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<jats:title>Abstract</jats:title><jats:p>Mechanical forces are known to drive cellular signalling programmes in cartilage development, health, and disease. Proteins of the primary cilium, implicated in mechanoregulation, control cartilage formation during skeletal development, but their role in post-natal cartilage is 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 thickness was assessed, through adolescence and adulthood, by histomorphometry and integrity by OARSI score. <jats:italic>In situ</jats:italic> cell biology was investigated by immunohistochemistry (IHC) and qPCR of micro-dissected cartilage. OA was induced by destabilisation of the medial meniscus (DMM). Some mice were provided with exercise wheels in their cage. Deletion of IFT88 resulted in a reduction in medial articular cartilage thickness (atrophy) during adolescence from 102.57μm, 95% CI [94.30, 119.80] in control (<jats:italic>Ift88</jats:italic><jats:sup><jats:italic>fl/fl</jats:italic></jats:sup>) to 87.36μm 95% CI [81.35, 90.97] 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> by 8-weeks p&lt;0.01, and adulthood (104.00μm, 95% CI [100.30, 110.50] in <jats:italic>Ift88</jats:italic><jats:sup><jats:italic>fl/fl</jats:italic></jats:sup> to 89.42μm 95% CI [84.00, 93.49] 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>, 34-weeks, p&lt;0.0001) through a reduction in calcified cartilage. Thinning in adulthood was associated with spontaneous 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 (OARSI scores at 12 weeks <jats:italic>Ift88</jats:italic><jats:sup><jats:italic>fl/fl</jats:italic></jats:sup> = 22.08 +/− 9.30, and <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> = 29.83 +/− 7.69). Atrophy was not associated with aggrecanase-mediated destruction or chondrocyte hypertrophy. <jats:italic>Ift88</jats:italic> expression positively correlated with <jats:italic>Tcf7l2</jats:italic> and connective tissue growth factor. Cartilage thickness was restored 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> by voluntary wheel exercise. Our results demonstrate that ciliary IFT88 regulates cartilage thickness and is chondroprotective, potentially through modulating mechanotransduction pathways in articular chondrocytes.</jats:p>

Original publication

DOI

10.1101/2020.07.29.225599

Type

Journal article

Publisher

Cold Spring Harbor Laboratory

Publication Date

30/07/2020