Neuropeptide-Mediated Crosstalk between Subchondral Bone and Articular Cartilage in Ankle Osteoarthritis: A Cross-Sectional Histologic Study of 17 Ankles

Background: This study aimed to investigate the expression patterns of the neuropeptides, calcitonin gene–related peptide (CGRP), and substance P (SP), in the subchondral bone of patients with ankle osteoarthritis (OA) and examine their association with subchondral bone changes and cartilage degeneration. We hypothesized that neuropeptides were expressed in sclerotic subchondral bone and that this expression was associated with the progression of cartilage degeneration. This study investigated neuropeptide expression and its relationship with subchondral bone changes and cartilage degeneration in ankle OA. Methods: Seventeen ankles of 16 patients who underwent total ankle arthroplasty for ankle OA were analyzed. Radiographic, histologic, and CT evaluations were conducted, including the measurement of Hounsfield unit (HU) values, subchondral bone plate thickness, trabecular bone area, and modified Mankin scores. Immunohistochemistry for CGRP; SP; collagen types I, II, and X; and TRAP staining for osteoclasts were performed. Results: Subchondral bone sclerosis and cartilage degeneration progressed concurrently with increased thickness and trabecular area beneath the degenerated cartilage. CGRP and SP expression were significantly upregulated in the sclerotic subchondral bone, showing strong positive correlations with HU values, subchondral bone thickness, and Mankin scores. CGRP expression appeared earlier than SP expression in moderate degeneration stages. The number of TRAP-positive osteoclasts increased with degeneration and followed a distribution pattern similar to that of CGRP and SP. Conclusion: CGRP and SP expression in the subchondral bone was closely linked to structural bone changes and cartilage degradation in ankle OA. Their early expression and association with osteoclast activity support a potential role in OA pathogenesis; however, causation cannot be inferred from this cross-sectional study.