Senescent cells and osteoarthritis: a painful connection

Abstract

Senescent cells (SnCs) are associated with age-related pathologies. Osteoarthritis is a chronic disease characterized by pain, loss of cartilage, and joint inflammation, and its incidence increases with age. For years, the presence of SnCs in cartilage isolated from patients undergoing total knee artificial implants has been noted, but these cells' relevance to disease was unclear. In this Review, we summarize current knowledge of SnCs in the multiple tissues that constitute the articular joint. New evidence for the causative role of SnCs in the development of posttraumatic and age-related arthritis is reviewed along with the therapeutic benefit of SnC clearance. As part of their senescence-associated secretory phenotype, SnCs secrete cytokines that impact the immune system and its response to joint tissue trauma. We present concepts of the immune response to tissue trauma as well as the interactions with SnCs and the local tissue environment. Finally, we discuss therapeutic implications of targeting SnCs in treating osteoarthritis.

Figure 1. A schematic overview of the joint structure.

Articular cartilage, subchondral bone, synovium, and infrapatellar fat pad (IPFP) are joint tissues that may harbor senescent cells and secrete a senescence-associated secretory phenotype (SASP) induced by aging or trauma. Loss or damage to the anterior cruciate ligament (ACL) or other joint structures is a primary cause of PTOA.

Figure 2. Senescent cells develop a SASP.

The nature of the SASP depends on the local microenvironment and will itself alter the local environment. The innate and adaptive immune system can respond to joint trauma and tissue injury. The SASP includes cytokines that attract and modulate immune cells, which remove debris and secrete cytokines that influence the tissue response toward repair or fibrosis. Elements of the immune system are also responsible for clearing SnCs that form after injury. When persistent, the molecules secreted by both SnCs and immune cells cause chronic inflammation and ultimately chronic disease. Three strategies (green text) potentially prevent or attenuate OA diseases by selectively eliminating SnCs: augmentation of immune-mediated SnC clearance (e.g., chimeric antigen receptor [CAR] T cells, which are engineered to express immunoglobulin variable fragments to SnC surface markers), SASP neutralization, and direct killing of SnCs by senolytics.