Role of Ciliary Protein Intraflagellar Transport Protein 88 in the Regulation of Cartilage Thickness and Osteoarthritis Development in Mice

Objective Mechanical and biologic cues drive cellular signaling in cartilage development, health, and disease. Primary cilia proteins, which are implicated in the transduction of biologic and physiochemical signals, control cartilage formation during skeletal development. This study was undertaken t...

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Published in:	Arthritis & rheumatology (Hoboken, N.J.) Vol. 74; no. 1; pp. 49 - 59
Main Authors:	Coveney, Clarissa R., Zhu, Linyi, Miotla‐Zarebska, Jadwiga, Stott, Bryony, Parisi, Ida, Batchelor, Vicky, Duarte, Claudia, Chang, Emer, McSorley, Eleanor, Vincent, Tonia L., Wann, Angus K. T.
Format:	Journal Article
Language:	English
Published:	Boston, USA Wiley Periodicals, Inc 01-01-2022 Wiley Subscription Services, Inc
Subjects:	Adolescents Animals Arthritis Atrophy Biomedical materials Calcification Cartilage Cartilage (articular) Cartilage diseases Cartilage, Articular - anatomy & histology Cartilage, Articular - growth & development Chondrocytes Cilia Confidence intervals Damage Destabilization Gene expression Hedgehog protein Histomorphometry Hypertrophy IFT88 gene Immunohistochemistry Male Meniscus Mice Mice, Knockout Organ Size Osteoarthritis Osteoarthritis - etiology Physiochemistry Polymerase chain reaction Protein transport Proteins Signal transduction Signaling Thickness Tumor Suppressor Proteins - physiology
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Summary:	Objective Mechanical and biologic cues drive cellular signaling in cartilage development, health, and disease. Primary cilia proteins, which are implicated in the transduction of biologic and physiochemical signals, control cartilage formation during skeletal development. This study was undertaken to assess the influence of the ciliary protein intraflagellar transport protein 88 (IFT88) on postnatal cartilage from mice with conditional knockout of the Ift88 gene (Ift88‐KO). Methods Ift88fl/fl and aggrecanCreERT2 mice were crossed to create a strain of cartilage‐specific Ift88‐KO mice (aggrecanCreERT2;Ift88fl/fl). In these Ift88‐KO mice and Ift88fl/fl control mice, tibial articular cartilage thickness was assessed by histomorphometry, and the integrity of the cartilage was assessed using Osteoarthritis Research Society International (OARSI) damage scores, from adolescence through adulthood. In situ mechanisms of cartilage damage were investigated in the microdissected cartilage sections using immunohistochemistry, RNAScope analysis, and quantitative polymerase chain reaction. Osteoarthritis (OA) was induced in aggrecanCreERT2;Ift88fl/fl mice and Ift88fl/fl control mice using surgical destabilization of the medial meniscus (DMM). Following tamoxifen injection and DMM surgery, the mice were given free access to exercise on a wheel. Results Deletion of Ift88 resulted in progressive reduction in the thickness of the medial tibial cartilage in adolescent mice, as well as marked atrophy of the cartilage in mice during adulthood. In aggrecanCreERT2;Ift88fl/fl mice at age 34 weeks, the median thickness of the medial tibial cartilage was 89.42 μm (95% confidence interval [95% CI] 84.00–93.49), whereas in Ift88fl/fl controls at the same age, the median cartilage thickness was 104.00 μm (95% CI 100.30–110.50; P < 0.0001). At all time points, the median thickness of the calcified cartilage was reduced. In some mice, atrophy of the medial tibial cartilage was associated with complete, spontaneous degradation of the cartilage. Following DMM, aggrecanCreERT2;Ift88fl/fl mice were found to have increased OARSI scores of cartilage damage. In articular cartilage from maturing mice, atrophy was not associated with obvious increases in aggrecanase‐mediated destruction or chondrocyte hypertrophy. Of the 44 candidate genes analyzed, only Tcf7l2 expression levels correlated with Ift88 expression levels in the microdissected cartilage. However, RNAScope analysis revealed that increased hedgehog (Hh) signaling (as indicated by increased expression of Gli1) was associated with the reductions in Ift88 expression in the tibial cartilage from Ift88‐deficient mice. Wheel exercise restored both the articular cartilage thickness and levels of Hh signaling in these mice. Conclusion Our results in a mouse model of OA demonstrate that IFT88 performs a chondroprotective role in articular cartilage by controlling the calcification of cartilage via maintenance of a threshold of Hh signaling during physiologic loading.
Bibliography:	Supported by Versus Arthritis (grants 20205 and 21621). Dr. Coveney's work was supported by the Kennedy Trust for Rheumatology Research (grant KENN181907). Dr. Zhu's work was supported by the European Research Council (grant 743016). Ms. Chang's work was supported by the St. Hughs College, University of Oxford (Student Summer Research award). Ms. McSorley's work was supported by the Magdalen College, University of Oxford (Student Summer Research award). Dr. Wann's work was supported by the Kennedy Trust for Rheumatology Research (KTRR Fellowship). Dr. Vincent has received consulting fees from Mundipharma and GlaxoSmithKline (less than $10,000 each). No other disclosures relevant to this article were reported. ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2326-5191 2326-5205
DOI:	10.1002/art.41894