Symptomatic joint degeneration is a common chronic musculoskeletal disorder worldwide. The literature has noted that some clinicians find treating this condition “technically challenging,” while others find it to be “unchallengingly routine.” We believe that all clinicians treating symptomatic joint degeneration should have a robust understanding of the mechanobiological interactions between the synovial lining, synovial cells, synovial fluid, articular cartilage, and subchondral bone. This four-part narrative review describes how inner lining synovitis and cellular changes in the subchondral region, including the development of bone marrow edema, are symptom generators in some patients with various grades of joint degeneration. This review suggests that physical therapists (PTs) should acquaint themselves with the concept of mechanotransduction and more fully consider cellular mechanosensitivity and mechanoresponsiveness as exercise loading and manual interventions loads are placed upon joints with degenerative change. We call for additional research efforts in the area of protocol development for low-load exercise intervention and between PTs and physicians who may have access to laboratory facilities and imaging equipment. This research could allow for both direct and indirect assessment of intra-articular pressure, synovial fluid, and bone marrow edema after the application of therapeutic exercise and joint mobilization.