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<jats:title>Abstract</jats:title><jats:p>Mechanical and biological cues drive cellular signalling in cartilage development, health, and disease. Proteins of the primary cilium, implicated in transduction of biophysiochemical signals, control cartilage formation during skeletal development, but their influence in post-natal cartilage remains unknown. <jats:italic>Ift88</jats:italic><jats:sup><jats:italic>fl/fl</jats:italic></jats:sup> and <jats:italic>AggrecanCreER</jats:italic><jats:sup><jats:italic>T2</jats:italic></jats:sup> mice were crossed to create a cartilage-specific, inducible knockout mouse <jats:italic>AggrecanCreER</jats:italic><jats:sup><jats:italic>T2</jats:italic></jats:sup><jats:italic>;Ift88</jats:italic><jats:sup><jats:italic>fl/fl</jats:italic></jats:sup>. Tibial articular cartilage (AC) thickness was assessed, through adolescence and adulthood, by histomorphometry and integrity by OARSI score. <jats:italic>In situ</jats:italic> mechanisms were investigated by immunohistochemistry (IHC), RNA scope and qPCR of micro-dissected cartilage. OA was induced by surgical destabilisation (DMM). Mice voluntarily exercised using wheels. Deletion of IFT88 resulted in progressive reductions in medial AC thickness during adolescence, and marked atrophy in adulthood. At 34 weeks of age, medial thickness was reduced from 104.00μm, [100.30-110.50, 95% CI] in <jats:italic>Ift88</jats:italic><jats:sup><jats:italic>fl/fl</jats:italic></jats:sup> to 89.42μm [84.00-93.49, 95% CI] in <jats:italic>AggrecanCreER</jats:italic><jats:sup><jats:italic>T2</jats:italic></jats:sup><jats:italic>;Ift88</jats:italic><jats:sup><jats:italic>fl/fl</jats:italic></jats:sup> (p&lt;0.0001), associated with reductions in calcified cartilage. Occasionally, atrophy was associated with complete, spontaneous, medial cartilage degradation. Following DMM, <jats:italic>AggrecanCreER</jats:italic><jats:sup><jats:italic>T2</jats:italic></jats:sup><jats:italic>;Ift88</jats:italic><jats:sup><jats:italic>fl/fl</jats:italic></jats:sup> mice had increased OA scores. Atrophy in mature AC was not associated with obvious increases in aggrecanase-mediated destruction or chondrocyte hypertrophy. <jats:italic>Ift88</jats:italic> expression positively correlated with <jats:italic>Tcf7l2</jats:italic>, connective tissue growth factor (<jats:italic>Ctgf</jats:italic>) and <jats:italic>Enpp1</jats:italic>. RNA scope revealed increased hedgehog (Hh) signalling (<jats:italic>Gli1)</jats:italic>, associated with reductions in <jats:italic>Ift88</jats:italic>, in <jats:italic>AggrecanCreER</jats:italic><jats:sup><jats:italic>T2</jats:italic></jats:sup><jats:italic>;Ift88</jats:italic><jats:sup><jats:italic>fl/fl</jats:italic></jats:sup> cartilage. Wheel exercise restored both AC thickness and levels of Hh signalling in <jats:italic>AggrecanCreER</jats:italic><jats:sup><jats:italic>T2</jats:italic></jats:sup><jats:italic>;Ift88</jats:italic><jats:sup><jats:italic>fl/fl</jats:italic></jats:sup>. Our results demonstrate that IFT88 is chondroprotective, regulating AC thickness, potentially by thresholding a Hh response to physiological loading that controls cartilage calcification.</jats:p>

Original publication

DOI

10.1101/2020.07.29.225599

Type

Journal article

Journal

Arthritis and rheumatology

Publisher

Wiley

Publication Date

10/06/2021