TRPV4 as a therapeutic target for joint diseases

Naunyn-Schmiedeberg's Archives of Pharmacology

Volumn 388, Issue 4, 2015, Pages 437-450

  McNulty, Amy L ^a   Leddy, Holly A ^a   Liedtke, Wolfgang ^a   Guilak, Farshid ^a  

^a DUKE UNIVERSITY MEDICAL CENTER   (United States)

Author keywords

Chondrocyte; Mechanotransduction; Osteoblast; Osteoclast; Proteinase activated receptor 2; Tissue engineering

Indexed keywords

GSK 2193874; HC 067047; RECEPTOR BLOCKING AGENT; UNCLASSIFIED DRUG; VANILLOID RECEPTOR 4; VANILLOID RECEPTOR;

ARTHRITIS; ARTHROPATHY; BONE; CARTILAGE; HUMAN; JOINT FUNCTION; NONHUMAN; OSTEOARTHRITIS; OSTEOCLAST; PAIN; PLURIPOTENT STEM CELL; PROTEIN FUNCTION; PROTEIN TARGETING; REVIEW; SYNOVIUM; ANIMAL; JOINT; JOINT DISEASES; METABOLISM;

ANIMALS; BONE AND BONES; CARTILAGE; HUMANS; JOINT DISEASES; JOINTS; PAIN; TRPV CATION CHANNELS;

EID: 84925497021     PISSN: 00281298     EISSN: 14321912     Source Type: Journal    
DOI: 10.1007/s00210-014-1078-x     Document Type: Review

References (135)

1. Akagi R, Sasho T, Saito M, Endo J, Yamaguchi S, Muramatsu Y, Mukoyama S, Akatsu Y, Katsuragi J, Fukawa T, Takahashi K (2014) Effective knock down of matrix metalloproteinase-13 by an intra-articular injection of small interfering RNA (siRNA) in a murine surgically-induced osteoarthritis model. J Orthop Res 32:1175-1180
2. Alenius GM, Jonsson S, Wallberg Jonsson S, Ny A, Rantapaa Dahlqvist S (2001) Matrix metalloproteinase 9 (MMP-9) in patients with psoriatic arthritis and rheumatoid arthritis. Clin Exp Rheumatol 19:760
3. Alessandri-Haber N, Joseph E, Dina OA, Liedtke W, Levine JD (2005) TRPV4 mediates pain-related behavior induced by mild hypertonic stimuli in the presence of inflammatory mediator. Pain 118:70-79
4. Amadesi S, Nie J, Vergnolle N, Cottrell GS, Grady EF, Trevisani M, Manni C, Geppetti P, McRoberts JA, Ennes H, Davis JB, Mayer EA, Bunnett NW (2004) Protease-activated receptor 2 sensitizes the capsaicin receptor transient receptor potential vanilloid receptor 1 to induce hyperalgesia. J Neurosci 24:4300-4312
5. Barbour KE, Helmick CG, Theis KA, Murphy LB, Hootman JM, Brady TJ, Cheng YJ (2013) Prevalence of Doctor-diagnosed arthritis and arthritis-attributable activity limitation - United States, 2010-2012. In: Moolenaar RL (ed) Morbidity and mortality weekly report centers for disease control and prevention, Washington, DC, pp. 869-873
6. Bignold LP, Lykke AW (1975) Increased vascular permeability evoked by mechanical trauma and haemarthrosis in synovium of the rat. Pathology 7:263-271
7. Bluteau G, Conrozier T, Mathieu P, Vignon E, Herbage D, Mallein-Gerin F (2001) Matrix metalloproteinase-1, -3, -13 and aggrecanase-1 and -2 are differentially expressed in experimental osteoarthritis. Biochim Biophys Acta 1526:147-158
8. Bohm SK, Khitin LM, Grady EF, Aponte G, Payan DG, Bunnett NW (1996) Mechanisms of desensitization and resensitization of proteinase-activated receptor-2. J Biol Chem 271:22003-22016
9. Bourque CW, Guilak F, Liedtke W (2012) A TRP that makes us feel hyper. J Physiol 590:1779-1780
10. Brama PA, TeKoppele JM, Beekman B, van Weeren PR, Barneveld A (1998) Matrix metalloproteinase activity in equine synovial fluid: influence of age, osteoarthritis, and osteochondrosis. Ann Rheum Dis 57:697-699
11. Brierley SM, Hughes PA, Page AJ, Kwan KY, Martin CM, O'Donnell TA, Cooper NJ, Harrington AM, Adam B, Liebregts T, Holtmann G, Corey DP, Rychkov GY, Blackshaw LA (2009) The ion channel TRPA1 is required for normal mechanosensation and is modulated by algesic stimuli. Gastroenterology 137:e2083
12. Bushell T (2007) The emergence of proteinase-activated receptor-2 as a novel target for the treatment of inflammation-related CNS disorders. J Physiol 581:7-16
13. Busso N, Frasnelli M, Feifel R, Cenni B, Steinhoff M, Hamilton J, So A (2007) Evaluation of protease-activated receptor 2 in murine models of arthritis. Arthritis Rheum 56:101-107
14. Camacho N, Krakow D, Johnykutty S, Katzman PJ, Pepkowitz S, Vriens J, Nilius B, Boyce BF, Cohn DH (2010) Dominant TRPV4 mutations in nonlethal and lethal metatropic dysplasia. Am J Med Genet A 152A:1169-1177
15. Cameron TL, Belluoccio D, Farlie PG, Brachvogel B, Bateman JF (2009) Global comparative transcriptome analysis of cartilage formation in vivo. BMC Dev Biol 9:20
16. Cattaruzza F, Spreadbury I, Miranda-Morales M, Grady EF, Vanner S, Bunnett NW (2010) Transient receptor potential ankyrin-1 has a major role in mediating visceral pain in mice. Am J Physiol Gastrointest Liver Physiol 298:G81-91
17. Cella G, Fiocco U, Palla A (1997) The thrombin-antithrombin complex in rheumatoid arthritis. J Rheumatol 24:410
18. Cenac N, Altier C, Chapman K, Liedtke W, Zamponi G, Vergnolle N (2008) Transient receptor potential vanilloid-4 has a major role in visceral hypersensitivity symptoms. Gastroenterology 135:937-946, 946 e931-932
19. Cevikbas F, Wang X, Akiyama T, Kempkes C, Savinko T, Antal A, Kukova G, Buhl T, Ikoma A, Buddenkotte J, Soumelis V, Feld M, Alenius H, Dillon SR, Carstens E, Homey B, Basbaum A, Steinhoff M (2014) A sensory neuron-expressed IL-31 receptor mediates T helper cell-dependent itch: Involvement of TRPV1 and TRPA1. J Allergy Clin Immunol 133:448-460
20. Chen Y, Yang C, Wang ZJ (2011) Proteinase-activated receptor 2 sensitizes transient receptor potential vanilloid 1, transient receptor potential vanilloid 4, and transient receptor potential ankyrin 1 in paclitaxel-induced neuropathic pain. Neuroscience 193:440-451
21. Chen Y, Williams SH, McNulty AL, Hong JH, Lee SH, Rothfusz NE, Parekh PK, Moore C, Gereau RW, Taylor AB, Wang F, Guilak F, Liedtke W (2013) Temporomandibular joint pain: a critical role for Trpv4 in the trigeminal ganglion. Pain 154:1295-1304
22. Chen Y, Kanju P, Fang Q, Lee S, Parekh P, Lee W, Moore C, Brenner D, Gereau R, Wang F, Liedtke W (2014) TRPV4 is necessary for trigeminal irritant pain and functions as a cellular formalin receptor. Pain. doi: 10.1016/j.pain.2014.09.033
23. Choi HM, Lee YA, Lee SH, Hong SJ, Hahm DH, Choi SY, Yang HI, Yoo MC, Kim KS (2009) Adiponectin may contribute to synovitis and joint destruction in rheumatoid arthritis by stimulating vascular endothelial growth factor, matrix metalloproteinase-1, and matrix metalloproteinase-13 expression in fibroblast-like synoviocytes more than proinflammatory mediators. Arthritis Res Ther 11:R161
24. Clark AL, Votta BJ, Kumar S, Liedtke W, Guilak F (2010) Chondroprotective role of the osmotically sensitive ion channel transient receptor potential vanilloid 4: age- and sex-dependent progression of osteoarthritis in Trpv4-deficient mice. Arthritis Rheum 62:2973-2983
25. Clark AK, Grist J, Al-Kashi A, Perretti M, Malcangio M (2012) Spinal cathepsin S and fractalkine contribute to chronic pain in the collagen-induced arthritis model. Arthritis Rheum 64:2038-2047
26. Coelho AM, Ossovskaya V, Bunnett NW (2003) Proteinase-activated receptor-2: physiological and pathophysiological roles. Curr Med Chem Cardiovasc Hematol Agents 1:61-72
27. Connor AM, Mahomed N, Gandhi R, Keystone EC, Berger SA (2012) TNFalpha modulates protein degradation pathways in rheumatoid arthritis synovial fibroblasts. Arthritis Res Ther 14:R62
28. Cowin SC, Weinbaum S, Zeng Y (1995) A case for bone canaliculi as the anatomical site of strain generated potentials. J Biomech 28:1281-1297
29. Dai Y, Moriyama T, Higashi T, Togashi K, Kobayashi K, Yamanaka H, Tominaga M, Noguchi K (2004) Proteinase-activated receptor 2-mediated potentiation of transient receptor potential vanilloid subfamily 1 activity reveals a mechanism for proteinase-induced inflammatory pain. J Neurosci 24:4293-4299
30. Dai Y, Wang S, Tominaga M, Yamamoto S, Fukuoka T, Higashi T, Kobayashi K, Obata K, Yamanaka H, Noguchi K (2007) Sensitization of TRPA1 by PAR2 contributes to the sensation of inflammatory pain. J Clin Invest 117:1979-1987
31. Denadai-Souza A, Martin L, de Paula MA, de Avellar MC, Muscara MN, Vergnolle N, Cenac N (2012) Role of transient receptor potential vanilloid 4 in rat joint inflammation. Arthritis Rheum 64:1848-1858
32. Dery O, Corvera CU, Steinhoff M, Bunnett NW (1998) Proteinase-activated receptors: novel mechanisms of signaling by serine proteases. Am J Physiol 274:C1429-1452
33. Eleswarapu SV, Athanasiou KA (2013) TRPV4 channel activation improves the tensile properties of self-assembled articular cartilage constructs. Acta Biomater 9:5554-5561
34. Erickson GR, Northrup DL, Guilak F (2003) Hypo-osmotic stress induces calcium-dependent actin reorganization in articular chondrocytes. Osteoarthritis Cartilage 11:187-197
35. Galasso O, Familiari F, De Gori M, Gasparini G (2012) Recent findings on the role of gelatinases (matrix metalloproteinase-2 and -9) in osteoarthritis. Adv Orthop 2012:834208
36. Goldbach-Mansky R, Suson S, Wesley R, Hack CE, El-Gabalawy HS, Tak PP (2005) Raised granzyme B levels are associated with erosions in patients with early rheumatoid factor positive rheumatoid arthritis. Ann Rheum Dis 64:715-721
37. Grace MS, Lieu T, Darby B, Abogadie FC, Veldhuis N, Bunnett NW, McIntyre P (2014) The tyrosine kinase inhibitor bafetinib inhibits PAR2-induced activation of TRPV4 channels in vitro and pain in vivo. Br J Pharmacol 171:3881-3894
38. Grant AD, Cottrell GS, Amadesi S, Trevisani M, Nicoletti P, Materazzi S, Altier C, Cenac N, Zamponi GW, Bautista-Cruz F, Lopez CB, Joseph EK, Levine JD, Liedtke W, Vanner S, Vergnolle N, Geppetti P, Bunnett NW (2007) Protease-activated receptor 2 sensitizes the transient receptor potential vanilloid 4 ion channel to cause mechanical hyperalgesia in mice. J Physiol 578:715-733
39. Guilak F (2011) Biomechanical factors in osteoarthritis. Best Pract Res Clin Rheumatol 25:815-823
40. Guilak F, Hung CT (2005) Physical regulation of cartilage metabolism. In: Mow VC, Huiskes R (eds) Basic orthopaedic biomechanics and mechanobiology, 3rd edn. Lippincott, Williams & Wilkins, Philedalphia, pp 259-300
41. Guilak F, Butler DL, Goldstein SA, Baaijens FP (2014) Biomechanics and mechanobiology in functional tissue engineering. J Biomech 47:1933-1940
42. Gupta K, Shukla M, Cowland JB, Malemud CJ, Haqqi TM (2007) Neutrophil gelatinase-associated lipocalin is expressed in osteoarthritis and forms a complex with matrix metalloproteinase 9. Arthritis Rheum 56:3326-3335
43. Hasegawa M, Nakoshi Y, Iino T, Sudo A, Segawa T, Maeda M, Yoshida T, Uchida A (2009) Thrombin-cleaved osteopontin in synovial fluid of subjects with rheumatoid arthritis. J Rheumatol 36:240-245
44. Hasegawa M, Segawa T, Maeda M, Yoshida T, Sudo A (2011) Thrombin-cleaved osteopontin levels in synovial fluid correlate with disease severity of knee osteoarthritis. J Rheumatol 38:129-134
45. Hashimoto Y, Kakegawa H, Narita Y, Hachiya Y, Hayakawa T, Kos J, Turk V, Katunuma N (2001) Significance of cathepsin B accumulation in synovial fluid of rheumatoid arthritis. Biochem Biophys Res Commun 283:334-339
46. Hdud IM, El-Shafei AA, Loughna P, Barrett-Jolley R, Mobasheri A (2012) Expression of Transient Receptor Potential Vanilloid (TRPV) channels in different passages of articular chondrocytes. Int J Mol Sci 13:4433-4445
47. Hdud IM, Mobasheri A, Loughna PT (2014) Effects of cyclic equibiaxial mechanical stretch on alpha-BK and TRPV4 expression in equine chondrocytes. Springer Plus 3:59
48. Helyes Z, Sandor K, Borbely E, Tekus V, Pinter E, Elekes K, Toth DM, Szolcsanyi J, McDougall JJ (2010) Involvement of transient receptor potential vanilloid 1 receptors in protease-activated receptor-2-induced joint inflammation and nociception. Eur J Pain 14:351-358
49. Horwich MD, Zamore PD (2008) Design and delivery of antisense oligonucleotides to block microRNA function in cultured Drosophila and human cells. Nat Protoc 3:1537-1549
50. Hu F, Zhu W, Wang L (2013) MicroRNA-203 up-regulates nitric oxide expression in temporomandibular joint chondrocytes via targeting TRPV4. Arch Oral Biol 58:192-199
51. Itoh Y, Hatano N, Hayashi H, Onozaki K, Miyazawa K, Muraki K (2009) An environmental sensor, TRPV4 is a novel regulator of intracellular Ca2+ in human synoviocytes. Am J Physiol Cell Physiol 297:C1082-1090
52. Jablonski CL, Ferguson S, Pozzi A, Clark AL (2014) Integrin alpha1beta1 participates in chondrocyte transduction of osmotic stress. Biochem Biophys Res Commun 445:184-190
53. Jia X, Zhang H, Cao X, Yin Y, Zhang B (2014) Activation of TRPV1 mediates thymic stromal lymphopoietin release via the Ca(2+)/NFAT pathway in airway epithelial cells. FEBS Lett 588:3047-3054
54. Jing D, Baik AD, Lu XL, Zhou B, Lai X, Wang L, Luo E, Guo XE (2014) In situ intracellular calcium oscillations in osteocytes in intact mouse long bones under dynamic mechanical loading. FASEB J 28:1582-1592
55. Johnson VL, Hunter DJ (2014) The epidemiology of osteoarthritis. Best Pract Res Clin Rheumatol 28:5-15
56. Kanke T, Takizawa T, Kabeya M, Kawabata A (2005) Physiology and pathophysiology of proteinase-activated receptors (PARs): PAR-2 as a potential therapeutic target. J Pharmacol Sci 97:38-42
57. Kato K, Morita I (2011) Acidosis environment promotes osteoclast formation by acting on the last phase of preosteoclast differentiation: a study to elucidate the action points of acidosis and search for putative target molecules. Eur J Pharmacol 663:27-39
58. Kawabata A (2002) PAR-2: structure, function and relevance to human diseases of the gastric mucosa. Expert Rev Mol Med 4:1-17
59. Kiselyov K, Soyombo A, Muallem S (2007) TRPpathies. J Physiol 578:641-653
60. Kochukov MY, McNearney TA, Fu Y, Westlund KN (2006) Thermosensitive TRP ion channels mediate cytosolic calcium response in human synoviocytes. Am J Physiol Cell Physiol 291:C424-432
61. Kochukov MY, McNearney TA, Yin H, Zhang L, Ma F, Ponomareva L, Abshire S, Westlund KN (2009) Tumor necrosis factor-alpha (TNF-alpha) enhances functional thermal and chemical responses of TRP cation channels in human synoviocytes. Mol Pain 5:49
62. Kong W, McConalogue K, Khitin LM, Hollenberg MD, Payan DG, Bohm SK, Bunnett NW (1997) Luminal trypsin may regulate enterocytes through proteinase-activated receptor 2. Proc Natl Acad Sci U S A 94:8884-8889
63. Krakow D, Vriens J, Camacho N, Luong P, Deixler H, Funari TL, Bacino CA, Irons MB, Holm IA, Sadler L, Okenfuss EB, Janssens A, Voets T, Rimoin DL, Lachman RS, Nilius B, Cohn DH (2009) Mutations in the gene encoding the calcium-permeable ion channel TRPV4 produce spondylometaphyseal dysplasia, Kozlowski type and metatropic dysplasia. Am J Hum Genet 84:307-315
64. Kummer JA, Tak PP, Brinkman BM, van Tilborg AA, Kamp AM, Verweij CL, Daha MR, Meinders AE, Hack CE, Breedveld FC (1994) Expression of granzymes A and B in synovial tissue from patients with rheumatoid arthritis and osteoarthritis. Clin Immunol Immunopathol 73:88-95
65. Lamande SR, Yuan Y, Gresshoff IL, Rowley L, Belluoccio D, Kaluarachchi K, Little CB, Botzenhart E, Zerres K, Amor DJ, Cole WG, Savarirayan R, McIntyre P, Bateman JF (2011) Mutations in TRPV4 cause an inherited arthropathy of hands and feet. Nat Genet 43:1142-1146
66. Lambert C, Dubuc JE, Montell E, Verges J, Munaut C, Noel A, Henrotin Y (2014) Gene expression pattern of cells from inflamed and normal areas of osteoarthritis synovial membrane. Arthritis Rheum 66:960-968
67. Leddy HA, McNulty AL, Guilak F, Liedtke W (2014a) Unraveling the mechanism of by which TRPV4 mutations cause skeletal dysplasias. Rare Dis 2:e962971
68. Leddy HA, McNulty AL, Lee SH, Rothfusz NE, Gloss B, Kirby ML, Hutson MR, Cohn DH, Guilak F, Liedtke W (2014b) Follistatin in chondrocytes: the link between TRPV4 channelopathies and skeletal malformations. FASEB J 28:2525-2537
69. Lee W, Leddy HA, Chen Y, Lee SH, Zelenski NA, McNulty AL, Wu J, Beicker KN, Coles J, Zauscher S, Grandl J, Sachs F, Guilak F, Liedtke WB (2014) Synergy between Piezo1 and Piezo2 channels confers high-strain mechanosensitivity to articular cartilage. Proc Natl Acad Sci U S A 111:E5114-5122
70. Lieben L, Carmeliet G (2012) The involvement of TRP channels in bone homeostasis. Front Endocrinol 3:99
71. Liedtke W, Friedman JM (2003) Abnormal osmotic regulation in trpv4-/- mice. Proc Natl Acad Sci U S A 100:13698-13703
72. Liedtke W, Kim C (2005) Functionality of the TRPV subfamily of TRP ion channels: add mechano-TRP and osmo-TRP to the lexicon! Cell Mol Life Sci 62:2985-3001
73. Liedtke W, Choe Y, Marti-Renom MA, Bell AM, Denis CS, Sali A, Hudspeth AJ, Friedman JM, Heller S (2000) Vanilloid receptor-related osmotically activated channel (VR-OAC), a candidate vertebrate osmoreceptor. Cell 103:525-535
74. Liedtke W, Tobin DM, Bargmann CI, Friedman JM (2003) Mammalian TRPV4 (VR-OAC) directs behavioral responses to osmotic and mechanical stimuli in Caenorhabditis elegans. Proc Natl Acad Sci U S A 100(Suppl 2):14531-14536
75. Loeser RF, Goldring SR, Scanzello CR, Goldring MB (2012) Osteoarthritis: a disease of the joint as an organ. Arthritis Rheum 64:1697-1707
76. Masuyama R, Vriens J, Voets T, Karashima Y, Owsianik G, Vennekens R, Lieben L, Torrekens S, Moermans K, Vanden Bosch A, Bouillon R, Nilius B, Carmeliet G (2008) TRPV4-mediated calcium influx regulates terminal differentiation of osteoclasts. Cell Metab 8:257-265
77. Masuyama R, Mizuno A, Komori H, Kajiya H, Uekawa A, Kitaura H, Okabe K, Ohyama K, Komori T (2012) Calcium/calmodulin-signaling supports TRPV4 activation in osteoclasts and regulates bone mass. J Bone Miner Res 27:1708-1721
78. McCarty WJ, Masuda K, Sah RL (2011) Fluid movement and joint capsule strains due to flexion in rabbit knees. J Biomech 44:2761-2767
79. McEntagart M (2012) TRPV4 axonal neuropathy spectrum disorder. J Clin Neurosci 19:927-933
80. Michael ES, Kuliopulos A, Covic L, Steer ML, Perides G (2013) Pharmacological inhibition of PAR2 with the pepducin P2pal-18S protects mice against acute experimental biliary pancreatitis. Am J Physiol Gastrointest Liver Physiol 304:G516-526
81. Mizoguchi F, Mizuno A, Hayata T, Nakashima K, Heller S, Ushida T, Sokabe M, Miyasaka N, Suzuki M, Ezura Y, Noda M (2008) Transient receptor potential vanilloid 4 deficiency suppresses unloading-induced bone loss. J Cell Physiol 216:47-53
82. Moffatt JD (2004) Proteinase-activated receptor pharmacology: trickier and trickier. Br J Pharmacol 143:441
83. Moore C, Cevikbas F, Pasolli HA, Chen Y, Kong W, Kempkes C, Parekh P, Lee SH, Kontchou NA, Yeh I, Jokerst NM, Fuchs E, Steinhoff M, Liedtke WB (2013) UVB radiation generates sunburn pain and affects skin by activating epidermal TRPV4 ion channels and triggering endothelin-1 signaling. Proc Natl Acad Sci U S A 110:E3225-3234
84. Morris R, Winyard PG, Blake DR, Morris CJ (1994) Thrombin in inflammation and healing: relevance to rheumatoid arthritis. Ann Rheum Dis 53:72-79
85. Mow VC, Ratcliffe A, Poole AR (1992) Cartilage and diarthrodial joints as paradigms for hierarchical materials and structures. Biomaterials 13:67-97
86. Mow VC, Bachrach NM, Setton LA, Guilak F (1994) Stress, strain, pressure and flow fields in articular cartilage and chondrocytes. In: Mow VC, Tran-Son-Tay R, Guilak F, Hochmuth RM (eds) Cell mechanics and cellular engineering. Springer, New York, pp 345-379
87. Muramatsu S, Wakabayashi M, Ohno T, Amano K, Ooishi R, Sugahara T, Shiojiri S, Tashiro K, Suzuki Y, Nishimura R, Kuhara S, Sugano S, Yoneda T, Matsuda A (2007) Functional gene screening system identified TRPV4 as a regulator of chondrogenic differentiation. J Biol Chem 282:32158-32167
88. Nakagawa TY, Brissette WH, Lira PD, Griffiths RJ, Petrushova N, Stock J, McNeish JD, Eastman SE, Howard ED, Clarke SR, Rosloniec EF, Elliott EA, Rudensky AY (1999) Impaired invariant chain degradation and antigen presentation and diminished collagen-induced arthritis in cathepsin S null mice. Immunity 10:207-217
89. Nilius B, Voets T (2004) Diversity of TRP channel activation. Novartis Found Symp 258:140-149, discussion 149-159, 263-146
90. Nilius B, Voets T (2013) The puzzle of TRPV4 channelopathies. EMBO Rep 14:152-163
91. Nishimura G, Lausch E, Savarirayan R, Shiba M, Spranger J, Zabel B, Ikegawa S, Superti-Furga A, Unger S (2012) TRPV4-associated skeletal dysplasias. Am J Med Genet C Semin Med Genet 160C:190-204
92. Noss EH, Chang SK, Watts GF, Brenner MB (2011) Modulation of matrix metalloproteinase production by rheumatoid arthritis synovial fibroblasts after cadherin 11 engagement. Arthritis Rheum 63:3768-3778
93. O'Conor CJ, Griffin TM, Liedtke W, Guilak F (2013) Increased susceptibility of Trpv4-deficient mice to obesity and obesity-induced osteoarthritis with very high-fat diet. Ann Rheum Dis 72:300-304
94. O'Conor CJ, Leddy HA, Benefield HC, Liedtke WB, Guilak F (2014) TRPV4-mediated mechanotransduction regulates the metabolic response of chondrocytes to dynamic loading. Proc Natl Acad Sci U S A 111:1316-1321
95. Okada Y, Takeuchi N, Tomita K, Nakanishi I, Nagase H (1989) Immunolocalization of matrix metalloproteinase 3 (stromelysin) in rheumatoid synovioblasts (B cells): correlation with rheumatoid arthritis. Ann Rheum Dis 48:645-653
96. Okuhara DY, Hsia AY, Xie M (2007) Transient receptor potential channels as drug targets. Expert Opin Ther Targets 11:391-401
97. Opdenakker G, Masure S, Grillet B, Van Damme J (1991) Cytokine-mediated regulation of human leukocyte gelatinases and role in arthritis. Lymphokine Cytokine Res 10:317-324
98. Phan MN, Leddy HA, Votta BJ, Kumar S, Levy DS, Lipshutz DB, Lee SH, Liedtke W, Guilak F (2009) Functional characterization of TRPV4 as an osmotically sensitive ion channel in porcine articular chondrocytes. Arthritis Rheum 60:3028-3037
99. Poole AR, Nelson F, Dahlberg L, Tchetina E, Kobayashi M, Yasuda T, Laverty S, Squires G, Kojima T, Wu W, Billinghurst RC (2003) Proteolysis of the collagen fibril in osteoarthritis. Biochem Soc Symp: 115-123
100. Poole DP, Amadesi S, Veldhuis NA, Abogadie FC, Lieu T, Darby W, Liedtke W, Lew MJ, McIntyre P, Bunnett NW (2013) Protease-activated receptor 2 (PAR2) protein and transient receptor potential vanilloid 4 (TRPV4) protein coupling is required for sustained inflammatory signaling. J Biol Chem 288:5790-5802
101. Posthumus MD, Limburg PC, Westra J, van Leeuwen MA, van Rijswijk MH (2003) Serum matrix metalloproteinase 3 levels in comparison to C-reactive protein in periods with and without progression of radiological damage in patients with early rheumatoid arthritis. Clin Exp Rheumatol 21:465-472
102. Pozgan U, Caglic D, Rozman B, Nagase H, Turk V, Turk B (2010) Expression and activity profiling of selected cysteine cathepsins and matrix metalloproteinases in synovial fluids from patients with rheumatoid arthritis and osteoarthritis. Biol Chem 391:571-579
103. Rannou F, Francois M, Corvol MT, Berenbaum F (2006) Cartilage breakdown in rheumatoid arthritis. Joint Bone Spine 73:29-36
104. Rattenholl A, Steinhoff M (2008) Proteinase-activated receptor-2 in the skin: receptor expression, activation and function during health and disease. Drug News Perspect 21:369-381
105. Rock MJ, Prenen J, Funari VA, Funari TL, Merriman B, Nelson SF, Lachman RS, Wilcox WR, Reyno S, Quadrelli R, Vaglio A, Owsianik G, Janssens A, Voets T, Ikegawa S, Nagai T, Rimoin DL, Nilius B, Cohn DH (2008) Gain-of-function mutations in TRPV4 cause autosomal dominant brachyolmia. Nat Genet 40:999-1003
106. Ronday HK, van der Laan WH, Tak PP, de Roos JA, Bank RA, TeKoppele JM, Froelich CJ, Hack CE, Hogendoorn PC, Breedveld FC, Verheijen JH (2001) Human granzyme B mediates cartilage proteoglycan degradation and is expressed at the invasive front of the synovium in rheumatoid arthritis. Rheumatology (Oxford) 40:55-61
107. Rosenthal AK, Gohr CM, Mitton-Fitzgerald E, Lutz MK, Dubyak GR, Ryan LM (2013) The progressive ankylosis gene product ANK regulates extracellular ATP levels in primary articular chondrocytes. Arthritis Res Ther 15:R154
108. Russell FA, Schuelert N, Veldhoen VE, Hollenberg MD, McDougall JJ (2012) Activation of PAR(2) receptors sensitizes primary afferents and causes leukocyte rolling and adherence in the rat knee joint. Br J Pharmacol 167:1665-1678
109. Saitta B, Passarini J, Sareen D, Ornelas L, Sahabian A, Argade S, Krakow D, Cohn DH, Svendsen CN, Rimoin DL (2014) Patient-derived skeletal dysplasia induced pluripotent stem cells display abnormal chondrogenic marker expression and regulation by BMP2 and TGFbeta1. Stem Cells Dev 23:1464-1478
110. Salat K, Moniczewski A, Librowski T (2013) Transient receptor potential channels - emerging novel drug targets for the treatment of pain. Curr Med Chem 20:1409-1436
111. Sampat SR, Dermksian MV, Oungoulian SR, Winchester RJ, Bulinski JC, Ateshian GA, Hung CT (2013) Applied osmotic loading for promoting development of engineered cartilage. J Biomech 46:2674-2681
112. Schaible H (2013) Joint pain: basic mechanisms. In: McMahon S, Koltzenburg M, Tracey I, Turk D (eds) Wall and Melzack's textbook of pain. Elsevier Churchill Livingstone Publishers, Philadelphia, pp 609-619
113. Sipe WE, Brierley SM, Martin CM, Phillis BD, Cruz FB, Grady EF, Liedtke W, Cohen DM, Vanner S, Blackshaw LA, Bunnett NW (2008) Transient receptor potential vanilloid 4 mediates protease activated receptor 2-induced sensitization of colonic afferent nerves and visceral hyperalgesia. Am J Physiol Gastrointest Liver Physiol 294:G1288-1298
114. Sostegni S, Diakov A, McIntyre P, Bunnett N, Korbmacher C, Haerteis S (2014) Sensitisation of TRPV4 by PAR is independent of intracellular calcium signalling and can be mediated by the biased agonist neutrophil elastase. Pflugers Arch Eur J Physiol. doi: 10.1007/s00424-014-1539-6
115. Stanczyk J, Ospelt C, Karouzakis E, Filer A, Raza K, Kolling C, Gay R, Buckley CD, Tak PP, Gay S, Kyburz D (2011) Altered expression of microRNA-203 in rheumatoid arthritis synovial fibroblasts and its role in fibroblast activation. Arthritis Rheum 63:373-381
116. Steinhoff M, Corvera CU, Thoma MS, Kong W, McAlpine BE, Caughey GH, Ansel JC, Bunnett NW (1999) Proteinase-activated receptor-2 in human skin: tissue distribution and activation of keratinocytes by mast cell tryptase. Exp Dermatol 8:282-294
117. Steinhoff M, Vergnolle N, Young SH, Tognetto M, Amadesi S, Ennes HS, Trevisani M, Hollenberg MD, Wallace JL, Caughey GH, Mitchell SE, Williams LM, Geppetti P, Mayer EA, Bunnett NW (2000) Agonists of proteinase-activated receptor 2 induce inflammation by a neurogenic mechanism. Nat Med 6:151-158
118. Strotmann R, Harteneck C, Nunnenmacher K, Schultz G, Plant TD (2000) OTRPC4, a nonselective cation channel that confers sensitivity to extracellular osmolarity. Nat Cell Biol 2:695-702
119. Sun HB, Yokota H (2002) Reduction of cytokine-induced expression and activity of MMP-1 and MMP-13 by mechanical strain in MH7A rheumatoid synovial cells. Matrix Biol 21:263-270
120. Suzuki T, Notomi T, Miyajima D, Mizoguchi F, Hayata T, Nakamoto T, Hanyu R, Kamolratanakul P, Mizuno A, Suzuki M, Ezura Y, Izumi Y, Noda M (2013) Osteoblastic differentiation enhances expression of TRPV4 that is required for calcium oscillation induced by mechanical force. Bone 54:172-178
121. Terada Y, Fujimura M, Nishimura S, Tsubota M, Sekiguchi F, Nishikawa H, Kawabata A (2013) Contribution of TRPA1 as a downstream signal of proteinase-activated receptor-2 to pancreatic pain. J Pharmacol Sci 123:284-287
122. Thorneloe KS, Cheung M, Bao W, Alsaid H, Lenhard S, Jian MY, Costell M, Maniscalco-Hauk K, Krawiec JA, Olzinski A, Gordon E, Lozinskaya I, Elefante L, Qin P, Matasic DS, James C, Tunstead J, Donovan B, Kallal L, Waszkiewicz A, Vaidya K, Davenport EA, Larkin J, Burgert M, Casillas LN, Marquis RW, Ye G, Eidam HS, Goodman KB, Toomey JR, Roethke TJ, Jucker BM, Schnackenberg CG, Townsley MI, Lepore JJ, Willette RN (2012) An orally active TRPV4 channel blocker prevents and resolves pulmonary edema induced by heart failure. Sci Transl Med 4:159ra-148
123. Tian W, Fu Y, Garcia-Elias A, Fernandez-Fernandez JM, Vicente R, Kramer PL, Klein RF, Hitzemann R, Orwoll ES, Wilmot B, McWeeney S, Valverde MA, Cohen DM (2009) A loss-of-function nonsynonymous polymorphism in the osmoregulatory TRPV4 gene is associated with human hyponatremia. Proc Natl Acad Sci U S A 106:14034-14039
124. Tindell AG, Kelso EB, Ferrell WR, Lockhart JC, Walsh DA, Dunning L, McInnes IB (2012) Correlation of protease-activated receptor-2 expression and synovitis in rheumatoid and osteoarthritis. Rheumatol Int 32:3077-3086
125. Troeberg L, Nagase H (2012) Proteases involved in cartilage matrix degradation in osteoarthritis. Biochim Biophys Acta 1824:133-145
126. Turkenburg JP, Lamers MB, Brzozowski AM, Wright LM, Hubbard RE, Sturt SL, Williams DH (2002) Structure of a Cys25->Ser mutant of human cathepsin S. Acta Crystallogr D Biol Crystallogr 58:451-455
127. van der Eerden BC, Oei L, Roschger P, Fratzl-Zelman N, Hoenderop JG, van Schoor NM, Pettersson-Kymmer U, Schreuders-Koedam M, Uitterlinden AG, Hofman A, Suzuki M, Klaushofer K, Ohlsson C, Lips PJ, Rivadeneira F, Bindels RJ, van Leeuwen JP (2013) TRPV4 deficiency causes sexual dimorphism in bone metabolism and osteoporotic fracture risk. Bone 57:443-454
128. Vergnolle N, Bunnett NW, Sharkey KA, Brussee V, Compton SJ, Grady EF, Cirino G, Gerard N, Basbaum AI, Andrade-Gordon P, Hollenberg MD, Wallace JL (2001) Proteinase-activated receptor-2 and hyperalgesia: a novel pain pathway. Nat Med 7:821-826
129. Vincent TL (2013) Targeting mechanotransduction pathways in osteoarthritis: a focus on the pericellular matrix. Curr Opin Pharmacol 13:449-454
130. Vincent F, Duncton MA (2011) TRPV4 agonists and antagonists. Curr Top Med Chem 11:2216-2226
131. Wang L, Wang Y, Han Y, Henderson SC, Majeska RJ, Weinbaum S, Schaffler MB (2005) In situ measurement of solute transport in the bone lacunar-canalicular system. Proc Natl Acad Sci U S A 102:11911-11916
132. Weidauer E, Yasuda Y, Biswal BK, Cherny M, James MN, Bromme D (2007) Effects of disease-modifying anti-rheumatic drugs (DMARDs) on the activities of rheumatoid arthritis-associated cathepsins K and S. Biol Chem 388:331-336
133. Weinstein MM, Tompson SW, Chen Y, Lee B, Cohn DH (2014) Mice expressing mutant Trpv4 recapitulate the human TRPV4 disorders. J Bone Miner Res. doi: 10.1002/jbmr.2220
134. Willard VP, Diekman BO, Sanchez-Adams J, Christoforou N, Leong KW, Guilak F (2014) Use of cartilage derived from murine induced pluripotent stem cells for osteoarthritis drug screening. Arthritis Rheumatol 66:3062-3072
135. Zhao P, Lieu T, Barlow N, Metcalf M, Veldhuis N, Jensen D, Kocan M, Sostegni S, Haerteis S, Baraznenok V, Henderson I, Lindstrom E, Guerrero-Alba R, Valdez-Morales E, Liedtke W, McIntyre P, Vanner SJ, Korbmacher C, Bunnett NW (2014) Cathepsin S causes inflammatory pain via biased agonism of PAR2 and TRPV4. J Biol Chem 289(39):27215-34. doi: 10.1074/jbc.M114.599712