Figure 3.

Putative changes in joint tissues after injury and during post-traumatic OA development. (Top, left) Acutely following injury, synovial lining macrophages are spatially re-orientated and the barrier is disrupted. DAMPs, PAMPs and catabolic enzymes are released into the synovial cavity by chondrocytes and damaged tissues (ligament, meniscus). Extra-vascular erythrocytes and associated free heme from blood vessel injury may pathologically imprint synovial macrophages. Barrier disruption may impede cyclic stretching of lining macrophages, resulting in NLRP3 inflammasome activation and increased IL-1ß production, known to promote of OA. Altered mechanics may also promote joint inflammation through TRPV1/4 cation channels. (Top right) At later stages of ptOA pathogenesis, the synovial lining layer may be restored. Levels of IL-1ß remain elevated, though involvement of the NLRP3 inflammasome is unclear. TRPV1 activation may continue to promote OA pathogenesis, although likely via signals other than or in addition to mechanical stimuli. Cellular debris, DAMPs and PAMPs remain abundant in the synovial cavity and thus potentially imprint pathological macrophage phenotypes. (Bottom, left) Increased numbers and activation of osteoclasts contribute to accelerated bone turnover and remodeling in the arthritic joint. Osteoclastogenesis may be promoted by CCL2 produced by activated osteoblasts and inflammatory cells, potentially resulting in recruitment and fusion of Ly6C^high and Ly6C^low monocytes, a process that may be further stimulated by RANKL produced by lining fibroblasts. (Bottom, right) In the sublining layer, exposure to ECM degradation products may stimulate interstitial macrophages to produce CCL2 and CCL5, leading to recruitment of Ly6C^high and Ly6C^low monocytes. Ly6C^high monocytes produce IL-1ß, TNF-α and IL-6, potentially in response to the adipokine visfatin, a TLR4 receptor agonist, which also induces changes in the subchondral bone. Ly6C^low monocytes may supply the interstitial macrophage pool, but these macrophages may retain higher baseline NF-κB and IL-1ß activity than those in healthy joints. Created with BioRender.com and smart.servier.com.