A Novel Concept of Tissue Micro-Instability as the Underlying Mechanism of Osteophytosis in Human Knee Osteoarthritis

Osteophytes (OPs) are a diagnostic hallmark of osteoarthritis (OA). However, the mechanisms underlying their initiation and their relationship with early subchondral bone changes remain poorly understood. Existing research primarily relies on animal models and late-stage OA tissue, leaving the initial morphological events leading to OP formation unclear. Background/Objectives: This study aimed to identify early changes in the subchondral bone as a key trigger for OP initiation in human OA through a comprehensive histological analysis of the subchondral area, including its peripheral regions. Methods: We conducted an extensive histological examination of full-section human tibial plateaus, including load-bearing and non-load-bearing compartments, obtained from patients with early and late stages of OA. Results: Our data demonstrate that subchondral bone changes, including osteoporosis, osteosclerosis, and microcracks, begin at the pre-chondropathic stage alongside microscopically intact cartilage. We identified a previously undescribed zone on the vertical wall of the tibial condyle (the VEPLS zone), characterized by reduced calcium content in the cortical plate and the persistence of embryonic cartilage, making it morphologically vulnerable. The first event in OP formation is microcracks in the cortical angle and the adjacent subchondral trabecula. These injuries initiate reparative osteogenesis, which, under continuous traumatic load (presumably shear forces due to joint instability), becomes insufficient, leading to cortical angle protrusion and OP formation. OP growth is accompanied by the deformation of the VEPLS zone cortical plate, causing vascular impairment and exacerbating bone weakness. Conclusions: Based on our findings, we propose the concept of tissue micro-instability. This concept posits that osteophytosis results from chronic microcracks and failed bone regeneration in vulnerable subchondral structures, induced by joint instability. We define an OP as a pathological outgrowth arising from this tissue micro-instability. Our study highlights the critical role of the peripheral subchondral area, particularly the VEPLS zone, in OA pathogenesis.