, TREM2 knockdown in M0 macrophages regulated CS polarity to enhance M2 and inhibit M1 polarisation, which improved chondrocyte proliferation, migration, invasion, and reduced apoptosis.

TREM2 upregulation in injured joint macrophages modulates CS polarity to control macrophage polarisation, inducing cartilage dysfunction and OA progression.