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Ageing related deficiency of miR-708-5p in osteoarthritic cartilage lesions [miRNA]

ABSTRACT: Aging is a major risk factors for osteoarthritis (OA), and cartilage of the elder are more sensitive to mechanical loading stress. Recently, cartilage progenitor cells (CPCs) arose much interests due to its important role in maintaining cartilage homeostasis. However, the potential mechanism of increased sensitivity to mechanical stress in CPCs has not been elucidated. The aim of this study was to investigate the potential links between aging and age-related OA through establish CPCs replicative senescence model and fluid flow shear stress (FFSS) stimulated degeneration model. Small RNA and mRNA sequence were conducted to investigate miRNA-related mechanisms in this process. By gain-and-lost strategy we investigated the age-related miRNAs and their impacts on exacerbating the progression of biomechanical stimulated TMJ-OA. miR-708-5p was identified as age-related miRNA in CPCs, and TLR4 was identified as its direct target through luciferase report assay. Age-related miR-708-5p deficiency increased sensitivity of CPCs for exposure to FFSS by liberating TLR4 expression. Intra-articular delivery agomiR-708-5p alleviated TMJ osteoarthritic cartilage lesions in mice. In conclusion, age-related miR-708-5p deficiency increases the sensitivity to mechanical loading stress and promotes CPCs senescence like degeneration via TLR4.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE236978 | GEO | 2023/07/11

REPOSITORIES: GEO

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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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Ageing related deficiency of miR-708-5p in osteoarthritic cartilage lesions [miRNA]

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