Depletion of primary cilia in articular chondrocytes results in reduced Gli3 repressor to activator ratio, increased Hedgehog signaling, and symptoms of early osteoarthritis

Osteoarthritis and Cartilage

Volumn 20, Issue 2, 2012, Pages 152-161

  Chang, C F ^a   Ramaswamy, G ^b   Serra, R ^a  

^a UNIVERSITY OF ALABAMA AT BIRMINGHAM   (United States)

^b and Radiation Oncology   (United States)

Author keywords

Cartilage; Chondrocyte; Gli3; Hedgehog signaling; Osteoarthritis; Primary cilia

Indexed keywords

AGGRECANASE 2; COLLAGEN TYPE 10; COLLAGENASE 3; PROTEIN PATCHED 1; SONIC HEDGEHOG PROTEIN; TRANSCRIPTION FACTOR GLI3; TRANSCRIPTION FACTOR RUNX2;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; APOPTOSIS; ARTICLE; ARTICULAR CARTILAGE; CARTILAGE CELL; CELL DENSITY; CELL PROLIFERATION; CONTROLLED STUDY; EUKARYOTIC FLAGELLUM; GENE REPRESSION; HISTOLOGY; JOINT STIFFNESS; MOUSE; NONHUMAN; OSTEOARTHRITIS; PRIORITY JOURNAL; PROTEIN ANALYSIS; PROTEIN EXPRESSION; PROTEIN FUNCTION; SIGNAL TRANSDUCTION; TIBIA; UPREGULATION;

ANIMALS; ARTHRITIS, EXPERIMENTAL; BIOLOGICAL MARKERS; CARTILAGE, ARTICULAR; CHONDROCYTES; CILIA; HEDGEHOG PROTEINS; KRUPPEL-LIKE TRANSCRIPTION FACTORS; MICE; MICE, TRANSGENIC; NERVE TISSUE PROTEINS; OSTEOARTHRITIS; RECEPTORS, CELL SURFACE; RNA, MESSENGER; SIGNAL TRANSDUCTION; STRESS, MECHANICAL; UP-REGULATION;

EID: 84862954468     PISSN: 10634584     EISSN: 15229653     Source Type: Journal    
DOI: 10.1016/j.joca.2011.11.009     Document Type: Article

References (44)

1. Pedersen L.B., Rosenbaum J.L. Intraflagellar transport (IFT) role in ciliary assembly, resorption and signalling. Curr Top Dev Biol 2008, 85:23-61.
2. Ishikawa H., Marshall W.F. Ciliogenesis: building the cell's antenna. Nat Rev Mol Cell Biol 2011, 12:222-234.
3. Berbari N.F., O'Connor A.K., Haycraft C.J., Yoder B.K. The primary cilium as a complex signaling center. Curr Biol 2009, 19:R526-R535.
4. Goetz S.C., Anderson K.V. The primary cilium: a signalling centre during vertebrate development. Nat Rev Genet 2010, 11:331-344.
5. Sharma N., Berbari N.F., Yoder B.K. Ciliary dysfunction in developmental abnormalities and diseases. Curr Top Dev Biol 2008, 85:371-427.
6. Tobin J.L., Beales P.L. The nonmotile ciliopathies. Genet Med 2009, 11:386-402.
7. Serra R. Role of intraflagellar transport and primary cilia in skeletal development. Anat Rec (Hoboken) 2008, 291:1049-1061.
8. Haycraft C.J., Serra R. Cilia involvement in patterning and maintenance of the skeleton. Curr Top Dev Biol 2008, 85:303-332.
9. Haycraft C.J., Zhang Q., Song B., Jackson W.S., Detloff P.J., Serra R., et al. Intraflagellar transport is essential for endochondral bone formation. Development 2007, 134:307-316.
10. Song B., Haycraft C.J., Seo H.S., Yoder B.K., Serra R. Development of the post-natal growth plate requires intraflagellar transport proteins. Dev Biol 2007, 305:202-216.
11. McGlashan S.R., Cluett E.C., Jensen C.G., Poole C.A. Primary cilia in osteoarthritic chondrocytes: from chondrons to clusters. Dev Dyn 2008, 237:2013-2020.
12. Poole C.A., Jensen C.G., Snyder J.A., Gray C.G., Hermanutz V.L., Wheatley D.N. Confocal analysis of primary cilia structure and colocalization with the Golgi apparatus in chondrocytes and aortic smooth muscle cells. Cell Biol Int 1997, 21:483-494.
13. Jensen C.G., Poole C.A., McGlashan S.R., Marko M., Issa Z.I., Vujcich K.V., et al. Ultrastructural, tomographic and confocal imaging of the chondrocyte primary cilium in situ. Cell Biol Int 2004, 28:101-110.
14. Corbit K.C., Aanstad P., Singla V., Norman A.R., Stainier D.Y., Reiter J.F. Vertebrate Smoothened functions at the primary cilium. Nature 2005, 437:1018-1021.
15. Haycraft C.J., Banizs B., Aydin-Son Y., Zhang Q., Michaud E.J., Yoder B.K. Gli2 and Gli3 localize to cilia and require the intraflagellar transport protein polaris for processing and function. PLoS Genet 2005, 1:e53.
16. Liu A., Wang B., Niswander L.A. Mouse intraflagellar transport proteins regulate both the activator and repressor functions of Gli transcription factors. Development 2005, 132:3103-3111.
17. Huangfu D., Anderson K.V. Signaling from Smo to Ci/Gli: conservation and divergence of Hedgehog pathways from Drosophila to vertebrates. Development 2006, 133:3-14.
18. Lin A.C., Seeto B.L., Bartoszko J.M., Khoury M.A., Whetstone H., Ho L., et al. Modulating hedgehog signaling can attenuate the severity of osteoarthritis. Nat Med 2009, 15:1421-1425.
19. Ovchinnikov D.A., Deng J.M., Ogunrinu G., Behringer R.R. Col2a1-directed expression of Cre recombinase in differentiating chondrocytes in transgenic mice. Genesis 2000, 26:145-146.
20. Caspary T., Larkins C.E., Anderson K.V. The graded response to Sonic Hedgehog depends on cilia architecture. Dev Cell 2007, 12:767-778.
21. Hyttinen M.M., Toyras J., Lapvetelainen T., Lindblom J., Prockop D.J., Li S.W., et al. Inactivation of one allele of the type II collagen gene alters the collagen network in murine articular cartilage and makes cartilage softer. Ann Rheum Dis 2001, 60:262-268.
22. Alexopoulos L.G., Youn I., Bonaldo P., Guilak F. Developmental and osteoarthritic changes in Col6a1-knockout mice: biomechanics of type VI collagen in the cartilage pericellular matrix. Arthritis Rheum 2009, 60:771-779.
23. Pfaffl M.W., Horgan G.W., Dempfle L. Relative expression software tool (REST) for group-wise comparison and statistical analysis of relative expression results in real-time PCR. Nucleic Acids Res 2002, 30:e36.
24. Aigner T., Soder S., Gebhard P.M., McAlinden A., Haag J. Mechanisms of disease: role of chondrocytes in the pathogenesis of osteoarthritis - structure, chaos and senescence. Nat Clin Pract Rheumatol 2007, 3:391-399.
25. Heinegard D., Saxne T. The role of the cartilage matrix in osteoarthritis. Nat Rev Rheumatol 2010, 7:50-56.
26. Dreier R. Hypertrophic differentiation of chondrocytes in osteoarthritis: the developmental aspect of degenerative joint disorders. Arthritis Res Ther 2010, 12:216.
27. Pritzker K.P., Gay S., Jimenez S.A., Ostergaard K., Pelletier J.P., Revell P.A., et al. Osteoarthritis cartilage histopathology: grading and staging. Osteoarthritis Cartilage 2006, 14:13-29.
28. Hilton M.J., Tu X., Cook J., Hu H., Long F. Ihh controls cartilage development by antagonizing Gli3, but requires additional effectors to regulate osteoblast and vascular development. Development 2005, 132:4339-4351.
29. Koziel L., Wuelling M., Schneider S., Vortkamp A. Gli3 acts as a repressor downstream of Ihh in regulating two distinct steps of chondrocyte differentiation. Development 2005, 132:5249-5260.
30. Hopyan S., Nadesan P., Yu C., Wunder J., Alman B.A. Dysregulation of hedgehog signalling predisposes to synovial chondromatosis. JPathol 2005, 206:143-150.
31. Iannone F., De Bari C., Scioscia C., Patella V., Lapadula G. Increased Bcl-2/p53 ratio in human osteoarthritic cartilage: a possible role in regulation of chondrocyte metabolism. Ann Rheum Dis 2005, 64:217-221.
32. Johnson E.O., Charchandi A., Babis G.C., Soucacos P.N. Apoptosis in osteoarthritis: morphology, mechanisms, and potential means for therapeutic intervention. JSurg Orthop Adv 2008, 17:147-152.
33. Knecht S., Vanwanseele B., Stussi E. Areview on the mechanical quality of articular cartilage - implications for the diagnosis of osteoarthritis. Clin Biomech (Bristol, Avon) 2006, 21:999-1012.
34. Goldring M.B., Goldring S.R. Osteoarthritis. JCell Physiol 2007, 213:626-634.
35. Poole C.A., Flint M.H., Beaumont B.W. Analysis of the morphology and function of primary cilia in connective tissues: a cellular cybernetic probe?. Cell Motil 1985, 5:175-193.
36. Poole C.A., Zhang Z.J., Ross J.M. The differential distribution of acetylated and detyrosinated alpha-tubulin in the microtubular cytoskeleton and primary cilia of hyaline cartilage chondrocytes. JAnat 2001, 199:393-405.
37. Farnum C.E., Wilsman N.J. Orientation of primary cilia of articular chondrocytes in three-dimensional space. Anat Rec (Hoboken) 2011, 294:533-549.
38. McGlashan S.R., Haycraft C.J., Jensen C.G., Yoder B.K., Poole C.A. Articular cartilage and growth plate defects are associated with chondrocyte cytoskeletal abnormalities in Tg737orpk mice lacking the primary cilia protein polaris. Matrix Biol 2007, 26:234-246.
39. McGlashan S.R., Knight M.M., Chowdhury T.T., Joshi P., Jensen C.G., Kennedy S., et al. Mechanical loading modulates chondrocyte primary cilia incidence and length. Cell Biol Int 2010, 34:441-446.
40. Kaushik A.P., Martin J.A., Zhang Q., Sheffield V.C., Morcuende J.A. Cartilage abnormalities associated with defects of chondrocytic primary cilia in Bardet-Biedl syndrome mutant mice. JOrthop Res 2009, 27:1093-1099.
41. Mak K.K., Kronenberg H.M., Chuang P.T., Mackem S., Yang Y. Indian hedgehog signals independently of PTHrP to promote chondrocyte hypertrophy. Development 2008, 135:1947-1956.
42. Hu M.C., Mo R., Bhella S., Wilson C.W., Chuang P.T., Hui C.C., et al. GLI3-dependent transcriptional repression of Gli1, Gli2 and kidney patterning genes disrupts renal morphogenesis. Development 2006, 133:569-578.
43. Hui C.C., Joyner A.L. Amouse model of greig cephalopolysyndactyly syndrome: the extra-toesJ mutation contains an intragenic deletion of the Gli3 gene. Nat Genet 1993, 3:241-246.
44. Zeng H., Jia J., Liu A. Coordinated translocation of mammalian Gli proteins and suppressor of fused to the primary cilium. PLoS One 2010, 5:e15900.