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LOXL2 protects temporomandibular joint from mitochondrial dysfunction, apoptosis and osteoarthritis like progression

ABSTRACT: Temporomandibular joint (TMJ) osteoarthritis (OA) affects a significant population, and there are no FDA-approved drugs for its treatment. Our previous studies showed that lysyl oxidase-like-2 (LOXL2) has anabolic effects on cartilage; however, whether LOXL2 plays a role in relieving TMJ-OA remains unknown. The goal of this study was to comprehensively investigate LOXL2 mechanism in TMJ protection, with an emphasis on transcriptomic network analysis, mitochondria, and apoptosis during TMJ-OA. We showed that the TMJ is transcriptionally unique compared to the knee, with elevated Loxl2 expression and cartilage-degenerative genes, potentially indicating its different mechanisms of action. Aggrecan promoter-specific homozygous deletion of Loxl2 in mice resulted in a cartilage-degeneration phenotype, mitochondrial dysfunction, NF-κβ-mediated chondrocyte apoptosis, and inflammatory immune response leading to TMJ-OA-like conditions. IL-1β is known to induce osteoarthritis via NF-κβ. With regard to translation, adenoviral-Loxl2 transduction in ex-vivo goat cartilage reduced the IL-1β-mediated degenerative effects. Importantly, LOXL2 preserved IL-1β–induced mitochondrial dysfunction, p62-mediated mitophagy, apoptosis, and extracellular matrix degeneration. Overall, we identified the protective role of LOXL2 during natural TMJ-OA-like progression and established LOXL2 as a potential candidate gene therapy candidate for future therapeutics.

ORGANISM(S): Mus musculus

PROVIDER: GSE276978 | GEO | 2026/02/11

REPOSITORIES: GEO

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	GSE276978_LOXL2_TMJ_Count.txt.gz	Txt

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Project description:Osteoarthritis (OA) is an age-related degenerative musculoskeletal disease characterised by loss of articular cartilage, synovitis, abnormal bone proliferation and subchondral bone sclerosis. The underlying pathogenesis of OA is yet to be fully elucidated with no OA specific biomarkers in clinical use. Nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry (MS) allow identification of the global metabolome and proteome respectively. During this study, ex-vivo equine cartilage explants (n=5) were incubated in TNF-α/IL-1β supplemented culture media for 8 days, with media removed and replaced at 2, 5 and 8 days. Acetonitrile metabolite extractions of 8 day cartilage explants and media samples at all time points underwent 1H NMR metabolic analysis with media samples also undergoing MS proteomic analysis. Within the cartilage, metabolites glucose and lysine were elevated following TNF-α/IL-1β treatment whilst adenosine, alanine, betaine, creatine, myo-inositol and uridine levels decreased. Within the culture media, four, four and six metabolites were identified as being differentially abundant between control and treatment groups for 1-2 day, 3-5 day and 6-8 day time points respectively. Culture media proteomics identified 154, 138 and 72 proteins differentially abundant, with > 2 fold change, between control and treatment groups for 1-2 day, 3-5 day and 6-8 day time points respectively. Nine potential novel OA neopeptides were elevated in treated media. This is the first study to use a multi ‘omics’ approach to simultaneously investigate the metabolomic profile of ex-vivo cartilage and metabolomic/proteomic profiles of culture media using the TNF-α/IL-1β ex-vivo OA cartilage model. This study has identified a panel of metabolites, proteins and extracellular matrix derived neopeptides which are differentially abundant during an early phase of the OA model which may provide further information on underlying disease pathogenesis, allow potential translation for clinical markers and possible novel therapeutic targets.

Project description:Background Extracellular matrix (ECM) protein malfunction or defect may lead to temporomandibular joint osteoarthritis (TMJ OA). Dentin sialophophoprotein (DSPP) is a mandibular condylar cartilage ECM protein, and its deletion impacted cell proliferation and other extracellular matrix alterations of postnatal condylar cartilage. However, it remains unclear if long-term loss of function of DSPP leads to TMJ OA. The study aimed to test the hypothesis that long-term haploinsufficiency of DSPP causes TMJ OA. Materials and Methods To determine whether Dspp+/- mice exhibit TMJ OA but no severe tooth defects, mandibles of wild-type (WT), Dspp+/-, and Dspp homozygous (Dspp-/-) mice were analyzed by Micro-computed tomography (micro-CT). To characterize the progression and possible mechanisms of osteoarthritic degeneration over time in Dspp+/- mice over time, condyles of Dspp+/- and WT mice were analyzed radiologically, histologically, and immunohistochemically. Results Micro-CT and histomorphometric analyses revealed that Dspp+/- and Dspp-/- mice had significantly lower subchondral bone mass, bone volume fraction, bone mineral density, and trabecular thickness compared to WT mice at 12 months. Interestingly, in contrast to Dspp-/- mice which exhibited tooth loss, Dspp+/- mice had minor tooth defects. RNA sequencing data showed that haplodeficency of DSPP affects the biological process of ossification and osteoclast differentiation. Additionally, histological analysis showed that Dspp+/- mice had condylar cartilage fissures, reduced cartilage thickness, decreased articular cell numbers and severe subchondral bone cavities, and with signs that were exaggerated with age. Radiographic data showed an increase in subchondral osteoporosis up to 18 months and osteophyte formation at 21 months. Moreover, Dspp+/- mice showed increased distribution of osteoclast in the subchondal bone and increased expression of MMP2, IL-6, FN-1, and TLR4 in the mandibular condylar cartilage. Conclusions Dspp+/- mice exhibit TMJ OA in a time-dependent manner, with lesions in the mandibular condyle attributed to hypomineralization of subchondral bone and breakdown of the mandibular condylar cartilage, accompanied by upregulation of inflammatory markers.

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LOXL2 protects temporomandibular joint from mitochondrial dysfunction, apoptosis and osteoarthritis like progression

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