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Mitochondrial DNA impact on joint damaged process in a conplastic mouse model after being surgically induced with osteoarthritis.

ABSTRACT: It has been suggested that mitochondrial dysfunction and mtDNA variations may contribute to osteoarthritis (OA) pathogenesis. However, the causative link to support this claim is lacking. Here, we surgically-induced OA in conplastic mice in order to evaluate the functional consequences of mtDNA haplotypes in their joint degeneration. BL/6^NZB strain was developed with C57BL/6JOlaHsd nuclear genome and NZB/OlaHsdmtDNA while BL/6^C57, which is the original, was developed with C57BL/6JOlaHsd nuclear genome and C57/OlaHsdmtDNA for comparison. The surgical DMM OA model was induced in both strains. Their knees were processed and examined for histopathological changes. Cartilage expression of markers of autophagy, apoptosis, oxidative stress and senescence were also analyzed by immunohistochemistry. The joints of BL/6^NZB mice that were operated presented more cellularity together with a reduced OARSI histopathology score, subchondral bone, menisci score and synovitis compared to those of BL/6^C57 mice. This was accompanied with higher autophagy and a lower apoptosis in the cartilage of BL/6^NZB mice that were operated. Therefore, the study demonstrates the functional impact of non-pathological variants of mtDNA on OA process using a surgically-induced OA model. Conplastic (BL/6^NZB ) mice develop less severe OA compared to the BL/6^C57original strain. These findings demonstrate that mitochondria and mtDNA are critical targets for potential novel therapeutic approaches to treat osteoarthritis.

SUBMITTER: Scotece M

PROVIDER: S-EPMC8079696 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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Mitochondrial DNA impact on joint damaged process in a conplastic mouse model after being surgically induced with osteoarthritis.

Scotece Morena M Rego-Pérez Ignacio I Lechuga-Vieco Ana Victoria AV Cortés Alberto Centeno AC Jiménez-Gómez María Concepción MC Filgueira-Fernández Purificación P Vaamonde-García Carlos C Enríquez José Antonio JA Blanco Francisco J FJ

Scientific reports 20210427 1

It has been suggested that mitochondrial dysfunction and mtDNA variations may contribute to osteoarthritis (OA) pathogenesis. However, the causative link to support this claim is lacking. Here, we surgically-induced OA in conplastic mice in order to evaluate the functional consequences of mtDNA haplotypes in their joint degeneration. BL/6<sup>NZB</sup> strain was developed with C57BL/6JOlaHsd nuclear genome and NZB/OlaHsdmtDNA while BL/6<sup>C57</sup>, which is the original, was developed with C ...[more]

PMID: 33907208

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Project description:ObjectiveThe prevalence of osteoarthritis (OA) varies between joints. Cartilage in eight different joints was evaluated to elucidate the disparate susceptibilities between joints to post-traumatic OA (PTOA) and provide evidence for joint-specific clinical treatments. The hypothesis was that cartilage in different joints would have varying cell death and anabolic gene expression profiles after injury.MethodsAdult equine cartilage explants were harvested from shoulder (SH), elbow (EL), carpal (CA), metacarpophalangeal (MC), patellofemoral (FP), tarsal (TA), metatarsophalangeal (MT), and proximal interphalangeal (PP) joints, and injured by loading with 30 MPa within 1 s. Fractional dissipated energy, cell density, cell death, and gene expression were quantified.ResultsPP had the highest fractional dissipated energy (94%, 95% confidence interval [CI] 88 to 101%). Cell density was highest in the superficial zone in all samples, with MC and MT having the highest peak density. Injured samples had significantly increased cell death (13.5%, 95% CI 9.1 to 17.9%) than non-injured samples (6.8%, 95% CI 2.5 to 11.1%, P = 0.016); however, cell death after injury was not significantly different between joints. Gene expression was significantly different between joints. CD-RAP expression in normal cartilage was lowest in FP (Cp = 21, 95% CI -80 to 122). After injury, the change in CD-RAP expression increased and was highest in FP (147% relative increase after injury, 95% CI 64 to 213).ConclusionDifferent joints have different baseline characteristics, including cell density and gene expression, and responses to injury, including energy dissipation and gene expression. These unique characteristics may explain differences in OA prevalence and suggest differences in susceptibility to PTOA.Clinical relevanceUnderstanding differences in the response to injury and potential susceptibility to OA can lead to the development of preventative or treatment strategies.Key termsGene expression, cartilage injury, chondrocyte, multiphoton microscopy, cartilage biomechanical properties, PTOA.What is known about the subjectThe prevalence of OA is variable among joints; however, most laboratory studies are performed on a single joint - most commonly the knee, and extrapolated to other joints such as the ankle or shoulder. A small number of studies have compared knee and ankle cartilage and reported differences in mechanical properties and gene expression.What this study adds to existing knowledgeThere are differences in baseline cell density and gene expression, and differences in response to injury, including gene expression and cell death. This suggests that there are inherent differences leading to varying susceptibilities in OA prevalence among joints. Joint-specific treatments may improve OA therapies.

Dataset Information

Mitochondrial DNA impact on joint damaged process in a conplastic mouse model after being surgically induced with osteoarthritis.

Publications

Mitochondrial DNA impact on joint damaged process in a conplastic mouse model after being surgically induced with osteoarthritis.

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