Background/Purpose: Changes in chondrocyte phenotype and energy metabolism occur in osteoarthritis (OA). The prevalence of OA is higher in females compared to males however whether there are sex differences in OA chondrocytes is unknown. The purpose of this study was to compare phenotype and energy metabolism in OA chondrocytes from male and female patients.

Methods: OA chondrocytes were isolated from male and female patients undergoing knee arthroplasty for end-stage primary OA (Kellgren-Lawrence Grade 4). Phenotype was determined by polymerase chain reaction, western blot and enzyme-linked immunoassays. Energy metabolism was determined by measuring glucose/fat consumption, lactate production, oxygen consumption rate and extracellular acidification rate.

Results: Protein levels of SOX9, a transcriptional regulator of COL2A1 and ACAN as well as a promoter of glycolysis, were higher in OA chondrocytes from male compared to female patients (Figure 1). OA chondrocytes from males secreted higher amounts of type II collagen, had higher protein levels of the GLUT1 glucose transporter, higher glucose consumption, higher lactate production and higher glycolytic rate than OA chondrocytes from females. Knockdown of SOX9 reduced expression of ACAN and the glycolytic gene PGK1, in chondrocytes from male but not female patients. SOX9 knockdown reduced COL2A1 expression in chondrocytes from both males and females, however the magnitude of effect was greater for males. OA chondrocytes from female patients consumed higher amounts of fat and had a higher oxygen consumption rate than OA chondrocytes from males indicating greater usage of oxidative energy metabolism.PGC1α protein levels (which promotes mitochondrial oxidative energy metabolism and potentiates SOX9-mediated collagen synthesis) were also higher in OA chondrocytes from females (Figure 1). Knockdown of PGC1α reduced COL2A1 expression in OA chondrocytes from female but not male patients.

Conclusion: SOX9 and PGC1α are differentially expressed in OA chondrocytes from male compared to female patients resulting in differences in energy metabolism pathway usage and the transcriptional control of COL2A1. OA chondrocytes from male patients synthesise higher amounts of type II collagen compared to OA chondrocytes from females. This may render females more susceptible to rapid cartilage loss in OA. Differences in chondrocyte biology between male and female patients raise the possibility that the mechanisms involved in OA development may also differ between the two highlighting the importance of considering gender and sex when studying OA pathogenesis and evaluating the efficacy of candidate OA treatments.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/phenotype-and-energy-metabolism-differ-between-osteoarthritic-chondrocytes-from-male-compared-to-female-patients/