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.

A Proteomic Atlas of Senescence-Associated Secretomes for Aging Biomarker Development

“…However, the increase in senescent cells with age and a chronic SASP are now known to be key drivers of many pathological hallmarks of aging, including chronic inflammation, tumorigenesis, impaired stem cell renewal, and others (Neves et al, 2015;Tominaga, 2015). Using either or both of two transgenic mouse models that allow the selective elimination of senescent cells (Baker et al, 2011;Demaria et al, 2014), or compounds that mimic the effect of these transgenes, data from several laboratories strongly support the idea that the presence of senescent cells drives multiple age-related phenotypes and pathologies, including age-related atherosclerosis , osteoarthritis (Jeon et al, 2018), cancer metastasis and cardiac dysfunction (Baar et al, 2017;Demaria et al, 2017), myeloid skewing in the bone marrow (Abdul-Aziz et al, 2018;Chang et al, 2016), kidney dysfunction (Valentijn et al, 2018), and overall decrements in healthspan .…”

Phenotypic instability of chondrocytes in osteoarthritis: on a path to hypertrophy

“…Biological aging is controlled partly by evolutionarily conserved mechanisms that represent the so‐called nine hallmarks of aging: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, stem cell exhaustion, altered intercellular communications, and cellular senescence . Senescence was initially defined as loss of replicative capacity associated with the accumulated shortening of telomeres with every cellular division (replicative senescence); but we now know that there are forms of senescence that are driven by the exposure to stress signals and do not correlate with the older age of the organism or the number of the cellular divisions (stress‐induced premature senescence) . The latter is especially relevant in cells with limited replicative ability that are involved in the long‐term maintenance of tissue homeostasis, like articular chondrocytes.…”

“…84 Senescence was initially defined as loss of replicative capacity associated with the accumulated shortening of telomeres with every cellular division (replicative senescence); but we now know that there are forms of senescence that are driven by the exposure to stress signals and do not correlate with the older age of the organism or the number of the cellular divisions (stress-induced premature senescence). 84,85 The latter is especially relevant in cells with limited replicative ability that are involved in the long-term maintenance of tissue homeostasis, like articular chondrocytes. Recent studies showed that OA chondrocytes display features of premature epigenetic aging 86 and the senescenceassociated secretory phenotype.…”

Mechanisms Underlying Bone and Joint Pain

“…fibroblasts, chondrocytes), blood, and local and migrating inflammatory cells [57, 47, 58, 59]. These factors may promote disease progression and pathology in disease states such as arthritis or cancer-induced bone pain.…”