Abstract
Cellular senescence drives a functional decline of numerous tissues with aging by limiting regenerative proliferation and/or by producing pro-inflammatory molecules known as the senescence-associated secretory phenotype (SASP). The senescence biomarker p16INK4a is a potent inhibitor of the cell cycle but is not essential for SASP production. Thus, it is unclear whether p16INK4a identifies senescence in hyporeplicative cells such as articular chondrocytes and whether p16INK4a contributes to pathologic characteristics of cartilage aging. To address these questions, we examined the role of p16INK4a in murine and human models of chondrocyte aging. We observed that p16INK4a mRNA expression was significantly upregulated with chronological aging in murine cartilage (~50-fold from 4 to 18 months of age) and in primary human chondrocytes from 57 cadaveric donors (r2 = .27, p < .0001). Human chondrocytes exhibited substantial replicative potential in vitro that depended on the activity of cyclin-dependent kinases 4 or 6 (CDK4/6), and proliferation was reduced in cells from older donors with increased p16INK4a expression. Moreover, increased chondrocyte p16INK4a expression correlated with several SASP transcripts. Despite the relationship between p16INK4a expression and these features of senescence, somatic inactivation of p16INK4a in chondrocytes of adult mice did not mitigate SASP expression and did not alter the rate of osteoarthritis (OA) with physiological aging or after destabilization of the medial meniscus. These results establish that p16INK4a expression is a biomarker of dysfunctional chondrocytes, but that the effects of chondrocyte senescence on OA are more likely driven by production of SASP molecules than by loss of chondrocyte replicative function.
Keywords:
Ink4a; aging; cellular senescence; chondrocyte; geroscience; mouse models; osteoarthritis; p16.