Cellular senescence in knee osteoarthritis: molecular mechanisms and therapeutic implications

• Current evidence for the role of cellular senescence of different cell types in the onset and progression of osteoarthritis were reviewed. • The underlying mechanisms of senescence in chondrocytes, especially Forkhead family of transcription factors were reviewed. • Potential therapeutic value and implications of targeting senescent cells using senolytic agents or immune therapies, targeting the senescence-associated secretory phenotype of these cells using senomorphic agents, and renewing the plasticity of stem cells and chondrocytes were reviewed. • The review highlights current gaps in understanding of the mechanism of senescence that may, when addressed, provided new options for modifying and treating disease in osteoarthritis. Cellular senescence is the inability of cells to proliferate, which has both beneficial and detrimental effects on tissue development and homeostasis. Chronic accumulation of senescent cells is associated with age-related disease, including osteoarthritis, a common joint disease responsible for joint pain and disability in older adults. The pathology of this disease includes loss of cartilage, synovium inflammation, and subchondral bone remodeling. Senescent cells are present in the cartilage of people with advanced osteoarthritis, but the link between cellular senescence and this disease is unclear. In this review, we summarize current evidence for the role of cellular senescence of different cell types in the onset and progression of osteoarthritis. We focus on the underlying mechanisms of senescence in chondrocytes, which maintain the cartilage in joints, and review the role of the Forkhead family of transcription factors, which are involved in cartilage maintenance and osteoarthritis. Finally, we discuss the potential therapeutic value and implications of targeting senescent cells using senolytic agents or immune therapies, targeting the senescence-associated secretory phenotype of these cells using senomorphic agents, and renewing the plasticity of stem cells and chondrocytes. Our review highlights current gaps in understanding of the mechanism of senescence that may, when addressed, provided new options for modifying and treating disease in osteoarthritis.