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Abstract Number: 1013

Mitochondrial Function Is Impaired in Human Knee Osteoarthritic (OA) Chondrocytes and Improved By Pharmacologic AMPK Activation Via SIRT1 and PGC-1α

Ru Bryan1, Yun Wang2, Xianling Zhao3, Martin Lotz4 and Robert Terkeltaub5, 1Medicine-Rheumatology, VA Medical Center/University of California San Diego, San Diego, CA, 2Medicine-Rheumatology, VA Medical Ctr/UCSD, San Diego, CA, 3VAMC, San Diego, CA, 4Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA, 5Medicine-Rheumatology, VA Medical Ctr/University of California San Diego, San Diego, CA

Meeting: 2014 ACR/ARHP Annual Meeting

Keywords: chondrocytes and mitochondria, OA

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Session Information

Title: Biology and Pathology of Bone and Joint: Cartilage, Synovium and Osteoarthritis

Session Type: Abstract Submissions (ACR)

Background/Purpose

Chondrocyte mitochondrial abnormalities have been identified in OA, and have the potential to mediate disease progression by promoting oxidative stress and inflammation-driven cartilage matrix catabolism. AMPK (AMP-activated protein kinase) and the NAD+-dependent protein deacetylase SIRT1 are cellular energy bio-sensors recently implicated in cartilage tissue homeostasis. In chondrocytes, AMPK promotes expression of PGC-1α, a master regulator of mitochondrial biogenesis. SIRT1 also regulates PGC-1α through deacetylation, and AMPK can regulate SIRT1 activity. Hence, we tested the hypothesis that pharmacologic activation of AMPK improves mitochondrial function via SIRT1 and PGC-1α in human knee OA chondrocytes. 

Methods

We studied cultured human knee chondrocytes from both normal and OA donors (passage 1) with and without the selective AMPK pharmacological activator A-769662, or overexpression of SIRT1 or PGC-1α via transfection. Phosphorylation and expression of AMPKa, expression of SIRT1, PGC-1α, acetylation status of PGC-1a, expression of mitochondrial transcriptional factor A (TFAM, a direct regulator of mitochondrial DNA replication and transcription), nuclear respiratory factor 1 and 2 (NRF1 and NRF2, stimulating transcription of TFAM), and oxidative phosphorylation (OXPHOS) were examined by Western blot analyses. Mitochondrial DNA copy number was determined by the ratio of cytochrome C oxidase I or II (COX I or COX II, mitochondrial-encoded gene) and 18S rRNA (nuclear gene) by quantitative PCR. Mitochondrial mass was assessed by Mitotracker Green FM staining. Oxygen consumption and intracellular ATP were measured.

Results

In comparison with normal chondrocytes, human OA chondrocytes (grade III and IV) exhibited reduced oxygen consumption (P=0.03), decreased intracellular ATP level (P=0.019), and less mitochondrial biogenesis indicated by decreased mitochondrial DNA content (P=0.001) and mitochondrial mass, decreased expression of NRF1, NRF2 and TFAM, as well as decreased expression of respiratory complexes I, II and III. These differences were linked to reduced phosphorylation of AMPKα and expression of SIRT1 and PGC-1α, and increased acetylated PGC-1α in OA chondrocytes. Stimulation of human OA chondrocytes with A-769662 increased phosphorylation of AMPKα and expression of SIRT1 and PGC-1α, and decreased acetylation of PGC-1α. A-769662 also increased oxygen consumption (p=0.003), intracellular ATP level (p=0.015), and mitochondrial biogenesis. Overexpression of SIRT1 or PGC-1α in chondrocytes also induced increased mitochondrial biogenesis. 

Conclusion

Both mitochondrial oxidative phosphorylation and mitochondrial biogenesis are impaired in human knee OA chondrocytes. AMPK activation improved the observed impairments of mitochondria in OA chondrocytes, and did so via SIRT1 and PGC-1α.These findings provide a novel molecular mechanism by which pharmacologic activation of AMPK has translational potential to inhibit progression of cartilage degradation in OA via restoration of chondrocyte mitochondrial biogenesis and function.


Disclosure:

R. Bryan,
None;

Y. Wang,
None;

X. Zhao,
None;

M. Lotz,
None;

R. Terkeltaub,
None.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/mitochondrial-function-is-impaired-in-human-knee-osteoarthritic-oa-chondrocytes-and-improved-by-pharmacologic-ampk-activation-via-sirt1-and-pgc-1%ce%b1/

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