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Mitochondrial biogenesis is impaired in osteoarthritis chondrocytes but reversible via peroxisome proliferator-activated receptor γ coactivator 1α.
Arthritis Rheumatol 2015; 67(8):2141-53AR

Abstract

OBJECTIVE

The etiology of chondrocyte mitochondrial dysfunction in osteoarthritis (OA) is not completely understood. OA chondrocytes are deficient in the metabolic biosensors active AMP-activated protein kinase (AMPK) and sirtuin 1 (SIRT-1), which modulate the mitochondrial biogenesis "master regulator" peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α). Moreover, PGC-1α critically mediates AMPK anticatabolic activity in chondrocytes. The aim of this study was to test the hypothesis that mitochondrial biogenesis is deficient in human OA chondrocytes and that this deficiency functionally increases chondrocyte procatabolic responses, which are reversed by activation of the AMPK/SIRT-1/PGC-1α pathway.

METHODS

We assessed the expression and activity (phosphorylation) of AMPKα, SIRT-1, and PGC-1α in human knee chondrocytes and human and mouse knee cartilage, and we defined and compared the content and function of mitochondria, including oxidative phosphorylation and expression of mitochondrial biogenesis factors (mitochondrial transcriptional factor A [TFAM] and nuclear respiratory factors [NRFs]).

RESULTS

Human knee OA chondrocytes had a decreased mitochondrial biogenesis capacity, which was linked to reduced AMPKα activity and decreased expression of SIRT-1, PGC-1α, TFAM, NRF-1, and NRF-2. Human knee OA and aging mouse knee cartilage had decreased expression of TFAM and ubiquinol-cytochrome c reductase core protein, a subunit of mitochondrial complex III, in situ. Chondrocyte TFAM knockdown inhibited mitochondrial biogenesis and enhanced procatabolic responses to interleukin-1β. Finally, activation of AMPK by A-769662 increased PGC-1α expression via SIRT-1 and reversed impairments in mitochondrial biogenesis, oxidative phosphorylation, and intracellular ATP in human knee OA chondrocytes.

CONCLUSION

Mitochondrial biogenesis is deficient in human OA chondrocytes, and this deficiency promotes chondrocyte procatabolic responses. TFAM-mediated activation of the AMPK/SIRT-1/PGC-1α pathway reverses these effects, suggesting translational potential of pharmacologic AMPK activators to limit OA progression.

Authors+Show Affiliations

University of California at San Diego, La Jolla.VA San Diego Healthcare System, San Diego, California.The Scripps Research Institute, La Jolla, California.University of California at San Diego, La Jolla, and VA San Diego Healthcare System, San Diego, California.University of California at San Diego, La Jolla, and VA San Diego Healthcare System, San Diego, California.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

Language

eng

PubMed ID

25940958

Citation

Wang, Yun, et al. "Mitochondrial Biogenesis Is Impaired in Osteoarthritis Chondrocytes but Reversible Via Peroxisome Proliferator-activated Receptor Γ Coactivator 1α." Arthritis & Rheumatology (Hoboken, N.J.), vol. 67, no. 8, 2015, pp. 2141-53.
Wang Y, Zhao X, Lotz M, et al. Mitochondrial biogenesis is impaired in osteoarthritis chondrocytes but reversible via peroxisome proliferator-activated receptor γ coactivator 1α. Arthritis & rheumatology (Hoboken, N.J.). 2015;67(8):2141-53.
Wang, Y., Zhao, X., Lotz, M., Terkeltaub, R., & Liu-Bryan, R. (2015). Mitochondrial biogenesis is impaired in osteoarthritis chondrocytes but reversible via peroxisome proliferator-activated receptor γ coactivator 1α. Arthritis & Rheumatology (Hoboken, N.J.), 67(8), pp. 2141-53. doi:10.1002/art.39182.
Wang Y, et al. Mitochondrial Biogenesis Is Impaired in Osteoarthritis Chondrocytes but Reversible Via Peroxisome Proliferator-activated Receptor Γ Coactivator 1α. Arthritis & rheumatology (Hoboken, N.J.). 2015;67(8):2141-53. PubMed PMID: 25940958.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Mitochondrial biogenesis is impaired in osteoarthritis chondrocytes but reversible via peroxisome proliferator-activated receptor γ coactivator 1α. AU - Wang,Yun, AU - Zhao,Xianling, AU - Lotz,Martin, AU - Terkeltaub,Robert, AU - Liu-Bryan,Ru, PY - 2014/12/18/received PY - 2015/04/28/accepted PY - 2015/5/6/entrez PY - 2015/5/6/pubmed PY - 2015/10/16/medline SP - 2141 EP - 53 JF - Arthritis & rheumatology (Hoboken, N.J.) VL - 67 IS - 8 N2 - OBJECTIVE: The etiology of chondrocyte mitochondrial dysfunction in osteoarthritis (OA) is not completely understood. OA chondrocytes are deficient in the metabolic biosensors active AMP-activated protein kinase (AMPK) and sirtuin 1 (SIRT-1), which modulate the mitochondrial biogenesis "master regulator" peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α). Moreover, PGC-1α critically mediates AMPK anticatabolic activity in chondrocytes. The aim of this study was to test the hypothesis that mitochondrial biogenesis is deficient in human OA chondrocytes and that this deficiency functionally increases chondrocyte procatabolic responses, which are reversed by activation of the AMPK/SIRT-1/PGC-1α pathway. METHODS: We assessed the expression and activity (phosphorylation) of AMPKα, SIRT-1, and PGC-1α in human knee chondrocytes and human and mouse knee cartilage, and we defined and compared the content and function of mitochondria, including oxidative phosphorylation and expression of mitochondrial biogenesis factors (mitochondrial transcriptional factor A [TFAM] and nuclear respiratory factors [NRFs]). RESULTS: Human knee OA chondrocytes had a decreased mitochondrial biogenesis capacity, which was linked to reduced AMPKα activity and decreased expression of SIRT-1, PGC-1α, TFAM, NRF-1, and NRF-2. Human knee OA and aging mouse knee cartilage had decreased expression of TFAM and ubiquinol-cytochrome c reductase core protein, a subunit of mitochondrial complex III, in situ. Chondrocyte TFAM knockdown inhibited mitochondrial biogenesis and enhanced procatabolic responses to interleukin-1β. Finally, activation of AMPK by A-769662 increased PGC-1α expression via SIRT-1 and reversed impairments in mitochondrial biogenesis, oxidative phosphorylation, and intracellular ATP in human knee OA chondrocytes. CONCLUSION: Mitochondrial biogenesis is deficient in human OA chondrocytes, and this deficiency promotes chondrocyte procatabolic responses. TFAM-mediated activation of the AMPK/SIRT-1/PGC-1α pathway reverses these effects, suggesting translational potential of pharmacologic AMPK activators to limit OA progression. SN - 2326-5205 UR - https://www.unboundmedicine.com/medline/citation/25940958/Mitochondrial_biogenesis_is_impaired_in_osteoarthritis_chondrocytes_but_reversible_via_peroxisome_proliferator_activated_receptor_γ_coactivator_1α_ L2 - https://doi.org/10.1002/art.39182 DB - PRIME DP - Unbound Medicine ER -