Mechanical loading inhibits cartilage inflammatory signalling via an HDAC6 and IFT-dependent mechanism regulating primary cilia elongation

被引:59
作者
Fu, S. [1 ]
Thompson, C. L. [1 ]
Ali, A. [1 ]
Wang, W. [1 ]
Chapple, J. P. [3 ]
Mitchison, H. M. [4 ]
Beales, P. L. [4 ]
Wann, A. K. T. [2 ]
Knight, M. M. [1 ]
机构
[1] Queen Mary Univ London, Sch Engn & Mat Sci, Inst Bioengn, London, England
[2] Univ Oxford, Kennedy Inst Rheumatol, Oxford, England
[3] Queen Mary Univ London, William Harvey Res Ctr, Dept Endocrinol, London, England
[4] UCL, Inst Child Hlth, London, England
基金
英国医学研究理事会;
关键词
IFT; Primary cilia; Chondrocyte; IL-1; beta; HDAC6; Tubulin; ENDOTHELIAL PRIMARY CILIA; PRESSURE-INDUCED STRAIN; ALPHA-5-BETA-1; INTEGRIN; CHONDROCYTE DEFORMATION; ARTICULAR-CARTILAGE; TISSUE STRAIN; NITRIC-OXIDE; COMPRESSION; STRESS; MICROTUBULES;
D O I
10.1016/j.joca.2019.03.003
中图分类号
R826.8 [整形外科学]; R782.2 [口腔颌面部整形外科学]; R726.2 [小儿整形外科学]; R62 [整形外科学(修复外科学)];
学科分类号
摘要
Objective: Physiological mechanical loading reduces inflammatory signalling in numerous cell types including articular chondrocytes however the mechanism responsible remains unclear. This study investigates the role of chondrocyte primary cilia and associated intraflagellar transport (IFT) in the mechanical regulation of interleukin-1 beta (IL-1 beta) signalling. Design: Isolated chondrocytes and cartilage explants were subjected to cyclic mechanical loading in the presence and absence of the cytokine IL-1 beta. Nitric oxide (NO) and prostaglandin E2 (PGE2) release were used to monitor IL-1 beta signalling whilst Sulphated glycosaminoglycan (sGAG) release provided measurement of cartilage degradation. Measurements were made of HDAC6 activity and tubulin polymerisation and acetylation. Effects on primary cilia were monitored by confocal and super resolution microscopy. Involvement of IFT was analysed using ORPK cells with hypomorphic mutation of IFT88. Results: Mechanical loading suppressed NO and PGE2 release and prevented cartilage degradation. Loading activated HDAC6 and disrupted tubulin acetylation and cilia elongation induced by IL-1 beta. HDAC6 inhibition with tubacin blocked the anti-inflammatory effects of loading and restored tubulin acetylation and cilia elongation. Hypomorphic mutation of IFT88 reduced IL-1 beta signalling and abolished the anti-inflammatory effects of loading indicating the mechanism is IFT-dependent. Loading reduced the pool of non-polymerised tubulin which was replicated by taxol which also mimicked the anti-inflammatory effects of mechanical loading and prevented cilia elongation. Conclusions: This study reveals that mechanical loading suppresses inflammatory signalling, partially dependent on IFT, by activation of HDAC6 and post transcriptional modulation of tubulin. (C) 2019 The Authors. Published by Elsevier Ltd on behalf of Osteoarthritis Research Society International.
引用
收藏
页码:1064 / 1074
页数:11
相关论文
共 45 条
[1]  
Agarwal S, 2001, ARTHRITIS RHEUM-US, V44, P608, DOI 10.1002/1529-0131(200103)44:3<608::AID-ANR109>3.0.CO
[2]  
2-2
[3]   Primary cilia modulate TLR4-mediated inflammatory responses in hippocampal neurons [J].
Baek, Hyunjung ;
Shin, Hyo Jung ;
Kim, Jwa-Jin ;
Shin, Nara ;
Kim, Sena ;
Yi, Min-Hee ;
Zhang, Enji ;
Hong, Jinpyo ;
Kang, Joon Won ;
Kim, Yonghyun ;
Kim, Cuk-Seong ;
Kim, Dong Woon .
JOURNAL OF NEUROINFLAMMATION, 2017, 14
[4]   Microtubule modifications and stability are altered by cilia perturbation and in cystic kidney disease [J].
Berbari, Nicolas F. ;
Sharma, Neeraj ;
Malarkey, Erik B. ;
Pieczynski, Jay N. ;
Boddu, Ravindra ;
Gaertig, Jacek ;
Guay-Woodford, Lisa ;
Yoder, Bradley K. .
CYTOSKELETON, 2013, 70 (01) :24-31
[5]   Effects of Cyclic Tensile Strain on Chondrocyte Metabolism: A Systematic Review [J].
Bleuel, Judith ;
Zaucke, Frank ;
Brueggemann, Gert-Peter ;
Niehoff, Anja .
PLOS ONE, 2015, 10 (03)
[6]   Role of endothelial shear stress in the natural history of coronary atherosclerosis and vascular remodeling - Molecular, cellular, and vascular behavior [J].
Chatzizisis, Yiannis S. ;
Coskun, Ahmet Umit ;
Jonas, Michael ;
Edelman, Elazer R. ;
Feldman, Charles L. ;
Stone, Peter H. .
JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, 2007, 49 (25) :2379-2393
[7]   Zonal changes in the three-dimensional morphology of the chondron under compression: The relationship among cellular, pericellular, and extracellular deformation in articular cartilage [J].
Choi, Jae Bong ;
Youn, Inchan ;
Cao, Li ;
Leddy, Holly A. ;
Gilchrist, Christopher L. ;
Setton, Lori A. ;
Guilak, Farshid .
JOURNAL OF BIOMECHANICS, 2007, 40 (12) :2596-2603
[8]   Dynamic compression inhibits the synthesis of nitric oxide and PGE2 by IL-1β-stimulated chondrocytes cultured in agarose constructs [J].
Chowdhury, TT ;
Bader, DL ;
Lee, DA .
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 2001, 285 (05) :1168-1174
[9]   Endothelial primary cilia inhibit atherosclerosis [J].
Dinsmore, Colin ;
Reiter, Jeremy F. .
EMBO REPORTS, 2016, 17 (02) :156-166
[10]   TGF-β1 impairs mechanosensation of human osteoblasts via HDAC6-mediated shortening and distortion of primary cilia [J].
Ehnert, Sabrina ;
Sreekumar, Vrinda ;
Aspera-Werz, Romina H. ;
Sajadian, Sahar O. ;
Wintermeyer, Elke ;
Sandmann, Gunther H. ;
Bahrs, Christian ;
Hengstler, Jan G. ;
Godoy, Patricio ;
Nussler, Andreas K. .
JOURNAL OF MOLECULAR MEDICINE-JMM, 2017, 95 (06) :653-663