Background/Purpose: Background/Purpose:  Cellular senescence is a natural state in which a cell permanently halts division through upregulation of a set of intracellular proteins including p16INK4A in response to various cellular stressors.  Senescent cells secrete factors collectively referred to as the Senescence Associated Secretory Phenotype (SASP) that are proinflammatory and degradative in the local tissue environment. With aging, senescent cells accumulate in multiple tissues, and senolytic therapies are being developed to address age-related diseases. We conducted a clinical study to evaluate the relationship between the accumulation of senescent cells in OA knee synovial tissue and SASP/OA biomarkers, OA severity, and knee pain.

Methods: Methods:  This was a non-drug, cross-sectional, single-center study of 30 patients with symptomatic, radiographic, femoro-tibial knee OA (defined by a modified version of the American College of Rheumatology Criteria) for ≥6 months. Synovial biopsies were obtained arthroscopically and analyzed for the presence of p16Ink4A positive cells by immunohistochemistry. Blood, urine, and synovial fluid were collected for measurement of candidate biomarkers. Fixed-flexion, standing radiographs of the knees and gadolinium contrast-enhanced (CE)-MRI scans were performed and analyzed respectively for Kellgren-Lawrence (KL) grade and 11-point semiquantitative synovitis score.  Patients completed the Knee Injury and Osteoarthritis Outcome Score (KOOS) Survey, from which were derived WOMAC pain subscale scores.  Correlation analyses of senescence burden (i.e. percent of p16Ink4A positive synoviocytes) to candidate biomarkers in synovial fluid, plasma, serum and urine, and to MRI-based synovitis scores, KL grades, WOMAC pain scores, were done. Partial correlation coefficients after adjustment for age, BMI, and KL grade were determined.

Results: Results:  The study cohort had a mean age of 59 yrs, 47% were women, 77% white, and 93% had a KL grade of 2 or higher.  Consistent with findings in ex vivo studies of human OA knee specimens and a surgically-induced OA model in mice, we detected p16Ink4A positive, senescent cells in synovial biopsies from OA patients.  Moreover, the percent of p16Ink4A positive synoviocytes correlated significantly with a number of protein biomarkers in synovial fluid and plasma; the most strongly correlated was synovial fluid interleukin-6 (IL-6). Senescent synoviocytes also correlated significantly with the degree of synovitis (range 0-2) at the site of biopsy as assessed by the MRI-based synovitis score.  A trend for the correlation between senescent synoviocytes and KL grade 1 to 4 was observed; when restricting to patients with KL grades 1 to 3, the correlation was statistically significant.  Interestingly, the percent of senescent synoviocytes was also moderately correlated with pain as measured by the WOMAC-A pain subscale.

Conclusion: Conclusion:  This cross-sectional study provides further evidence for a relationship between the accumulation of senescent cells in the OA joint, SASP secretion, pain symptoms, and structural changes of knee OA.  It supports investigation of senolytics as a therapy for OA.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/senescent-synoviocytes-in-knee-osteoarthritis-correlate-with-disease-biomarkers-synovitis-and-knee-pain/