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Targeting chondrocytes for arresting bony fusion in ankylosing spondylitis

ABSTRACT: Bony fusion caused by pathological new bone formation manifests the clinical feature of ankylosing spondylitis (AS). However, the underlying mechanism remains elusive. Here we discovered spontaneous kyphosis, arthritis and bony fusion in mature CD4-Cre;Ptpn11f/f mice, which present the pathophysiological features of AS. A population of CD4-Cre-expressing proliferating chondrocytes was SHP2 deficient, which could differentiate into pre-hypertrophic and hypertrophic chondrocytes. Functionally, SHP2 deficiency in chondrocytes impeded the fusion of epiphyseal plate and promoted chondrogenesis in joint cavity and enthesis. Mechanistically, aberrant chondrocytes promoted ectopic new bone formation through BMP6/pSmad1/5 signaling. It is worth emphasizing that such pathological thickness of growth plates was evident in adolescent humans with enthesitis-related arthritis, which could progress to AS in adulthood. Targeting dysfunctional chondrogenesis with Smo inhibitor sonidegib significantly alleviated the AS-like bone disease in mice. These findings suggest that blockade of chondrogenesis by sonidegib would be a drug repurposing strategy for AS treatment. Current treatments cannot significantly alleviate the radiographic progression in ankylosing spondylitis (AS), which results in joints stiffness and bony fusion of AS. Smo inhibitor sonidegib retards the pathological new bone formation in AS through targeting dysfunctional chondrogenesis.

SUBMITTER: Shao F

PROVIDER: S-EPMC8585952 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:We have compared synovial biopsies from ankylosing spondylitis and undifferentiated spondylitis patients with healthy controls and osteoarthritis patients Objective: In spondylarthropies, whole-genome gene expression profiling studies have been limited to peripheral blood to date. By undertaking a study in knee synovial biopsies from spondylarthropy (SpA) and ankylosing spondylitis (AS) patients we aimed to identified joint-specific candidate genes and pathways. These pathways may mediate systemic inflammation driven joint damaging processes and more specifically, the osteoproliferation that is characteristic of these conditions. Methods: RNA was extracted from six seronegative SpA, two AS, three osteoarthritis (OA) and four normal control knee synovial biopsies. Whole genome expression profiling was undertaken using the Illumina DASL system, which assays 24000 cDNA probes. Differentially expressed candidate genes were then validated using quantitative PCR and immunohistochemistry. Results: 416 differentially expressed genes were identified that clearly delineated between AS/SpA and control groups. Pathway analysis showed altered gene-expression in oxidoreductase activity, osteoblast activity, B-cell associated, matrix catabolic, and metabolic pathways. The inflammatory mediator, MMP3, was strongly upregulated in AS/SpA samples and the Wnt pathway inhibitors DKK3 and Kremen1 were downregulated. Conclusion: Pathways mediating both systemic inflammation as well as local tissue changes were identified. This suggests initial systemic inflammation in spondylarthropies transfers to and persists in the local joint environment, subsequently mediating changes in genes directly involved in the destructive tissue remodelling. Fifteen knee synovial biopsy tissue samples consisting of six seronegative spondyloarthropy (SpA), two ankylosing spondylitis (AS), three osteoarthritis (OA) and four normal control biopsies were obtained from the Synovial Tissue Bank at the Repatriation General Hospital in Adelaide, South Australia with the appropriate ethical approval (Supplementary Table 1). All patients provided informed written consent.

Project description:BackgroundPreference-based measures of health-related quality of life (HRQoL), such as the EQ-5D or the SF-6D, are essential for health economic evaluation. However, they are rarely included in clinical trials of ankylosing spondylitis (AS). This study aims to develop mapping algorithms to predict EQ-5D-3L and EQ-5D-5L health utility scores from the Bath Ankylosing Disease Activity Index (BASDAI) and the Bath Ankylosing Spondylitis Functional Index (BASFI).MethodsPatients with AS were recruited from the largest tertiary hospital in Shandong province, China, between December 2019 and October 2020. Patients were selected by convenience sampling method according to the following criteria: (1) diagnosed with AS according to the New York criteria; (2) aged 18 years and above; and (3) without mental disorders; (4) able to understand the questionnaires; (5) without serious complications. There were 243 patients who completed the face-to-face questionnaire survey, and 5 cases with missing values in key variables were excluded. Ordinary least squares, censored least absolute deviations, Tobit, adjusted limited dependent variable mixture model and beta-mixture model (BM) in the direct approach and ordered logit and multinomial logit (Mlogit) model in the response approach were used to develop mapping algorithms. Mean absolute error, root mean square error, Spearman's correlation coefficient and concordance correlation coefficient were used to access predictive performance.ResultsThe 238 patients with AS had a mean age of 35.19 (SD = 9.59) years, and the majority (74.47%) were male. The observed EQ-5D-3L and EQ-5D-5L health utility values were 0.88 (SD = 0.12) and 0.74 (SD = 0.27), respectively. The EQ-5D-5L had higher conceptual overlap with the BASDAI and BASFI than the EQ-5D-3L did. The Mlogit was the best-performing model for the EQ-5D-3L, and the BM showed better performance in predicting EQ-5D-5L than other direct and indirect mapping models did.ConclusionThis study demonstrates that the EQ-5D-5L, rather than EQ-5D-3L, should be selected as the target outcome measure of HRQoL in patients with AS in China, and the BM mapping algorithm could be used to predict EQ-5D-5L values from BASDAI and BASFI for health economic evaluation.

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Targeting chondrocytes for arresting bony fusion in ankylosing spondylitis

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