MAPK Pathway Activation Patterns in the Synovium Reveal ERK1/2 and EGFR as Key Players in Osteoarthritis

<b>Background/Objectives</b>: Chronic synovitis is a hallmark of osteoarthritis (OA) progression, driving cartilage degradation via inflammatory mediators. While the MAPK signaling pathway is implicated in OA pathogenesis its activation patterns in hip synovium remain poorly characterized, and regional differences within the synovial membrane have not been systematically examined. This research aims to determine the expression of extracellular signal-regulated kinase 1/2 (ERK1/2), p38 mitogen-activated protein kinase (p38 MAPK), c-Jun N-terminal kinase (JNK), and the Epidermal Growth Factor Receptor (EGFR) in the MAPK signaling pathway in the synovial membrane of osteoarthritic hips. <b>Methods</b>: We compared synovial immunofluorescence expression of the aforementioned proteins in a control (CTRL) group of subjects with femoral neck fractures and a group with hip OA. <b>Results</b>: Higher ERK1/2 immunoexpression was detected in the intima compared with the subintima in the CTRL group (<i>p</i> < 0.05), and a similar distribution was observed in the OA group (<i>p</i> < 0.0001). The intima of the OA group exhibited a considerably greater area percentage of positive signal than the intima of the CTRL group (<i>p</i> < 0.01). In all groups examined, we observed that p38 MAPK expression was markedly more positive in the intima than in the subintima (<i>p</i> < 0.0001), but without statistically significant differences between groups. JNK and EGFR immunoexpression were higher in the intima than in the subintima across all analyzed groups, but the difference did not reach statistical significance (<i>p</i> > 0.05). No differences in the expression of these two markers were detected between the CTRL and OA groups (<i>p</i> > 0.05). Differential analysis of the GEO dataset revealed no significant differences in expression between the OA and CTRL groups in the expression of <i>MAPK1</i>, <i>MAPK3</i>, <i>MAPK8</i>, <i>MAPK9</i>, <i>MAPK10</i>, and <i>MAPK11. EGFR</i> was significantly elevated in OA compared to CTRLs in the differential analysis of the GEO dataset. <b>Conclusions</b>: This study provides the first comprehensive analysis of MAPK pathway activation in hip OA synovium, revealing ERK1/2 as a key player with region-specific upregulation in the synovial intima. Combined with elevated EGFR expression, these findings suggest potential therapeutic targets for hip OA synovitis. The discordance between protein and mRNA levels for ERK1/2 indicates post-transcriptional regulation, warranting further investigation into phosphorylation status and functional activation. Our results support the development of targeted interventions for hip OA, a condition with limited treatment options beyond joint replacement.