Abstract
Discoidin domain receptor2 (DDR2), a cell membrane tyrosine kinase on chondrocytes surface plays main role in cell-ECM interaction during the progressive degeneration of articular cartilage in osteoarthritis. The degraded component of ECM, type II collagen upon DDR2 binding provokes synthesis of matrix metalloproteinases (MMPs), responsible for severe destruction of joint tissues. DDR2 knockout has been investigated to decline the expression of MMP-1 and 13. Previously, various molecules were effective in preclinical level against different targets in OA, but found to be collapsed in clinical trial due to insufficient target specificity and clinical toxicity. Review emphasizes the role of DDR2 in the degeneration of cartilage in osteoarthritis (OA) and its blocking by DDR2 antagonist attenuates the disease severity. DDR2 in chondrocytes contributes paramount role in degradation of cartilage at early stage of osteoarthritis via collagen 2 binding through the felicitation of TGF-β signaling molecule and other triggering factors. DDR2 involvement in regulation of matrix metalloproteinase (MMP), cross talking interaction in maintenance of ECM-chondrocytes, bone developments, interference RNA and designing the DDR2 antagonists have been critically investigated. The exploration may conclude that the DDR2 could be the novel pharmacological target to prevent the progression of osteoarthritis at early stage because of over expression of DDR2 and MMP which further promotes severe cartilage degeneration. Owing to pharmacological specificity of DDR2 in OA as drug target, it is to be hypothesized that development of safe molecules as DDR2 antagonist could be the good option in the treatment of OA with promising landmark.
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Vogel W, Gish GD, Alves F, Pawson T. The discoidin domain receptor tyrosine kinases are activated by collagen. Mol Cell 1997;1:13–23.
Shrivastava A, Radziejewski C, Campbell E, Kovac L, McGlynn M, Ryan TE, et al. An orphan receptor tyrosine kinase family whose members serve as nonintegrin collagen receptors. Mol Cell 1997;1:25–34.
Labrador JP, Aconitia V, Tuckerman J, Lin C, Oleos E, Manes S, et al. The collagen receptor ddr2 regulates proliferation and its elimination leads to dwarfism. EMBO Rep 2001;2:446–52.
Xu L, Peng H, Wu D, Hu K, Goldring MB, Olsen BR, et al. Activation of the discoidin domain receptor 2 induces expression of matrix metalloproteinase 13 associated with osteoarthritis in mice. J Biol Chem 2005;280:548–55.
Us J, Yu J, Ren T, Zhang W, Zhang Y, Liu X, et al. Discoidin domain receptor 2 is associated with the increased expression of matrix metalloproteinase-13 in synovial fibroblasts of rheumatoid arthritis. Mol Cell Biochem 2009;330(1–2):141–52.
Xu L, Servais J, Polar I, Kim D, Lee PL, Chung K, et al. Attenuation of osteoarthritis progression by reduction of discoid in domain receptor 2 in mice. Arthritis Rheum 2010;62:2736–44.
Gentile C, Concede R. Cartilage and bone extracellular matrix. Cur Pharm Des 2009;15(12):1334–48.
Siam S, Irina K, Mare L, Hannes T, Marina A, Andres A, et al. Evaluation of correlation of articular cartilage staining for ddr2 and proteoglycans with histological tissue damage and the results of radiographic assessment in patients with early stages of knee osteoarthritis. Int J Clin Exp Pathol 2015;8:5658–65.
Clutterbuck AL, Aspin KE, Harris P, Alloway D, Mubashir A. Targeting matrix metalloproteinases in inflammatory conditions. Curr Drug Targets 2009;10(12):1245–54.
Miyasaka N, Hirata Y. Nitric oxide and inflammatory arthritis’s. Life Sci 1997;61(21):2073–81.
De Isla NG, Mainard D, Muller S, Stoltz JF. In vitro effects of diacerein on NO production by chondrocytes in response to proinflammatory mediators. Biomed Mater Eng 2008;18(1 Suppl):S99–S104.
Kern T, Helmrich U, Gruninger A, Bohme B, Wolf G, Rübsamen-Waigmann H, et al. Structure, expression and chromosomal mapping of tkt from man and mouse: a new subclass of receptor tyrosine kinases with a factor viii-like domain. Oncogene 1993;8:3433–40.
Johnson JD, Edman JC, Rutter WJ. A receptor tyrosine kinase found in breast carcinoma cells has an extracellular discoidin-like domain. Proc Natl Acad Sci U S A 1993;90:5677–81.
Marco ED, Cutuli N, Guerra L, Cancedda R, Luca MD. Molecular cloning of trke, a novel trk-related putative tyrosine kinase receptor isolated from normal human keratinocytes and widely expressed by normal human tissues. J Biol Chem 1993;268:24290–6.
Zerlin M, Julius MA, Goldfarb M. Nep A novel receptor-like tyrosine kinase expressed in proliferating neuroepithelia. Oncogene 1993;8:2731–9.
Perez JL, Shen X, Finkernagel S, Sciorra L, Jenkins NA, Gilbert DJ. Identification and chromosomal mapping of a receptor tyrosine kinase with a putative phospholipid binding sequence in its ectodomain. Oncogene 1994;9:211–9.
Perez JL, Jing SQ, Wong TW. Identification of two isoform of cak receptor kinase that are expressed in breast tumor cell line. Oncogene 1996;12:1469–77.
Lai C, Lemke G. Structure and expression of the tyro 10 receptor tyrosine kinase. Oncogene 1994;9:877–83.
Sanchez MP, Tapley P, Saini SS, He B, Pulido D, Barbacid M. Multiple tyrosine protein kinases in rat hippocampal neurons: isolation of ptk-3, a receptor expressed in proliferative zones of the developing brain. Proc Natl Acad Sci U S A 1994;91:1819–23.
Alves F, Vogel W, Mossie K, Millauer B, Höfler H, Ullrich A. Distinct structural characteristics of discoidin subfamily receptor tyrosine kinases and complementary expression in human cancer. Oncogene 1995;10:609–18.
Borza CM, Pozzi A. Discoidin domain receptors in disease. Matrix Biol 2014;34:185–92.
Zhao H, Bian H, Bu X, Zhang S, Zhang P, Yu J, et al. Targeting of discoidin domain receptor 2 (DDR2) prevents myofibroblast activation and neovessel formation during pulmonary fibrosis. Mol Ther 2016;24:1734–44.
Little CB, Braai A, Burkhardt D, Smith SM, Fusing AJ, Web Z, et al. Matrix metalloproteinase 13-deficient mice are resistant to osteoarthritic cartilage erosion but not chondrocyte hypertrophy or osteophyte development. Arthritis Rheum 2009;60:3723–33.
Lin KL, Chou CH, Hsieh SC, Hwa SY, Lee MT, Wang FF. Transcriptional upregulation of ddr2 by atf4 facilitates osteoblastic differentiation through p38 mapk-mediated runx2 activation. J Bone Miner Res 2010;25:2489–503.
Elvira O, Kazuo I, Francis JE, Lieming X, Li-Hsien W, Hsin CL, et al. Ddr2 receptor promotes mmp-2-mediated proliferation and invasion by hepatic stellate cells. J Clin Invest 2001;108:1369–78.
Botter SM, van Osch GJ, Clockaerts S, Waarsing JH, Weinman’s H, van Leeuwen JP. Osteoarthritis induction leads to early and temporal subchondral plate porosity in the tibial plateau of mice: an in vivo microfocal computed tomography study. Arthritis Rheum 2011;63:2690–9.
Gu XI, Palacio-Mancheno PE, Leong DJ, Borisov YA, Williams E, Maldonado N, et al. High-resolution micro arthrography of hard and soft tissues in a murine model. Osteoarthr Cartil 2012;20:1011–9.
Yang X, Chen L, Xu X, Li C, Huang C, Deng C. TGF-beta/Smad3 signals repress chondrocyte hypertrophic differentiation and are required for maintaining articular cartilage. J Cell Biol 2001;153:35–46.
Xu L, Peng H, Glasson S, Lee PL, Hu K, Ijiri K, et al. Increased expression of the collagen receptor discoidin domain receptor 2 in articular cartilage as a key event in the pathogenesis of osteoarthritis. Arthritis Rheum 2007;56:2663–73.
Tchetina EV, Kobayashi M, Yasuda T, Meijers T, Pidoux I, Poole AR. Chondrocyte hypertrophy can be induced by a cryptic sequence of type II collagen and is accompanied by the induction of MMP-13 and collagenase activity: implications for development and arthritis. Matrix Biol 2007;26:247–58.
Yasuda T, Tchetina E, Ohsawa K, Roughley PJ, Wu W, Mousa A, et al. Peptides of type II collagen can induce the cleavage of type II collagen and aggrecan in articular cartilage. Matrix Biol 2006;25:419–29.
Jennings L, Wu L, King KB, Hämmerle H, Cs-Szabo G, Mollenhauer J. The effects of collagen fragments on the extracellular matrix metabolism of bovine and human chondrocytes. Connect Tissue Res 2001;42:71–86.
Xu L, Polur I, Servais JM, Hsieh S, Lee PL, Goldring MB, et al. Intact pericellular matrix of articular cartilage is required for unactivated discoidin domain receptor 2 in the mouse model. Am J Pathol 2011;179:1338–46.
Zhen G, Wen C, Jia X, Li Y, Crane JL, Mears SC, et al. Inhibition of TGF-β signaling in mesenchymal stem cells of subchondral bone attenuates osteoarthritis. Nat Med 2013;19(6):704–12.
Xu L, Polur I, Lim C, Servais JM, Dobeck J, Li Y, et al. Early-onset osteoarthritis of mouse temporomandibular joint induced by partial discectomy. Osteoarthr Cartil 2009;17(7):917–22.
Kawamura I, Maeda S, Imamura K, Setoguchi T, Yokouchi M, Ishidou Y, et al. SnoN suppresses maturation of chondrocytes by mediating signal cross-talk between transforming growth factor-β and bone morphogenetic protein pathways. J Biol Chem 2012;287(34):29101–13.
Xu L, Golshirazian I, Asbury BJ, Li Y. Induction of high temperature requirement A1, a serine protease, by TGF-b1 in articular chondrocytes of mouse models of OA. Histol Histopathol 2014;29:609–18.
Blaney Davidson EN, Vitters EL, van Beuningen HM, van de Loo FA, van den Berg WB, van der Kraan PM. Resemblance of osteophytes in experimental osteoarthritis to transforming growth factor beta-induced osteophytes: limited role of bone morphogenetic protein in early osteoarthritic osteophyte formation. Arthritis Rheum 2007;56:4065–73.
Bakker AC, van de Loo FA, van Beuningen HM, Sime P, van Lent PL, van der Kraan PM, et al. Overexpression of active TGF-beta-1 in the murine knee joint: evidence for synovial-layerdependent chondro-osteophyte formation. Osteoarthr Cartil 2001;9:128–36.
Osamu I, Masanori O, Noritaka N, Naoki G, Nobuo N, Ichio S. Structural basis of the collagen-binding mode of discoidin domain receptor 2. EMBO J 2007;26:4168–76.
Ali BR, Xu H, Akawi NA, John A, Karuvantevida NS, Langer R, et al. Trafficking defects and loss of ligand binding are the underlying causes of all reported ddr2 missense mutations found in smed-sl patients. Hum Mol Genet 2010;19:2239–50.
Mitchell PG, Magna HA, Reeves LM, Lopresti-Morrow LL, Yocum SA, Rosner PJ, et al. Cloning, expression, and type II collagenolytic activity of matrix metalloproteinase-13 from human osteoarthritic cartilage. J Clin Invest 1996;97:761–8.
Shlopov BV, Lie WR, Mainardi CL, Cole AA, Chubinskaya S, Hasty KA. Osteoarthritic lesion: involvement of three different collagenases. Arthritis Rheum 1997;40:2062–74.
Pulsatelli L, Addimanda O, Brusi V, Pavloska B, Meliconi R. New findings inosteoarthritis pathogenesis: therapeutic implication. Ther Adv Chronic Dis 2013;4(1):23–43.
McDonald LT, Johnson SD, Russell DL, Young MR, LaRue AC. Role of a novel immune modulating DDR2-expressing population in silica-induced pulmonary fibrosis. PLoS One 2017;12(7) e0180724.
Buckwalter JA, Anderson DD, Brown TD, Tochigi Y, Martin JA. The roles of mechanical stresses in the pathogenesis of osteoarthritis: implications for treatment of joint injuries. Cartilage 2013;4(4):286–94.
Leitinger B. Discoidin domain receptor functions in physiological and pathological conditions. Int Rev Cell Mol Biol 2014;310:39–87.
Bargal R, Cormier-Daire V, Ben-Neriah Z, Merrer ML, Sosna J, Melki J, et al. Mutations in ddr2 gene cause smed with short limbs and abnormal calcifications. Am J Hum Genet 2009;84:80–4.
Ge C, Mohamed F, Binrayes A, Kapila S, Franceschi RT. Selective role of discoidin domain receptor 2 in murine temporomandibular joint development and aging. J Dent Res 2018;97(3):321–8.
Matyas J, Atley L, Ionescu M, Eyre D, Poole A. Analysis of cartilage biomarkers in the early phases of canine experimental osteoarthritis. Arthritis Rheum 2004;50:543–52.
Leitinger B, Steplewski A, Fertala A. The D2 period of collagen II contains a specific binding site for the human discoidin domain receptor DDR2. J Mol Biol 2004;344(4):993–1003.
Reboul P, Pelletier JP, Tardif G, Cloutier JM. The new collagenase, collagenase-3, is expressed and synthesized by human chondrocytes but not by synoviocytes. A role in osteoarthritis. J Clin Invest 1996;97:2011–9.
Klatt AR, Zech D, Kühn G, Paul-Klausch B, Klinger G, Renno JH, et al. Discoidin domain receptor 2 mediates the collagen II dependent release of interleukin-6 in primary human chondrocytes. J Pathol 2009;218:241–7.
Bau B, Gebhard PM, Haag J, Knorr T, Bartnik E, Aigner T. Relative messenger rna expression profiling of collagenases and aggrecanases in human articular chondrocytes in vivo and in vitro. Arthritis Rheum 2002;46:2648–57.
Tetlow LC, Adlam DJ, Woolley DE. Matrix metalloproteinase and proinflammatory cytokine production by chondrocytes of human osteoarthritic cartilage: associations with degenerative changes. Arthritis Rheum 2001;44:585–94.
Neuhold LA, Killar L, Zhao W, Sung ML, Warner L, Kulik J, et al. Postnatal expression in hyaline cartilage of constitutively active human collagenase-3 (mmp-13) induces osteoarthritis in mice. J Clin Invest 2001;107:35–44.
Sunk IG, Bobacz K, Hofstaetter JG, Amoyo L, Soleiman A, Smolen J, et al. Increased expression of discoidin domain receptor 2 is linked to the degree of cartilage damage in human knee joints: a potential role in osteoarthritis pathogenesis. Arthritis Rheum 2007;56:3685–92.
Matyas J, Astley L, Ionescu M, Eyre D, Poole A. Analysis of cartilage biomarkers in the early phases of canine experimental osteoarthritis. Arthritis Rheum 2004;50:543–52.
Iwai LK, Payne LS, Luczynski MT, Chang F, Xu H, Clinton RW, et al. Phosphoproteomics of collagen receptor networks reveals shp-2 phosphorylation downstream of wild-type ddr2 and its lung cancer mutants. Biochem J 2013;454:501–13.
Ikeda K, Wang LH, Torres R, Zhao H, Olaso E, Eng FJ, et al. Discoidin domain receptor 2 interacts with src and shc following its activation by type I collagen. J Biol Chem 2002;277:19206–12.
Zhang Y, Su J, Yu J, Bu X, Ren T, Liu X, et al. An essential role of discoidin domain receptor 2 (ddr2) in osteoblast differentiation and chondrocyte maturation via modulation of runx2 activation. J Bone Miner Res 2011;26:604–17.
Yamasaki K, Nakasa T, Miyaki S, Ishikawa M, Deie M, Adachi N, et al. Expression of microrna-146a in osteoarthritis cartilage. Arthritis Rheum 2009;60:1035–41.
Jones SW, Watkins G, Le Good N, Roberts S, Murphy CL, Brockbank SM, et al. The identification of differentially expressed microRNA in osteoarthritic tissue that modulate the production of TNF-alpha and MMP13. Osteoarthr Cartil 2009;17:464–72.
Iliopoulos D, Malizos KN, Oikonomou P, Tsezou A. Integrative microrna and proteomic approaches identify novel osteoarthritis genes and their collaborative metabolic and inflammatory networks. PLoS One 2008;3:e3740.
Akhtar N, Rasheed Z, Ramamurthy S, Anbazhagan AN, Voss FR, Haqqi TM. microRNA-27b regulates the expression of matrix metalloproteinase 13 in human osteoarthritis chondrocytes. Arthritis Rheum 2010;62:1361–71.
Salazar A, Polur I, Servais JM, Li Y, Xu L. Delayed progression of condylar cartilage degeneration, by reduction of the discoidin domain receptor 2, in the temporomandibular joints of osteoarthritic mouse models. J Oral Pathol Med 2014;43:317–21.
Siddiqui K, Kim GW, Lee DH, Shin HR, Yang EG, Lee NT, et al. Actinomycin D identified as an inhibitor of discoidin domain receptor 2 interactions with collagen through an insect cell based screening of a drug compound library. Biol Pharm Bull 2009;32(1):136–41.
Richters A, Nguyen HD, Phan T, Simard JR, Grütter C, Engel J, et al. Identification of type II and III ddr2 inhibitors. J Med Chem 2014;57:4252–62.
Manning LB, Li Y, Chickamauga NS, Li X, Xu L. Discoidin domain receptor 2 as a potential therapeutic target for development of disease-modifying osteoarthritis drugs. Am J Pathol 2016;186(11):3000–10.
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Kumar, A., Dutta Choudhury, M., Ghosh, P. et al. Discoidin domain receptor 2: An emerging pharmacological drug target for prospective therapy against osteoarthritis. Pharmacol. Rep 71, 399–408 (2019). https://doi.org/10.1016/j.pharep.2019.01.007
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DOI: https://doi.org/10.1016/j.pharep.2019.01.007