Dataset Information

Spontaneous Facet Joint Osteoarthritis in NFAT1-Mutant Mice: Age-Dependent Histopathologic Characteristics and Molecular Mechanisms.

ABSTRACT:

Background

Facet joint (FJ) osteoarthritis (FJOA) is a widely prevalent spinal disorder but its pathogenesis remains unclear, largely due to the difficulties in conducting longitudinal human studies and lack of spontaneous-FJOA animal models for mechanistic investigations. This study aimed to investigate whether spontaneous FJOA occurs in mice bearing mutant NFAT1 (nuclear factor of activated T cells 1) transcription factor.

Methods

The lumbar FJs of 50 NFAT1-mutant mice and of 50 wild-type control mice, of both sexes, were examined by histopathology, quantitative gene expression analysis, semiquantitative immunohistochemistry, and a novel FJOA scoring system for semiquantitative assessment of the histopathologic changes at 2, 6, 12, and 18 months of age. Age-dependent and tissue-specific histopathologic and gene or protein expression changes were analyzed statistically.

Results

FJs in NFAT1-mutant mice displayed significantly increased expression of specific catabolic genes (p < 0.05) and proteins (p < 0.001) in cartilage and synovium as early as 2 months of age, followed by early osteoarthritic structural changes such as articular surface fissuring and chondro-osteophyte formation at 6 months. More severe cartilage lesions, osteophytes, subchondral bone changes, synovitis, and tissue-specific molecular alterations in FJs of NFAT1-mutant mice were observed at 12 and 18 months. Osteoarthritic structural changes were not detected in FJs of wild-type mice at any ages, although age-related cartilage degeneration was observed at 18 months. The novel FJOA scoring system had high intraobserver and interobserver reproducibility (correlation coefficients: r > 0.97). Whole-joint FJOA scoring showed significantly higher OA scores in FJs of NFAT1-mutant mice compared with wild-type mice at all time points (p = 0.0033 at 2 months, p = 0.0001 at 6 months, p < 0.0001 at 12 and 18 months).

Conclusions

This study has identified the NFAT1-mutant mouse as a novel animal model of spontaneous FJOA with age-dependent and slowly progressing osteoarthritic features, developed the first FJOA scoring system, and elucidated the molecular mechanisms of NFAT1 mutation-induced FJOA.

Clinical relevance

This murine FJOA model resembles the features of human FJOA and may provide new insights into the pathogenesis of and therapeutic strategies for FJOA in humans.

SUBMITTER: Wang J

PROVIDER: S-EPMC9208959 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

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Publications

Spontaneous Facet Joint Osteoarthritis in NFAT1-Mutant Mice: Age-Dependent Histopathologic Characteristics and Molecular Mechanisms.

Wang Jinxi J Lu Qinghua Q Mackay Matthew J MJ Liu Xiangliang X Feng Yi Y Burton Douglas C DC Asher Marc A MA

The Journal of bone and joint surgery. American volume 20220215 10

<h4>Background</h4>Facet joint (FJ) osteoarthritis (FJOA) is a widely prevalent spinal disorder but its pathogenesis remains unclear, largely due to the difficulties in conducting longitudinal human studies and lack of spontaneous-FJOA animal models for mechanistic investigations. This study aimed to investigate whether spontaneous FJOA occurs in mice bearing mutant NFAT1 (nuclear factor of activated T cells 1) transcription factor.<h4>Methods</h4>The lumbar FJs of 50 NFAT1-mutant mice and of 50 ...[more]

PMID: 35167509

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Project description:BackgroundBoth vertebral bodies and posterior elements of the vertebrae (facet joints, FJ) can engage in bone formation in radiographic axial spondyloarthritis (r-axSpA). However, little is known about the specific structural lesions and progression patterns of FJs in r-axSpA.ObjectivesTo identify specific lesions related to r-axSpA and to investigate the distinct progression patterns by comparing the FJ changes of r-axSpA with that of diffuse idiopathic skeletal hyperostosis (DISH), osteoarthritis (OA), and control group (CG).DesignSingle-center, retrospective study. Longitudinal imaging data were retrieved and collected.MethodsAge- and sex-matched patients with complete thoracic and lumbar spine computed tomography (CT) data were included and their bilateral FJs were assessed. FJ changes were divided into erosions, ankylosis, joint-space narrowing, osteophytes, subchondral sclerosis, subchondral cysts, and vacuum phenomena. Average progressed year was defined as "number of changed vertebrae × interval years"/number of changed vertebrae.ResultsIn all, 50 patients in each group were included. Subchondral cysts and vacuum phenomena were not observed. Bilateral FJ ankylosis (FJA)/erosions in the thoracic and lumbar spine, and unilateral ankylosis/erosions in T1-4, T9-12 were significantly more common in r-axSpA. Joint-space narrowing/osteophytes/subchondral sclerosis were significantly more common in DISH and OA. FJ lesions progressed in 56.34% of vertebrae of r-axSpA. The most common pattern was "FJ normal advanced to ankylosis" (17.54%) which required 2.63 years. It was followed by "erosions advanced to ankylosis" (12.3%) which took 2.05 years, and by "normal FJ advanced to erosions" (11.04%) which took 2.29 years, respectively. Degenerative changes could also progress to FJ erosions/ankylosis (24.83%). The majority pattern in DISH/OA was "FJ changes advanced to subchondral sclerosis/osteophytes/joint-space narrowing."ConclusionBilateral FJA/erosions are r-axSpA-specific lesions. The specific progression pattern for r-axSpA was "FJ changes advanced to ankylosis/erosions." Repeated CT examination in intervals of at least 2 years will be more appropriate for monitoring FJ progression.

Project description:BackgroundLow back pain (LBP) is generally caused by lumbar degeneration without effective treatment. Lumbar degeneration is influenced by aberrant axial mechanical stress (MS), with facet joint osteoarthritis (FJOA) representing one of its primary pathological manifestations. MicroRNA (miRNA), functioning as an early intermediate in the transcription process, has frequently been demonstrated to serve as a critical mediator linking mechanical stress perception with cellular processes such as growth, development, aging, and apoptosis. We hypothesized that miR-3085-3p regulates chondrocyte apoptosis under mechanical stress, influencing FJOA and serving as a key regulator.MethodsThe severity of cartilage degeneration in bipedal standing models (BSM) was established and validated through micro-CT and histopathology. Cyclic tensile strain experiments (CTS) were conducted on the ATDC5 cell line to simulate MS. In situ hybridization was utilized to assess the expression levels of miR-3085-3p in degraded facet articular cartilage. The role of miR-3085-3p and its interaction with the downstream mRNA target Hspb6 were investigated through a combination of bioinformatic analysis, quantitative real-time polymerase chain reaction, western blotting, immunofluorescence, and luciferase assay. In vivo experiments on BSM, the functional impact of miR-3085-3p was further examined through transfection with adeno-associated virus (AAV).ResultsIt was observed that miR-3085-3p induced endoplasmic reticulum (ER) stress and apoptosis in chondrocytes and cartilage tissues under MS. The detrimental impact of miR-3085-3p was associated with the downregulation of Hspb6 expression, resulting in disruption of endoplasmic reticulum folding function. Additionally, intra-articular transfection of AAV miR-3085-3p mimics in mice facet joints led to spontaneous cartilage loss, while AAV miRNA-3085-3p sponge administration mitigated FJOA in the murine BSM model.ConclusionMechanical stress-regulated miR-3085-3p up regulation induced the ER stress and aggravates FJOA development through targeting HSPB6, suggesting miR-3085-3p may be a novel therapeutic target for FJOA.Translational potential of this article: Our study confirmed the elevated expression of miR-3085-3p in lumbar facet joints following mechanical stress loading, suggesting that miR-3085-3p may serve as a biomarker for the clinical management of FJOA. Additionally, we demonstrated that the knockdown of miR-3085-3p in animal facet joints mitigated facet joint degeneration, thereby identifying a potential therapeutic target for FJOA.

Dataset Information

Spontaneous Facet Joint Osteoarthritis in NFAT1-Mutant Mice: Age-Dependent Histopathologic Characteristics and Molecular Mechanisms.

Background

Methods

Results

Conclusions

Clinical relevance

Publications

Spontaneous Facet Joint Osteoarthritis in NFAT1-Mutant Mice: Age-Dependent Histopathologic Characteristics and Molecular Mechanisms.

Similar Datasets

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