Matrix metalloproteinases in bone development and pathology: current knowledge and potential clinical utility

References

• Ortega N, Behonick DJ, Werb Z. Matrix remodeling during endochondral ossification. Trends Cell Biol. 2004;14(2):86–93.
   PubMed Web of Science ®Google Scholar
• Mackie EJ, Ahmed YA, Tatarczuch L, Chen KS, Mirams M. Endochondral ossification: how cartilage is converted into bone in the developing skeleton. Int J Biochem Cell Biol. 2008;40(1):46–62.
   PubMed Web of Science ®Google Scholar
• Takaishi H, Kimura T, Dalal S, Okada Y, D’Armiento J. Joint diseases and matrix metalloproteinases: a role for MMP-13. Curr Pharm Biotechnol. 2008;9(1):47–54.
   PubMed Web of Science ®Google Scholar
• Behonick DJ, Xing Z, Lieu S, et al. Role of matrix metalloproteinase 13 in both endochondral and intramembranous ossification during skeletal regeneration. PloS One. 2007;2(11):e1150.
   Web of Science ®Google Scholar
• Vu TH, Werb Z. Matrix metalloproteinases: effectors of development and normal physiology. Genes Dev. 2000;14(17):2123–2133.
   PubMed Web of Science ®Google Scholar
• Hua H, Li M, Luo T, Yin Y, Jiang Y. Matrix metalloproteinases in tumorigenesis: an evolving paradigm. Cell Mol Life Sci. 2011;68(23):3853–3868.
   PubMed Web of Science ®Google Scholar
• Deryugina EI, Quigley JP. Tumor angiogenesis: MMP-mediated induction of intravasation- and metastasis-sustaining neovasculature. Matrix Biol. 2015;44–46:94–112.
   Web of Science ®Google Scholar
• Paiva KB, Granjeiro JM. Bone tissue remodeling and development: focus on matrix metalloproteinase functions. Arch Biochem Biophys. 2014;561:74–87.
   PubMed Web of Science ®Google Scholar
• Xue M, Le NT, Jackson CJ. Targeting matrix metalloproteases to improve cutaneous wound healing. Expert Opin Ther Targets. 2006;10(1):143–155.
   PubMed Web of Science ®Google Scholar
• Le NT, Xue M, Castelnoble LA, Jackson CJ. The dual personalities of matrix metalloproteinases in inflammation. Front Biosci. 2007;12:1475–1487.
   PubMedGoogle Scholar
• Nagase H, Visse R, Murphy G. Structure and function of matrix metalloproteinases and TIMPs. Cardiovasc Res. 2006;69(3):562–573.
   PubMed Web of Science ®Google Scholar
• Holmbeck K, Bianco P, Caterina J, et al. MT1-MMP-deficient mice develop dwarfism, osteopenia, arthritis, and connective tissue disease due to inadequate collagen turnover. Cell. 1999;99(1):81–92.
   PubMed Web of Science ®Google Scholar
• Ra HJ, Parks WC. Control of matrix metalloproteinase catalytic activity. Matrix Biol. 2007;26(8):587–596.
   PubMed Web of Science ®Google Scholar
• Yan C, Boyd DD. Regulation of matrix metalloproteinase gene expression. J Cell Physiol. 2007;211(1):19–26.
   PubMed Web of Science ®Google Scholar
• Clark IM, Swingler TE, Sampieri CL, Edwards DR. The regulation of matrix metalloproteinases and their inhibitors. Int J Biochem Cell Biol. 2008;40(6–7):1362–1378.
   PubMed Web of Science ®Google Scholar
• Stamenkovic I. Extracellular matrix remodelling: the role of matrix metalloproteinases. J Pathol. 2003;200(4):448–464.
   PubMed Web of Science ®Google Scholar
• Hadler-Olsen E, Fadnes B, Sylte I, Uhlin-Hansen L, Winberg JO. Regulation of matrix metalloproteinase activity in health and disease. FEBS J. 2011;278(1):28–45.
   PubMed Web of Science ®Google Scholar
• Shimokawa Ki K, Katayama M, Matsuda Y, et al. Matrix metalloproteinase (MMP)-2 and MMP-9 activities in human seminal plasma. Mol Hum Reprod. 2002;8(1):32–36.
   Web of Science ®Google Scholar
• Al Aqeel A, Al Sewairi W, Edress B, Gorlin RJ, Desnick RJ, Martignetti JA. Inherited multicentric osteolysis with arthritis: a variant resembling Torg syndrome in a Saudi family. Am J Med Genet. 2000;93(1):11–18.
   Web of Science ®Google Scholar
• Al-Mayouf SM, Majeed M, Hugosson C, Bahabri S. New form of idiopathic osteolysis: nodulosis, arthropathy and osteolysis (NAO) syndrome. Am J Med Genet. 2000;93(1):5–10.
   Web of Science ®Google Scholar
• Mosig RA, Dowling O, DiFeo A, et al. Loss of MMP-2 disrupts skeletal and craniofacial development and results in decreased bone mineralization, joint erosion and defects in osteoblast and osteoclast growth. Hum Mol Genet. 2007;16(9):1113–1123.
   PubMed Web of Science ®Google Scholar
• Martignetti JA, Aqeel AA, Sewairi WA, et al. Mutation of the matrix metalloproteinase 2 gene (MMP2) causes a multicentric osteolysis and arthritis syndrome. Nat Genet. 2001;28(3):261–265.
   PubMed Web of Science ®Google Scholar
• Itoh T, Ikeda T, Gomi H, Nakao S, Suzuki T, Itohara S. Unaltered secretion of beta-amyloid precursor protein in gelatinase A (matrix metalloproteinase 2)-deficient mice. J Biol Chem. 1997;272(36):22389–22392.
   Web of Science ®Google Scholar
• Inoue K, Mikuni-Takagaki Y, Oikawa K, et al. A crucial role for matrix metalloproteinase 2 in osteocytic canalicular formation and bone metabolism. J Biol Chem. 2006;281(44):33814–33824.
   PubMed Web of Science ®Google Scholar
• Marenzana M, Shipley AM, Squitiero P, Kunkel JG, Rubinacci A. Bone as an ion exchange organ: evidence for instantaneous cell-dependent calcium efflux from bone not due to resorption. Bone. 2005;37(4):545–554.
   Web of Science ®Google Scholar
• Lieu S, Hansen E, Dedini R, et al. Impaired remodeling phase of fracture repair in the absence of matrix metalloproteinase-2. Dis Model Mech. 2011;4(2):203–211.
   Web of Science ®Google Scholar
• Nyman JS, Lynch CC, Perrien DS, et al. Differential effects between the loss of MMP-2 and MMP-9 on structural and tissue-level properties of bone. J Bone Miner Res. 2011;26(6):1252–1260.
   PubMed Web of Science ®Google Scholar
• Madsen DH, Jurgensen HJ, Ingvarsen S, et al. Differential actions of the endocytic collagen receptor uPARAP/Endo180 and the collagenase MMP-2 in bone homeostasis. PloS One. 2013;8(8):e71261.
   Web of Science ®Google Scholar
• Egeblad M, Shen HC, Behonick DJ, et al. Type I collagen is a genetic modifier of matrix metalloproteinase 2 in murine skeletal development. Dev Dyn. 2007;236(6):1683–1693.
   PubMed Web of Science ®Google Scholar
• Mosig RA, Martignetti JA. Loss of MMP-2 in murine osteoblasts upregulates osteopontin and bone sialoprotein expression in a circuit regulating bone homeostasis. Dis Model Mech. 2013;6(2):397–403.
   Web of Science ®Google Scholar
• Gordon JA, Tye CE, Sampaio AV, Underhill TM, Hunter GK, Goldberg HA. Bone sialoprotein expression enhances osteoblast differentiation and matrix mineralization in vitro. Bone. 2007;41(3):462–473.
   PubMed Web of Science ®Google Scholar
• Shapses SA, Cifuentes M, Spevak L, et al. Osteopontin facilitates bone resorption, decreasing bone mineral crystallinity and content during calcium deficiency. Calcif Tissue Int. 2003;73(1):86–92.
   Web of Science ®Google Scholar
• Vu TH, Shipley JM, Bergers G, et al. MMP-9/gelatinase B is a key regulator of growth plate angiogenesis and apoptosis of hypertrophic chondrocytes. Cell. 1998;93(3):411–422.
   PubMed Web of Science ®Google Scholar
• Reponen P, Sahlberg C, Munaut C, Thesleff I, Tryggvason K. High expression of 92-kDa type IV collagenase (gelatinase) in the osteoclast lineage during mouse development. Ann N Y Acad Sci. 1994;732:472–475.
   PubMed Web of Science ®Google Scholar
• Alexander CM, Hansell EJ, Behrendtsen O, et al. Expression and function of matrix metalloproteinases and their inhibitors at the maternal-embryonic boundary during mouse embryo implantation. Development. 1996;122(6):1723–1736.
   PubMed Web of Science ®Google Scholar
• Kojima T, Hasegawa T, de Freitas PH, et al. Histochemical aspects of the vascular invasion at the erosion zone of the epiphyseal cartilage in MMP-9-deficient mice. Biomed Res. 2013;34(3):119–128.
   Web of Science ®Google Scholar
• Ortega N, Behonick DJ, Colnot C, Cooper DN, Werb Z. Galectin-3 is a downstream regulator of matrix metalloproteinase-9 function during endochondral bone formation. Mol Biol Cell. 2005;16(6):3028–3039.
   Web of Science ®Google Scholar
• Nyman JS, Reyes M, Wang X. Effect of ultrastructural changes on the toughness of bone. Micron. 2005;36(7–8):566–582.
   Web of Science ®Google Scholar
• Kim K, Punj V, Kim JM, et al. MMP-9 facilitates selective proteolysis of the histone H3 tail at genes necessary for proficient osteoclastogenesis. Genes Dev. 2016;30(2):208–219.
   Web of Science ®Google Scholar
• Krane SM. Petulant cellular acts: destroying the ECM rather than creating it. J Clin Invest. 2001;107(1):31–32.
   Web of Science ®Google Scholar
• Haeusler G, Walter I, Helmreich M, Egerbacher M. Localization of matrix metalloproteinases, (MMPs) their tissue inhibitors, and vascular endothelial growth factor (VEGF) in growth plates of children and adolescents indicates a role for MMPs in human postnatal growth and skeletal maturation. Calcif Tissue Int. 2005;76(5):326–335.
   Web of Science ®Google Scholar
• Knauper V, Will H, Lopez-Otin C, et al. Cellular mechanisms for human procollagenase-3 (MMP-13) activation. Evidence that MT1-MMP (MMP-14) and gelatinase a (MMP-2) are able to generate active enzyme. J Biol Chem. 1996;271(29):17124–17131.
   PubMed Web of Science ®Google Scholar
• Neuhold LA, Killar L, Zhao W, et al. Postnatal expression in hyaline cartilage of constitutively active human collagenase-3 (MMP-13) induces osteoarthritis in mice. J Clin Invest. 2001;107(1):35–44.
   PubMed Web of Science ®Google Scholar
• Attur M, Yang Q, Shimada K, et al. Elevated expression of periostin in human osteoarthritic cartilage and its potential role in matrix degradation via matrix metalloproteinase-13. FASEB J. 2015;29(10):4107–4121.
   PubMed Web of Science ®Google Scholar
• Wang M, Sampson ER, Jin H, et al. MMP13 is a critical target gene during the progression of osteoarthritis. Arthritis Res Ther. 2013;15(1):R5.
   PubMed Web of Science ®Google Scholar
• Hu W, Zhang W, Li F, Guo F, Chen A. Bortezomib prevents the expression of MMP-13 and the degradation of collagen type 2 in human chondrocytes. Biochem Biophys Res Commun. 2014;452(3):526–530.
   Web of Science ®Google Scholar
• Ruminski PG, Massa M, Strohbach J, et al. Discovery of N-(4-fluoro-3-methoxybenzyl)-6-(2-(((2S,5R)-5-(hydroxymethyl)-1,4-dioxan-2-yl)met hyl)-2H-tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide. A highly selective and orally bioavailable matrix metalloproteinase-13 inhibitor for the potential treatment of osteoarthritis. J Med Chem. 2016;59(1):313–327.
   Web of Science ®Google Scholar
• Lim NH, Meinjohanns E, Meldal M, Bou-Gharios G, Nagase H. In vivo imaging of MMP-13 activity in the murine destabilised medial meniscus surgical model of osteoarthritis. Osteoarthritis Cartilage. 2014;22(6):862–868.
   PubMed Web of Science ®Google Scholar
• Lim NH, Meinjohanns E, Bou-Gharios G, et al. In vivo imaging of matrix metalloproteinase 12 and matrix metalloproteinase 13 activities in the mouse model of collagen-induced arthritis. Arthritis Rheumatol. 2014;66(3):589–598.
   Web of Science ®Google Scholar
• Singh A, Rajasekaran N, Hartenstein B, et al. Collagenase-3 (MMP-13) deficiency protects C57BL/6 mice from antibody-induced arthritis. Arthritis Res Ther. 2013;15(6):R222.
   Web of Science ®Google Scholar
• Inada M, Wang Y, Byrne MH, et al. Critical roles for collagenase-3 (Mmp13) in development of growth plate cartilage and in endochondral ossification. Proc Natl Acad Sci U S A. 2004;101(49):17192–17197.
   PubMed Web of Science ®Google Scholar
• Stickens D, Behonick DJ, Ortega N, et al. Altered endochondral bone development in matrix metalloproteinase 13-deficient mice. Development. 2004;131(23):5883–5895.
   Web of Science ®Google Scholar
• Tang SY, Herber RP, Ho SP, Alliston T. Matrix metalloproteinase-13 is required for osteocytic perilacunar remodeling and maintains bone fracture resistance. J Bone Miner Res. 2012;27(9):1936–1950.
   Web of Science ®Google Scholar
• Jimenez MJ, Balbin M, Lopez JM, Alvarez J, Komori T, Lopez-Otin C. Collagenase 3 is a target of Cbfa1, a transcription factor of the runt gene family involved in bone formation. Mol Cell Biol. 1999;19(6):4431–4442.
   PubMed Web of Science ®Google Scholar
• Jimenez MJ, Balbin M, Alvarez J, et al. A regulatory cascade involving retinoic acid, Cbfa1, and matrix metalloproteinases is coupled to the development of a process of perichondrial invasion and osteogenic differentiation during bone formation. J Cell Biol. 2001;155(7):1333–1344.
   Web of Science ®Google Scholar
• MacLean HE, Kim JI, Glimcher MJ, Wang J, Kronenberg HM, Glimcher LH. Absence of transcription factor c-maf causes abnormal terminal differentiation of hypertrophic chondrocytes during endochondral bone development. Dev Biol. 2003;262(1):51–63.
   Web of Science ®Google Scholar
• Little CB, Meeker CT, Hembry RM, et al. Matrix metalloproteinases are not essential for aggrecan turnover during normal skeletal growth and development. Mol Cell Biol. 2005;25(8):3388–3399.
   PubMed Web of Science ®Google Scholar
• Kennedy AM, Inada M, Krane SM, et al. MMP13 mutation causes spondyloepimetaphyseal dysplasia, Missouri type (SEMD(MO). J Clin Invest. 2005;115(10):2832–2842.
   Web of Science ®Google Scholar
• Ohuchi E, Imai K, Fujii Y, Sato H, Seiki M, Okada Y. Membrane type 1 matrix metalloproteinase digests interstitial collagens and other extracellular matrix macromolecules. J Biol Chem. 1997;272(4):2446–2451.
   PubMed Web of Science ®Google Scholar
• Kinoh H, Sato H, Tsunezuka Y, et al. MT-MMP, the cell surface activator of proMMP-2 (pro-gelatinase A), is expressed with its substrate in mouse tissue during embryogenesis. J Cell Sci. 1996;109(Pt 5):953–959.
   PubMed Web of Science ®Google Scholar
• Oh J, Takahashi R, Adachi E, et al. Mutations in two matrix metalloproteinase genes, MMP-2 and MT1-MMP, are synthetic lethal in mice. Oncogene. 2004;23(29):5041–5048.
   Web of Science ®Google Scholar
• Hatch NE. FGF signaling in craniofacial biological control and pathological craniofacial development. Crit Rev Eukaryot Gene Expr. 2010;20(4):295–311.
   Web of Science ®Google Scholar
• Oblander SA, Zhou Z, Galvez BG, et al. Distinctive functions of membrane type 1 matrix-metalloprotease (MT1-MMP or MMP-14) in lung and submandibular gland development are independent of its role in pro-MMP-2 activation. Dev Biol. 2005;277(1):255–269.
   Web of Science ®Google Scholar
• Strongin AY, Collier I, Bannikov G, Marmer BL, Grant GA, Goldberg GI. Mechanism of cell surface activation of 72-kDa type IV collagenase. Isolation of the activated form of the membrane metalloprotease. J Biol Chem. 1995;270(10):5331–5338.
   Web of Science ®Google Scholar
• Zhao W, Byrne MH, Wang Y, Krane SM. Osteocyte and osteoblast apoptosis and excessive bone deposition accompany failure of collagenase cleavage of collagen. J Clin Invest. 2000;106(8):941–949.
   Web of Science ®Google Scholar
• Holmbeck K, Bianco P, Pidoux I, et al. The metalloproteinase MT1-MMP is required for normal development and maintenance of osteocyte processes in bone. J Cell Sci. 2005;118(Pt 1):147–156.
   Web of Science ®Google Scholar
• Kajita M, Itoh Y, Chiba T, et al. Membrane-type 1 matrix metalloproteinase cleaves CD44 and promotes cell migration. J Cell Biol. 2001;153(5):893–904.
   PubMed Web of Science ®Google Scholar
• Hughes DE, Salter DM, Simpson R. CD44 expression in human bone: a novel marker of osteocytic differentiation. J Bone Miner Res. 1994;9(1):39–44.
   Web of Science ®Google Scholar
• Eisenach PA, Roghi C, Fogarasi M, Murphy G, English WR. MT1-MMP regulates VEGF-A expression through a complex with VEGFR-2 and Src. J Cell Sci. 2010;123(Pt 23):4182–4193.
   Web of Science ®Google Scholar
• Kulkarni RN, Bakker AD, Gruber EV, et al. MT1-MMP modulates the mechanosensitivity of osteocytes. Biochem Biophys Res Commun. 2012;417(2):824–829.
   Web of Science ®Google Scholar
• Szabova L, Yamada SS, Wimer H, et al. MT1-MMP and type II collagen specify skeletal stem cells and their bone and cartilage progeny. J Bone Miner Res. 2009;24(11):1905–1916.
   Web of Science ®Google Scholar
• Holmbeck K, Bianco P, Chrysovergis K, Yamada S, Birkedal-Hansen H. MT1-MMP-dependent, apoptotic remodeling of unmineralized cartilage: a critical process in skeletal growth. J Cell Biol. 2003;163(3):661–671.
   Web of Science ®Google Scholar
• Shi J, Son MY, Yamada S, et al. Membrane-type MMPs enable extracellular matrix permissiveness and mesenchymal cell proliferation during embryogenesis. Dev Biol. 2008;313(1):196–209.
   PubMed Web of Science ®Google Scholar
• Loffek S, Schilling O, Franzke CW. Series “matrix metalloproteinases in lung health and disease”: biological role of matrix metalloproteinases: a critical balance. Eur Respir J. 2011;38(1):191–208.
   PubMed Web of Science ®Google Scholar
• Szabova L, Yamada SS, Birkedal-Hansen H, Holmbeck K. Expression pattern of four membrane-type matrix metalloproteinases in the normal and diseased mouse mammary gland. J Cell Physiol. 2005;205(1):123–132.
   Web of Science ®Google Scholar
• Bord S, Horner A, Beeton CA, Hembry RM, Compston JE. Tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) distribution in normal and pathological human bone. Bone. 1999;24(3):229–235.
   Web of Science ®Google Scholar
• Geoffroy V, Marty-Morieux C, Le Goupil N, et al. In vivo inhibition of osteoblastic metalloproteinases leads to increased trabecular bone mass. J Bone Miner Res. 2004;19(5):811–822.
   Web of Science ®Google Scholar
• Sobue T, Hakeda Y, Kobayashi Y, et al. Tissue inhibitor of metalloproteinases 1 and 2 directly stimulate the bone-resorbing activity of isolated mature osteoclasts. J Bone Miner Res. 2001;16(12):2205–2214.
   Web of Science ®Google Scholar
• Su S, Grover J, Roughley PJ, et al. Expression of the tissue inhibitor of metalloproteinases (TIMP) gene family in normal and osteoarthritic joints. Rheumatol Int. 1999;18(5–6):183–191.
   Web of Science ®Google Scholar
• Huang W, Li WQ, Dehnade F, Zafarullah M. Tissue inhibitor of metalloproteinases-4 (TIMP-4) gene expression is increased in human osteoarthritic femoral head cartilage. J Cell Biochem. 2002;85(2):295–303.
   PubMed Web of Science ®Google Scholar
• Sahebjam S, Khokha R, Mort JS. Increased collagen and aggrecan degradation with age in the joints of Timp3(-/-) mice. Arthritis Rheum. 2007;56(3):905–909.
   PubMed Web of Science ®Google Scholar
• Shen Y, Winkler IG, Barbier V, Sims NA, Hendy J, Levesque JP. Tissue inhibitor of metalloproteinase-3 (TIMP-3) regulates hematopoiesis and bone formation in vivo. PloS One. 2010;5(9):e13086.
   Web of Science ®Google Scholar
• Prideaux M, Staines KA, Jones ER, Riley GP, Pitsillides AA, Farquharson C. MMP and TIMP temporal gene expression during osteocytogenesis. Gene Expr Patterns. 2015;18(1–2):29–36.
   Web of Science ®Google Scholar
• Dallas SL, Miyazono K, Skerry TM, Mundy GR, Bonewald LF. Dual role for the latent transforming growth factor-beta binding protein in storage of latent TGF-beta in the extracellular matrix and as a structural matrix protein. J Cell Biol. 1995;131(2):539–549.
   Web of Science ®Google Scholar
• Balooch G, Balooch M, Nalla RK, et al. TGF-beta regulates the mechanical properties and composition of bone matrix. Proc Natl Acad Sci U S A. 2005;102(52):18813–18818.
   Web of Science ®Google Scholar
• Karsdal MA, Larsen L, Engsig MT, et al. Matrix metalloproteinase-dependent activation of latent transforming growth factor-beta controls the conversion of osteoblasts into osteocytes by blocking osteoblast apoptosis. J Biol Chem. 2002;277(46):44061–44067.
   Web of Science ®Google Scholar
• Karsdal MA, Fjording MS, Foged NT, Delaisse JM, Lochter A. Transforming growth factor-beta-induced osteoblast elongation regulates osteoclastic bone resorption through a p38 mitogen-activated protein kinase- and matrix metalloproteinase-dependent pathway. J Biol Chem. 2001;276(42):39350–39358.
   Web of Science ®Google Scholar
• Biver E, Hardouin P, Caverzasio J. The “bone morphogenic proteins” pathways in bone and joint diseases: translational perspectives from physiopathology to therapeutic targets. Cytokine Growth Factor Rev. 2013;24(1):69–81.
   PubMed Web of Science ®Google Scholar
• Kamiya N, Mishina Y. New insights on the roles of BMP signaling in bone – A review of recent mouse genetic studies. BioFactors. 2011;37(2):75–82.
   Web of Science ®Google Scholar
• Kamiya N, Ye L, Kobayashi T, et al. BMP signaling negatively regulates bone mass through sclerostin by inhibiting the canonical Wnt pathway. Development. 2008;135(22):3801–3811.
   PubMed Web of Science ®Google Scholar
• Rajaram S, Murawala H, Buch P, Patel S, Balakrishnan S. Inhibition of BMP signaling reduces MMP-2 and MMP-9 expression and obstructs wound healing in regenerating fin of teleost fish Poecilia latipinna. Fish Physiol Biochem. 2016;42(2):787–794.
   Web of Science ®Google Scholar
• Choi YA, Kang SS, Jin EJ. BMP-2 treatment of C3H10T1/2 mesenchymal cells blocks MMP-9 activity during chondrocyte commitment. Cell Biol Int. 2009;33(8):887–892.
   Web of Science ®Google Scholar
• Ge X, Ma X, Meng J, Zhang C, Ma K, Zhou C. Role of Wnt-5A in interleukin-1beta-induced matrix metalloproteinase expression in rabbit temporomandibular joint condylar chondrocytes. Arthritis Rheum. 2009;60(9):2714–2722.
   PubMedGoogle Scholar
• Rabelo Fde S, da Mota LM, Lima RA, et al. The Wnt signaling pathway and rheumatoid arthritis. Autoimmun Rev. 2010;9(4):207–210.
   Web of Science ®Google Scholar
• Luyten FP, Tylzanowski P, Lories RJ. Wnt signaling and osteoarthritis. Bone. 2009;44(4):522–527.
   Web of Science ®Google Scholar
• Usami Y, Gunawardena AT, Iwamoto M, Enomoto-Iwamoto M. Wnt signaling in cartilage development and diseases: lessons from animal studies. Lab Invest. 2016;96(2):186–196.
   PubMed Web of Science ®Google Scholar
• Nakamura Y, Nawata M, Wakitani S. Expression profiles and functional analyses of Wnt-related genes in human joint disorders. Am J Pathol. 2005;167(1):97–105.
   Web of Science ®Google Scholar
• Imai K, Morikawa M, D’Armiento J, Matsumoto H, Komiya K, Okada Y. Differential expression of WNTs and FRPs in the synovium of rheumatoid arthritis and osteoarthritis. Biochem Biophys Res Commun. 2006;345(4):1615–1620.
   PubMed Web of Science ®Google Scholar
• Sen M, Lauterbach K, El-Gabalawy H, Firestein GS, Corr M, Carson DA. Expression and function of wingless and frizzled homologs in rheumatoid arthritis. Proc Natl Acad Sci U S A. 2000;97(6):2791–2796.
   PubMed Web of Science ®Google Scholar
• Hiyama A, Sakai D, Risbud MV, et al. Enhancement of intervertebral disc cell senescence by WNT/beta-catenin signaling-induced matrix metalloproteinase expression. Arthritis Rheum. 2010;62(10):3036–3047.
   Google Scholar
• Ma B, van Blitterswijk CA, Karperien M. A Wnt/beta-catenin negative feedback loop inhibits interleukin-1-induced matrix metalloproteinase expression in human articular chondrocytes. Arthritis Rheum. 2012;64(8):2589–2600.
   PubMedGoogle Scholar
• Papathanasiou I, Malizos KN, Tsezou A. Bone morphogenetic protein-2-induced Wnt/beta-catenin signaling pathway activation through enhanced low-density-lipoprotein receptor-related protein 5 catabolic activity contributes to hypertrophy in osteoarthritic chondrocytes. Arthritis Res Ther. 2012;14(2):R82.
   PubMed Web of Science ®Google Scholar
• Chen M, Zhu M, Awad H, et al. Inhibition of beta-catenin signaling causes defects in postnatal cartilage development. J Cell Sci. 2008;121(Pt 9):1455–1465.
   Web of Science ®Google Scholar
• Nakashima A, Tamura M. Regulation of matrix metalloproteinase-13 and tissue inhibitor of matrix metalloproteinase-1 gene expression by WNT3A and bone morphogenetic protein-2 in osteoblastic differentiation. Front Biosci. 2006;11:1667–1678.
   Web of Science ®Google Scholar
• Tamamura Y, Otani T, Kanatani N, et al. Developmental regulation of Wnt/beta-catenin signals is required for growth plate assembly, cartilage integrity, and endochondral ossification. J Biol Chem. 2005;280(19):19185–19195.
   PubMed Web of Science ®Google Scholar
• Pufe T, Harde V, Petersen W, Goldring MB, Tillmann B, Mentlein R. Vascular endothelial growth factor (VEGF) induces matrix metalloproteinase expression in immortalized chondrocytes. J Pathol. 2004;202(3):367–374.
   Web of Science ®Google Scholar
• Mayr-Wohlfart U, Waltenberger J, Hausser H, et al. Vascular endothelial growth factor stimulates chemotactic migration of primary human osteoblasts. Bone. 2002;30(3):472–477.
   Web of Science ®Google Scholar
• Ortega N, Wang K, Ferrara N, Werb Z, Vu TH. Complementary interplay between matrix metalloproteinase-9, vascular endothelial growth factor and osteoclast function drives endochondral bone formation. Dis Model Mech. 2010;3(3–4):224–235.
   Web of Science ®Google Scholar
• Bergers G, Brekken R, McMahon G, et al. Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis. Nat Cell Biol. 2000;2(10):737–744.
   PubMed Web of Science ®Google Scholar
• Engsig MT, Chen QJ, Vu TH, et al. Matrix metalloproteinase 9 and vascular endothelial growth factor are essential for osteoclast recruitment into developing long bones. J Cell Biol. 2000;151(4):879–889.
   PubMed Web of Science ®Google Scholar
• Bouwens EA, Stavenuiter F, Mosnier LO. Mechanisms of anticoagulant and cytoprotective actions of the protein C pathway. J Thromb Haemost. 2013;11(Suppl 1):242–253.
   Google Scholar
• Weiler H. Regulation of inflammation by the protein C system. Crit Care Med. 2010;38(2 Suppl):S18–S25.
   PubMed Web of Science ®Google Scholar
• Griffin JH, Zlokovic BV, Mosnier LO. Protein C anticoagulant and cytoprotective pathways. Int J Hematol. 2012;95(4):333–345.
   PubMed Web of Science ®Google Scholar
• Griffin JH, Zlokovic BV, Mosnier LO. Activated protein C: biased for translation. Blood. 2015;125(19):2898–2907.
   Web of Science ®Google Scholar
• Shen K, Murphy CM, Chan B, et al. Activated protein C (APC) can increase bone anabolism via a protease-activated receptor (PAR)1/2 dependent mechanism. J orthopaed Res. 2014;32(12):1549–1556.
   Web of Science ®Google Scholar
• Nguyen M, Arkell J, Jackson CJ. Activated protein C directly activates human endothelial gelatinase A. J Biol Chem. 2000;275(13):9095–9098.
   Web of Science ®Google Scholar
• Xue M, March L, Sambrook PN, Jackson CJ. Differential regulation of matrix metalloproteinase 2 and matrix metalloproteinase 9 by activated protein C: relevance to inflammation in rheumatoid arthritis. Arthritis Rheum. 2007;56(9):2864–2874.
   Google Scholar
• Buisson-Legendre N, Smith S, March L, Jackson C. Elevation of activated protein C in synovial joints in rheumatoid arthritis and its correlation with matrix metalloproteinase 2. Arthritis Rheum. 2004;50(7):2151–2156.
   Google Scholar
• Xue M, McKelvey K, Shen K, et al. Endogenous MMP-9 and not MMP-2 promotes rheumatoid synovial fibroblast survival, inflammation and cartilage degradation. Rheumatology. 2014;53(12):2270–2279.
   PubMed Web of Science ®Google Scholar