0869: Clinical Impact of PTEN as a Marker for Diabetes-Associated Osteoarthritis

Irene Lorenzo Gomez¹, Uxía nogueira Recalde², Christian García Domínguez¹, Natividad Oreiro Villar³, Jose Antonio Pinto Tasende³, Mohit Kapoor⁴, Francisco J. Blanco³ and Beatriz Carames¹, ¹Unidad de Biología del Cartílago, Grupo de Reumatología, Instituto de Investigación Biomédica de A Coruña (iNIBIC), A Coruña, Spain, ²Unidad de Biología del Cartílago, Grupo de Reumatología, Instituto de Investigación Biomedica de A Coruña (iNIBIC), A Coruña, Spain, ³Rheumatology department, Complexo Hospitalario Universitario A Coruña (CHUAC). Instituto de Investigación Biomédica A Coruña (INIBIC), A Coruña, Spain, ⁴Division of Orthopaedics, Osteoarthritis Research Program, Schroeder Arthritis Institute, and Krembil Research Institute, University Health Network, Toronto, ON, Canada

Background/Purpose: Defects in homeostatic mechanisms, such as autophagy, contribute to joint aging and Osteoarthritis (OA) and precede joint damage (1). OA is a complex and multifactorial disease where systemic metabolic status plays a key role. Hence, patients with Type 2 Diabetes (T2D) present more prevalent and severe OA, so it has been recognized as an independent clinical phenotype of OA. However, mechanisms underlying this comorbidity are poorly understood. Previous results from our group showed that diabetic conditions compromise autophagy in chondrocytes, and this facilitates OA development and progression, suggesting that impaired autophagy can be one of the mechanisms involved in OA-T2D interaction (2). Moreover, pharmacological activation of autophagy was sufficient to protect against diabetes-induced joint destruction (3). These observations support studies exploring autophagy markers at systemic and tissue levels to identify key mechanisms of OA-T2D interactions.

Methods: To address this objective a comparative analysis of 35 autophagy genes was performed using an autophagy expression gene array from blood of non-OA subjects (n=18) and Knee OA subjects (n=18, OA grade III-IV) from the Prospective Cohort of OA of A Coruñ a (PROCOAC) and then validated in a second set of subjects (Non-OA and Knee-OA subjects (n=30) by qPCR. Differentially regulated candidate genes were analyzed by qPCR in blood from Knee OA-T2D subjects (n=30, OA grade III-IV) and cartilage from Knee OA and OA-T2D subjects (n=12, OA grade III-IV). Contribution of candidate marker to chondrocyte homeostasis was explored by using a model of diabetes exposing human chondrocytes to high glucose and insulin (3).

Results: The gene expression array and the validation studies confirmed a significant downregulation of PTEN, HSP90AA1 and MAP1LC3B in blood from knee OA subjects compared to non-OA subjects. Then, these candidate genes were analyzed in a subgroup of subjects from the PROCOAC cohort with knee OA-T2D. The results confirmed a significant down-regulation of HSP90AA1 in knee OA-T2D subjects (p< 0.01) and no significant differences were found for MAP1LC3B (4). Interestingly, PTEN, a potent tumor suppressor gene that inhibits the PI3K/Akt signaling pathway and governs basic celular metabolic processes, was significantly upregulated in blood and cartilage from subjects with knee OA-T2D compared to knee OA subjects (p < 0.01). In addition, the regression analysis showed that upregulation of PTEN is associated with a risk incidence for knee OA-T2D. Preliminary data from in vitro model of diabetes in human chondrocytes reveals that PTEN is increased upon high glucose and insulin exposure. Moreover, this increase was correlated with defective autophagy flux and increased chondrocyte senescence.

Conclusion: These results suggest that PTEN is a promising candidate marker for Knee OA-T2D subjects. Further studies of this homeostasis mechanism in OA associated to diabetes might elucidate its relevance in the progression of disease.
1. Caramés et al. doi: 10.1002/art.39073. 2. Ribeiro et al. doi: 10.1016/j.joca.2015.10.017. 3. Ribeiro et al.. doi: 10.1016/j.joca.2016.06.019. 4. Lorenzo-Gómez et al. doi: 10.1016/j.joca.2023.02.076


I. Lorenzo Gomez: None; U. nogueira Recalde: None; C. García Domínguez: None; N. Oreiro Villar: None; J. Pinto Tasende: None; M. Kapoor: None; F. Blanco: None; B. Carames: None.