Hypothetical model that shows in what manner changes of cartilage, subchondral bone, and synovial macrophages all contribute to osteoarthritis development. (A) Schematically depicted healthy joint with chondrocytes in cartilage extracellular matrix, bone and inactive osteoclasts, and resting synovial macrophages. (B) Chondrocytes with a pathological strain produce cytokines and growth factors that diffuse toward the underlying bone marrow and synovium. There these products stimulate osteoclastogenesis and can activate macrophages. (C) Progressive phase of OA. Chondrocytes become hypertrophic and produce less sulfated-glycosaminoglycans (sGAGs) to sustain the cartilage, making the ECM more susceptible to compressive forces. Osteoclasts start tunneling through the subchondral bone, which compromises plate stability, and changing its supportive function for the overlying cartilage. Activated synovial macrophages produce growth factors of their own that promote synovial fibrosis, osteophyte formation, and may stimulate ECM degradation. (D) Eventually, cartilage is severely sGAG depleted and becomes structurally deprived. Activated macrophages stimulate fibrotic remodeling of the synovium and induce osteophyte growth. Osteoclast activity extends into the calcified cartilage, up to the border with the deep zone of the cartilage. Through subchondral pores, vascular ingrowth occurs into the cartilage. Later, osteoblasts infiltrate and start to deposit bone that results in end-stage sclerosis.