Pathogenesis of Arthrofibrosis
‘Stiff knee’, ‘frozen shoulder’ and ‘stiff elbow’ are all caused by the same painful joint condition called “arthrofibrosis”. Scar tissue, contractions and adhesions are produced by highly specialised cells in response to injury and inflammation. TGF-β is the key cytokine involved in activating and maintaining fibrosis, and myofibroblasts are the specialised cells that cause the disease.
Myofibroblasts only exist in order to heal injuries and in healthy healing myofibroblasts die or disappear when healing is complete. In fibrosis this does not occur, and myofibroblasts effectively become immortal, continuing to produce scar tissue and inflammatory cytokines. The disease processes for arthrofibrosis and other fibrotic diseases, for example, organ fibrosis and hypertrophic scars, are the same.
An insult such as surgery or injury causes hypoxia and activates inflammasomes in cells, resulting in the production of reactive oxygen species (ROS), platelet-derived growth factor (PDGF), transforming growth factor beta (TGF-β) and a range of inflammatory cytokines and mediators. These activate immune cells, causing more inflammation and a cascade of events that stimulates fibroblasts to differentiate into myofibroblasts, the key mediators of fibrosis.
Dysregulation and positive feedback loops (curved yellow arrows) result in persistent pathological fibrosis. TGF-β activates and transforms fibroblasts into myofibroblasts, and plays a central role in fibrotic processes. TGF-β also induces the production of ROS and regulates T cell differentiation and proliferation. Nuclear factor kB (NF-κB) produced by macrophages is activated by TGF-β, as well as many of the inflammatory cytokines induced by it. PDGF promotes the migration, proliferation and survival of myofibroblasts and upregulates TGF-β synthesis by fibroblasts. The production of IL-1β by macrophages further stimulates inflammasomes.
The fibres of α smooth muscle actin (α –SMA) inside myofibroblasts terminate with adhesion complexes on myofibroblast surfaces and attach to ECM and other cells, generating contractile forces. These mechanical forces also activate fibroblasts. Over time the cross-linkages in the ECM and focal adhesions become more complex and further tissue contractions occur, creating more mechanical stress and positive feedback effects. Myofibroblasts resist apoptosis and are able to maintain themselves by secreting TGF-β.
Usher, K. M. et al. Pathological mechanisms and therapeutic outlooks for arthrofibrosis. Bone Research 7, doi:10.1038/s41413-019-0047-x (2019).
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