Deciphering the spatial and microstructural landscape in subchondral bone remodeling of temporomandibular joint osteoarthritis

• Nanoscale gradient structure reveals biphasic bone remodeling in osteoarthritis. • Nanomechanical impairment serves as the earliest event in disease progression. • Alendronate early intervention mitigates pathological bone remodeling. The pathological remodeling of subchondral bone is a hallmark of osteoarthritis (OA), yet the spatial heterogeneity and dynamic evolution of its microstructural, compositional, and nanomechanical properties remain poorly understood. Herein, we conducted a multiscale analysis of subchondral bone in a rat temporomandibular joint osteoarthritis (TMJOA) model induced by disc displacement without reduction (DDw/oR). A nano gradient assembly of osteochondral junction was identified, and a biphasic pathological transformation was revealed: subchondral bone resorption in early-stage TMJOA (1-week post-surgery) was marked by shrunken mineralized particles, a thinned osteochondral junction, loosely arranged trabecular fibers, decreased mineralization, and a reduced indentation modulus; whereas abnormal bone formation in late-stage TMJOA (8-week post-surgery) exhibited opposing trends, including enlarged mineralized particles, increased thickness of osteochondral junction, partial mineralization of trabecular fibers, elevated mineralization degree, and increased indentation modulus. Notably, reductions in trabecular mineralization and nanomechanical properties preceded other compositional and structural changes. Early intervention with alendronate (ALN) effectively mitigated these pathological alterations in both early and late stages. By establishing nanomechanical impairment as an early event in OA progression, this study unravels the nanoscale architectural dynamics of subchondral bone remodeling, providing invaluable insights for the design of biomimetic materials that target early-stage OA.