Abstract
Mitochondrial mutations and dysfunction have been demonstrated in several age-related disorders including osteoarthritis, yet its relative contribution to pathogenesis remains unknown. Here we evaluated whether premature aging caused by accumulation of mitochondrial DNA mutations in PolgD275A mice predisposes to the development of knee osteoarthritis. Compared with wild type animals, homozygous PolgD275A mice displayed a specific bone phenotype characterized by osteopenia of epiphyseal trabecular bone and subchondral cortical plate. Trabecular thickness was significantly associated with osteocyte apoptosis rates and osteoclasts numbers were increased in subchondral bone tissues. While chondrocyte apoptosis rates in articular and growth plate cartilage were similar between groups, homozygous mitochondrial DNA mutator mice displayed elevated numbers of hypertrophic chondrocytes in articular calcified cartilage. Low grade cartilage degeneration, predominantly loss of proteoglycans, was present in all genotypes and the development of osteoarthritis features was not found accelerated in premature aging. Somatically acquired mitochondrial DNA mutations predispose to elevated subchondral bone turnover and hypertrophy in calcified cartilage, yet additional mechanical or metabolic stimuli would seem required for induction and accelerated progression of aging-associated osteoarthritis.
Highlights
Mitochondrial dysfunction and DNA mutations in articular chondrocytes has gained increasing interest as a pathophysiological mechanism underpinning development of aging-associated osteoarthritis (OA)[1,2,3,4]
This descriptive analysis using a convenience sample of Mitochondrial dysfunction and DNA (mtDNA) mutator mice, characterized by a premature aging phenotype, suggest that accumulation of mtDNA mutations in joint tissues in vivo may predispose to osteopenia of subchondral bone and chondrocyte hypertrophy, but not accelerated development of osteoarthritis
While both mitochondrial dysfunction and accumulation of mtDNA mutations have been associated with increased cellular apoptosis in culture-expanded chondrocytes[1,2,3], the impact of both features might be different in vivo
Summary
Mitochondrial dysfunction and DNA (mtDNA) mutations in articular chondrocytes has gained increasing interest as a pathophysiological mechanism underpinning development of aging-associated osteoarthritis (OA)[1,2,3,4]. Mice with defective DNA damage repair did not show accelerated OA development during premature ageing, despite elevated turnover of subchondral bone tissues[8]. But not ROS production, between the age of 3 and 6 months in tissues with rapid cellular turnover has been identified as the pivotal mechanism underpinning the premature aging phenotype. We assessed degeneration of subchondral bone and articular cartilage tissues in knee joints of prematurely aging homozygous PolgD275A mtDNA mutator mice in comparison with heterozygous mutants and wild type littermates
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