Carbonic anhydrase 2 is important for articular chondrocyte function and metabolic homeostasis.

Autor: Yan M; Department of Orthopaedic Surgery, Washington University School of Medicine, St. Louis, MO, USA; Department of Orthopaedic Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan, PR China., Cai L; Department of Orthopaedic Surgery, Washington University School of Medicine, St. Louis, MO, USA., Duan X; Department of Orthopaedic Surgery, Washington University School of Medicine, St. Louis, MO, USA; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA., Tycksen ED; Genome Technology Access Center, McDonell Genome Institute, Washington University School of Medicine, St. Louis, MO, USA., Rai MF; Department of Biological Sciences, College of Medicine and Health Sciences, Khalifa University, Abu Dhabi, United Arab Emirates; Center for Biotechnology, Khalifa University, Abu Dhabi, United Arab Emirates; Division of Rheumatology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA; Department of Biomedical Engineering, Saint Louis University School of Science and Engineering, St. Louis, MO, USA. Electronic address: muhammad.rai@ku.ac.ae.
Jazyk: angličtina
Zdroj: Bone [Bone] 2024 Oct 31; Vol. 190, pp. 117313. Date of Electronic Publication: 2024 Oct 31.
DOI: 10.1016/j.bone.2024.117313
Abstrakt: Objectives: Aberrant chondrocyte metabolism significantly contributes to cartilage degeneration and osteoarthritis (OA) genesis. However, the mechanisms driving the metabolic shift in OA chondrocytes remain unclear. Interestingly, carbonic anhydrase 2 (CA2) is implicated in metabolic regulation, and its expression dramatically increases in OA chondrocytes, but its exact role and mechanism are poorly understood. This study investigates the mechanistic role of CA2 in chondrocyte metabolic homeostasis under hypoxic and inflammatory conditions.
Methods: RNA-seq was performed on CA2-deficient C28/I2 cells to identify pathways affected by the loss of CA2 function. We examined CA2's impact on chondrocyte metabolism, anabolism, and catabolism using C28/I2 cells and primary chondrocytes under normoxia and hypoxia and in a model of inflammatory OA.
Results: RNA-seq revealed enrichment of glycolysis, apoptosis, and TNF signaling pathways in CA2-deficient cells. Under hypoxia, CA2 expression increased 10-fold in a HIF-1α-independent manner. Knockdown of CA2 reduced extracellular lactate production, increased ADP/ATP ratio, impaired glycolysis, reduced glycolytic capacity, and lowered expression of glycolysis rate-limiting enzymes but did not disrupt pH i and ROS production. CA2 deficiency altered chondrocyte anabolic and catabolic equilibrium by affecting PI3K/AKT and RELA/p65 signaling. CA2-deficient chondrocytes displayed impeded migration, suppressed proliferation, and cell cycle arrest at the G0/G1 phase. Forced expression of CA2 stabilized chondrocyte metabolism and restored cellular functions.
Conclusions: Our research uncovered a hitherto unknown mechanistic role for CA2 in regulating chondrocyte energy metabolism and inflammation, underscoring its potential as a critical mediator in OA pathogenesis. Further research using a murine model of experimental OA is warranted to capture the functional implications of CA2.
Competing Interests: Declaration of competing interest All authors declare that they have no known financial conflicts of interest or personal relationships that could have influenced the work reported in this article.
(Copyright © 2024 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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