Mitochondrial Biogenesis Is Impaired in Osteoarthritis Chondrocytes but Reversible via Peroxisome Proliferator–Activated Receptor γ Coactivator 1α

Abstract

Objective The etiology of chondrocyte mitochondrial dysfunction in OA is incompletely understood. OA chondrocytes are deficient in active AMPK-activated protein kinase (AMPK) and sirtuin 1 (SIRT1), metabolic biosensors that modulate the mitochondrial biogenesis “master regulator” peroxisome proliferator-activated receptor-γ coactivator (PGC)-1α. Moreover, PGC-1α critically mediates AMPK anti-catabolic activity in chondrocytes. Here, we tested the hypotheses that mitochondrial biogenesis is deficient in human OA chondrocytes, which functionally increases chondrocyte pro-catabolic responses, but is reversed by activation of the AMPK-SIRT1-PGC-1α pathway. Methods We studied human knee chondrocytes, human and mouse knee cartilages. We examined expression and activity (phosphorylation) of AMPKα, and SIRT1 and PGC-1α, and defined and compared mitochondrial content and functions including oxidative phosphorylation (OXPHOS) with expression of mitochondrial biogenesis factors (mitochondrial transcriptional factor A (TFAM), nuclear respiratory factors (NRFs)). Results Human knee OA chondrocytes had decreased mitochondrial biogenesis capacity, linked to reduced AMPKα activity and decreased SIRT1, PGC-1α, TFAM, and NRF1,2 expression. Human knee OA and aged mouse knee cartilages had decreased TFAM and ubiquinol-cytochrome c reductase core protein I (UQCEC1), a subunit of mitochondrial complex III, in situ. Functionally, chondrocyte TFAM knockdown inhibited mitochondrial biogenesis and enhanced pro-catabolic responses to IL-1β. Last, pharmacologic AMPK activation by A-769662 increased PGC-1α via SIRT1, and reversed impairments in mitochondrial biogenesis, OXPHOS, and intracellular ATP in human knee OA chondrocytes. Conclusions Mitochondrial biogenesis is deficient in human OA chondrocytes and this promotes chondrocyte pro-catabolic responses. Activation of the AMPK-SIRT1-PGC-1α pathway reverses these effects, mediated by TFAM, suggesting translational potential to limit OA progression.

Mitochondrial DNA haplogroups influence the risk of incident knee osteoarthritis in OAI and CHECK cohorts. A meta-analysis and functional study

“…Thus, the pathogenesis of OA is still unclear; however, it is widely accepted that genetics plays a main role in the prevalence and progression of this disease;4 even prediction tools for knee OA based on genetic and clinical information have been developed 5 6. Besides, during the last years, increasing evidence points to the implication of the mitochondria and the mitochondrial DNA (mtDNA) haplogroups in the pathogenesis of the disease 2 7 8…”

Comparative Analysis of Efficacy and Safety of Diacerein Versus S-Adenosyl Methionine in the Management of Osteoarthritis of Knee Joint

“…Although OA was previously thought to be a progressive, degenerative disorder, recent evidence has resulted in ambiguity concerning the pathogenesis and natural history of OA. It is now known that spontaneous arrest or reversal of the disease can occur [6]. The main objectives in the management of OA are to reduce symptoms, minimise functional disability, limit the progression of structural changes and ultimately delay the need for surgery.…”

Puerarin Attenuates Osteoarthritis via Upregulating AMP-Activated Protein Kinase/Proliferator-Activated Receptor-γ Coactivator-1 Signaling Pathway in Osteoarthritis Rats

“…This mitochondrial dysfunction may affect several pathways that have been implicated in cartilage degradation, including oxidative stress, defective chondrocyte biosynthesis and growth responses, increased cytokine-induced chondrocyte inflammation and matrix catabolism, cartilage matrix calcification, and increased chondrocyte apoptosis [7]. Human knee osteoarthritis chondrocytes had a decreased mitochondrial biogenesis capacity [13]. Mitochondria derive from dual genetic origin, the nuclear and mtDNA, so that biosynthesis from both genomes has to be coordinated.…”

“…It has been described that mitochondrial biogenesis was impaired in osteoarthritis chondrocytes [13], while puerarin could restore mitochondrial function [18]. As puerarin protected rats from cartilage damages and osteoarthritis, we continued to investigate the effect of puerarin on mitochondrial biogenesis in osteoarthritis rats.…”

“…The activation of AMPK-SITR1-PGC-1α has been shown to limit osteoarthritis progression [13]. Puerarin (C 21 H 20 O 9 ) is an isoflavone glycoside that is extracted from the root of the wild leguminous creeper Pueraria lobata and has been widely used to treat myocardial infarction, cerebral ischemia, cancer, and osteoporosis, and diabetic nephropathy in China [14].…”