Crosstalk between autophagy and matrix remodeling pathways in the synovial tissue of estrogen-deficient and diabetic rats

Estrogen deficiency and diabetes mellitus (DM) are major endocrine and metabolic disorders contributing to musculoskeletal degeneration through oxidative stress, inflammation, and extracellular matrix remodeling. The synovial membrane, essential for joint homeostasis, is particularly vulnerable to these systemic disturbances. Autophagy, a key cellular mechanism for maintaining synovial integrity by degrading damaged organelles and proteins, may be dysregulated under such conditions; however, its regulation in response to estrogen deficiency and DM remains poorly understood. This study investigated the combined effects of estrogen deficiency and streptozotocin-induced DM on rat knee synovial tissue, focusing on histopathological changes and the immunoexpression of autophagy (Beclin-1, LC3B), angiogenic (VEGF-A), matrix remodeling (MMP-9), and inflammasome-related (NLRP3) markers. Twenty adult female Wistar rats were ovariectomized (OVX) or SHAM-operated (SHAM) and assigned to SHAM, OVX, SHAM-DM, and OVX-DM groups. DM was induced by intraperitoneal streptozotocin injection in the diabetic groups. After seven weeks, knee joints were fixed in paraformaldehyde, decalcified, and embedded in paraffin. Sections were analyzed histologically and immunohistochemically. OVX-DM rats showed pronounced synovial lining hyperplasia, fibrosis, and vascular proliferation, with increased expression of Beclin-1, LC3B, MMP-9, VEGF-A, and NLRP3. Significant positive correlations were observed among these markers and with fibrosis, vascularity, and inflammation scores. These findings suggest that estrogen deficiency and DM synergistically promote pathological synovial remodeling via activation of autophagic, angiogenic, and matrix degradation pathways.