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 Polg D275A mice predisposes to the development of knee osteoarthritis. Compared with wild type animals, homozygous Polg D275A 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.Mitochondrial dysfunction and DNA (mtDNA) mutations in articular chondrocytes has gained increasing interest as a pathophysiological mechanism underpinning development of aging-associated osteoarthritis (OA) 1-4 . Mitochondrial dysfunction can be induced in chondrocytes by both mechanical 2 and inflammatory stimuli 3 and in turn promotes the production of reactive oxygen species (ROS) and the induction of apoptosis and cell death. Selective removal of damaged and dysfunctional mitochondria from OA chondrocytes under pathological conditions results in diminished ROS levels and inhibition of apoptosis 3 . Lower chondrocyte apoptosis rates in specific mtDNA haplotypes have been associated with a lower risk of incident knee OA in prospective cohort studies 1,5 . However, the evidence linking mtDNA mutations to OA susceptibility has been demonstrated in ex vivo studies only. While the accumulation of mtDNA mutations in vivo has been shown to affect musculoskeletal tissues and induce premature aging 6,7 , the joint phenotype has not been evaluated thus far. Mice with defective DNA damage repair did not show accelerated OA development during premature ageing, despite elevated turnover of subchondral bone tissues 8 .Mice carrying a homozygous homozygous proof-reading deficient version of the mtDNA polymerase gene Polg are characterized by a reduced life span, with a maximum survival of 15 months, and progeroid features such as sarcopenia and kyphosis that become apparent from the age of 9 months 6,7 . Increased apoptosis rates, but not

Facet joint osteoarthritis is a prominent feature of degenerative spine disorders, highly prevalent in ageing populations, and considered a major cause for chronic lower back pain. Since there is no targeted pharmacological therapy, clinical management of disease includes analgesic or surgical treatment. The specific cellular, molecular, and structural changes underpinning facet joint osteoarthritis remain largely elusive. The aim of this study was to determine osteoarthritis-related structural alterations in cortical and trabecular subchondral bone compartments. To this end, we conducted comparative micro computed tomography analysis in healthy (n = 15) and osteoarthritic (n = 22) lumbar facet joints. In osteoarthritic joints, subchondral cortical plate thickness and porosity were significantly reduced. The trabecular compartment displayed a 42 percent increase in bone volume fraction due to an increase in trabecular number, but not trabecular thickness. Bone structural alterations were associated with radiological osteoarthritis severity, mildly age-dependent but not gender-dependent. There was a lack of association between structural parameters of cortical and trabecular compartments in healthy and osteoarthritic specimens. The specific structural alterations suggest elevated subchondral bone resorption and turnover as a potential treatment target in facet joint osteoarthritis.

BackgroundAge is the most prominent risk factor for osteoarthritis and mitochondrial DNA dysfunction has been repeatedly described in human osteoarthritic chondrocytes. Mice expressing a proofreading-deficient mitochondrial DNA polymerase (POLG) mutant accumulate an excess of reactive oxygen species and apoptosis and develop a premature aging phenotype. While these mice display a reduction in bone density, it is unclear whether they are more prone to developing osteoarthritis.ObjectivesIn this study, we assessed the histomorphometric properties of subchondral bone and cartilage tissues in premature aging mice.MethodsMice carrying heterozygous (wt/mut n=5) or homozygous (mut/mut n=4) D257A mutations in POLG were compared with wildtype littermates (wt n=7). Animals were aged between eleven and fifteen months. Sagittal histological sections from knee joints were stained with Safranin-O/Fast Green and cartilage degeneration was assessed using OARSI scores. Subchondral bone area fraction (B.Ar/T.Ar) and osteoclast numbers (Oc.N/mm perimeter) between epiphyses and articular cartilage was determined on tissues stained for tartrate-resistant acid phosphatase (TRAP) and methylene blue using bone histomorphometric analyses.ResultsWild type mice revealed only low grade cartilage degeneration (OARSI score <1), predominantly loss of cartilage proteoglycans. OARSI scores were found to be equally low in wt/mut and mut/mut mice, showing no statistical differences between groups. Notably, subchondral bone area fraction was significantly decreased in mut/mut (0.20±0.1) compared with wt/mut (0.42±0.03) and wt (0.45±0.04) animals. Correspondingly, Oc.N per mm subchondral bone surface were strongly increased (p<0.05) between mut/mut (0.88±0.30) and wt/mut (0.25±0.03) and wt (0.12±0.04) mice.ConclusionsMice with premature aging due to accumulation of mtDNA mutations display increased bone remodelling favouring subchondral bone resorption. Additional biomechanical factors might be required in this premature aging phenotype for development of osteoarthritis.Disclosure of InterestNone declared