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Biochem J. Jul 1, 2002; 365(Pt 1): 119–126.
PMCID: PMC1222662

The chitinase 3-like protein human cartilage glycoprotein 39 (HC-gp39) stimulates proliferation of human connective-tissue cells and activates both extracellular signal-regulated kinase- and protein kinase B-mediated signalling pathways.

Abstract

Human cartilage glycoprotein 39 (HC-gp39) is a glycoprotein secreted by articular chondrocytes, synoviocytes and macrophages. Increased levels of HC-gp39 have been demonstrated in synovial fluids of patients with rheumatoid or osteoarthritis. The increased secretion of HC-gp39 under physiological and pathological conditions with elevated connective-tissue turnover suggests its involvement in the homoeostasis of these tissues. We report here that HC-gp39 promotes the growth of human synovial cells as well as skin and fetal lung fibroblasts. A dose-dependent growth stimulation was observed when each of the fibroblastic cell lines was exposed to HC-gp39 in a concentration range from 0.1 to 2 nM, which is similar to the effective dose of the well-characterized mitogen, insulin-like growth factor-1. At suboptimal concentrations, the two growth factors work in a synergistic fashion. The use of selective inhibitors of the mitogen-activated protein kinase and the protein kinase B (AKT) signalling pathways indicates that both are involved in mediating the mitogenic response to HC-gp39. Phosphorylation of both extracellular signal-regulated kinases 1/2 and AKT occurred in a dose- and time-dependent fashion upon addition of HC-gp39. Activation of these signalling pathways could also be demonstrated in human chondrocytes. Thus HC-gp39 initiates a signalling cascade in connective-tissue cells which leads to increased cell proliferation, suggesting that this protein could play a major role in the pathological conditions leading to tissue fibrosis.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Hakala BE, White C, Recklies AD. Human cartilage gp-39, a major secretory product of articular chondrocytes and synovial cells, is a mammalian member of a chitinase protein family. J Biol Chem. 1993 Dec 5;268(34):25803–25810. [PubMed]
  • Arias EB, Verhage HG, Jaffe RC. Complementary deoxyribonucleic acid cloning and molecular characterization of an estrogen-dependent human oviductal glycoprotein. Biol Reprod. 1994 Oct;51(4):685–694. [PubMed]
  • Boot RG, Renkema GH, Strijland A, van Zonneveld AJ, Aerts JM. Cloning of a cDNA encoding chitotriosidase, a human chitinase produced by macrophages. J Biol Chem. 1995 Nov 3;270(44):26252–26256. [PubMed]
  • Hu B, Trinh K, Figueira WF, Price PA. Isolation and sequence of a novel human chondrocyte protein related to mammalian members of the chitinase protein family. J Biol Chem. 1996 Aug 9;271(32):19415–19420. [PubMed]
  • Boot RG, Blommaart EF, Swart E, Ghauharali-van der Vlugt K, Bijl N, Moe C, Place A, Aerts JM. Identification of a novel acidic mammalian chitinase distinct from chitotriosidase. J Biol Chem. 2001 Mar 2;276(9):6770–6778. [PubMed]
  • Renkema GH, Boot RG, Muijsers AO, Donker-Koopman WE, Aerts JM. Purification and characterization of human chitotriosidase, a novel member of the chitinase family of proteins. J Biol Chem. 1995 Feb 3;270(5):2198–2202. [PubMed]
  • Connor JR, Dodds RA, Emery JG, Kirkpatrick RB, Rosenberg M, Gowen M. Human cartilage glycoprotein 39 (HC gp-39) mRNA expression in adult and fetal chondrocytes, osteoblasts and osteocytes by in-situ hybridization. Osteoarthritis Cartilage. 2000 Mar;8(2):87–95. [PubMed]
  • Volck B, Ostergaard K, Johansen JS, Garbarsch C, Price PA. The distribution of YKL-40 in osteoarthritic and normal human articular cartilage. Scand J Rheumatol. 1999;28(3):171–179. [PubMed]
  • Johansen JS, Hvolris J, Hansen M, Backer V, Lorenzen I, Price PA. Serum YKL-40 levels in healthy children and adults. Comparison with serum and synovial fluid levels of YKL-40 in patients with osteoarthritis or trauma of the knee joint. Br J Rheumatol. 1996 Jun;35(6):553–559. [PubMed]
  • Johansen JS, Jensen HS, Price PA. A new biochemical marker for joint injury. Analysis of YKL-40 in serum and synovial fluid. Br J Rheumatol. 1993 Nov;32(11):949–955. [PubMed]
  • Shackelton LM, Mann DM, Millis AJ. Identification of a 38-kDa heparin-binding glycoprotein (gp38k) in differentiating vascular smooth muscle cells as a member of a group of proteins associated with tissue remodeling. J Biol Chem. 1995 Jun 2;270(22):13076–13083. [PubMed]
  • Nyirkos P, Golds EE. Human synovial cells secrete a 39 kDa protein similar to a bovine mammary protein expressed during the non-lactating period. Biochem J. 1990 Jul 1;269(1):265–268. [PMC free article] [PubMed]
  • Rehli M, Krause SW, Andreesen R. Molecular characterization of the gene for human cartilage gp-39 (CHI3L1), a member of the chitinase protein family and marker for late stages of macrophage differentiation. Genomics. 1997 Jul 15;43(2):221–225. [PubMed]
  • Krause SW, Rehli M, Kreutz M, Schwarzfischer L, Paulauskis JD, Andreesen R. Differential screening identifies genetic markers of monocyte to macrophage maturation. J Leukoc Biol. 1996 Oct;60(4):540–545. [PubMed]
  • Kirkpatrick RB, Emery JG, Connor JR, Dodds R, Lysko PG, Rosenberg M. Induction and expression of human cartilage glycoprotein 39 in rheumatoid inflammatory and peripheral blood monocyte-derived macrophages. Exp Cell Res. 1997 Nov 25;237(1):46–54. [PubMed]
  • Johansen JS, Cintin C, Jørgensen M, Kamby C, Price PA. Serum YKL-40: a new potential marker of prognosis and location of metastases of patients with recurrent breast cancer. Eur J Cancer. 1995;31A(9):1437–1442. [PubMed]
  • Cintin C, Johansen JS, Christensen IJ, Price PA, Sørensen S, Nielsen HJ. Serum YKL-40 and colorectal cancer. Br J Cancer. 1999 Mar;79(9-10):1494–1499. [PMC free article] [PubMed]
  • Johansen JS, Møller S, Price PA, Bendtsen F, Junge J, Garbarsch C, Henriksen JH. Plasma YKL-40: a new potential marker of fibrosis in patients with alcoholic cirrhosis? Scand J Gastroenterol. 1997 Jun;32(6):582–590. [PubMed]
  • Morrison BW, Leder P. neu and ras initiate murine mammary tumors that share genetic markers generally absent in c-myc and int-2-initiated tumors. Oncogene. 1994 Dec;9(12):3417–3426. [PubMed]
  • Rejman JJ, Hurley WL. Isolation and characterization of a novel 39 kilodalton whey protein from bovine mammary secretions collected during the nonlactating period. Biochem Biophys Res Commun. 1988 Jan 15;150(1):329–334. [PubMed]
  • Renkema GH, Boot RG, Strijland A, Donker-Koopman WE, van den Berg M, Muijsers AO, Aerts JM. Synthesis, sorting, and processing into distinct isoforms of human macrophage chitotriosidase. Eur J Biochem. 1997 Mar 1;244(2):279–285. [PubMed]
  • Watanabe T, Kobori K, Miyashita K, Fujii T, Sakai H, Uchida M, Tanaka H. Identification of glutamic acid 204 and aspartic acid 200 in chitinase A1 of Bacillus circulans WL-12 as essential residues for chitinase activity. J Biol Chem. 1993 Sep 5;268(25):18567–18572. [PubMed]
  • Perrakis A, Tews I, Dauter Z, Oppenheim AB, Chet I, Wilson KS, Vorgias CE. Crystal structure of a bacterial chitinase at 2.3 A resolution. Structure. 1994 Dec 15;2(12):1169–1180. [PubMed]
  • Kawamura K, Shibata T, Saget O, Peel D, Bryant PJ. A new family of growth factors produced by the fat body and active on Drosophila imaginal disc cells. Development. 1999 Jan;126(2):211–219. [PubMed]
  • De Ceuninck F, Gaufillier S, Bonnaud A, Sabatini M, Lesur C, Pastoureau P. YKL-40 (cartilage gp-39) induces proliferative events in cultured chondrocytes and synoviocytes and increases glycosaminoglycan synthesis in chondrocytes. Biochem Biophys Res Commun. 2001 Jul 27;285(4):926–931. [PubMed]
  • Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976 May 7;72:248–254. [PubMed]
  • Golds EE, Mason P, Nyirkos P. Inflammatory cytokines induce synthesis and secretion of gro protein and a neutrophil chemotactic factor but not beta 2-microglobulin in human synovial cells and fibroblasts. Biochem J. 1989 Apr 15;259(2):585–588. [PMC free article] [PubMed]
  • Recklies AD, Golds EE. Induction of synthesis and release of interleukin-8 from human articular chondrocytes and cartilage explants. Arthritis Rheum. 1992 Dec;35(12):1510–1519. [PubMed]
  • Bracey LT, Paigen K. Changes in translational yield regulate tissue-specific expression of beta-glucuronidase. Proc Natl Acad Sci U S A. 1987 Dec;84(24):9020–9024. [PMC free article] [PubMed]
  • Olmsted JB. Analysis of cytoskeletal structures using blot-purified monospecific antibodies. Methods Enzymol. 1986;134:467–472. [PubMed]
  • Johansen JS, Olee T, Price PA, Hashimoto S, Ochs RL, Lotz M. Regulation of YKL-40 production by human articular chondrocytes. Arthritis Rheum. 2001 Apr;44(4):826–837. [PubMed]
  • Moriguchi T, Gotoh Y, Nishida E. Roles of the MAP kinase cascade in vertebrates. Adv Pharmacol. 1996;36:121–137. [PubMed]
  • Waskiewicz AJ, Cooper JA. Mitogen and stress response pathways: MAP kinase cascades and phosphatase regulation in mammals and yeast. Curr Opin Cell Biol. 1995 Dec;7(6):798–805. [PubMed]
  • Datta SR, Brunet A, Greenberg ME. Cellular survival: a play in three Akts. Genes Dev. 1999 Nov 15;13(22):2905–2927. [PubMed]
  • Nomura M, Kaji A, Ma WY, Zhong S, Liu G, Bowden GT, Miyamoto KI, Dong Z. Mitogen- and stress-activated protein kinase 1 mediates activation of Akt by ultraviolet B irradiation. J Biol Chem. 2001 Jul 6;276(27):25558–25567. [PubMed]
  • Johansen JS, Stoltenberg M, Hansen M, Florescu A, Hørslev-Petersen K, Lorenzen I, Price PA. Serum YKL-40 concentrations in patients with rheumatoid arthritis: relation to disease activity. Rheumatology (Oxford) 1999 Jul;38(7):618–626. [PubMed]
  • Gille H, Downward J. Multiple ras effector pathways contribute to G(1) cell cycle progression. J Biol Chem. 1999 Jul 30;274(31):22033–22040. [PubMed]
  • Jones SM, Kazlauskas A. Growth-factor-dependent mitogenesis requires two distinct phases of signalling. Nat Cell Biol. 2001 Feb;3(2):165–172. [PubMed]
  • Sun YJ, Chang NC, Hung SI, Chang AC, Chou CC, Hsiao CD. The crystal structure of a novel mammalian lectin, Ym1, suggests a saccharide binding site. J Biol Chem. 2001 May 18;276(20):17507–17514. [PubMed]
  • Chang NC, Hung SI, Hwa KY, Kato I, Chen JE, Liu CH, Chang AC. A macrophage protein, Ym1, transiently expressed during inflammation is a novel mammalian lectin. J Biol Chem. 2001 May 18;276(20):17497–17506. [PubMed]
  • Owhashi M, Nawa Y. Eosinophil chemotactic lymphokine produced by spleen cells of Schistosoma japonicum-infected mice. Int Arch Allergy Appl Immunol. 1987;82(1):20–25. [PubMed]
  • Owhashi M, Arita H, Hayai N. Identification of a novel eosinophil chemotactic cytokine (ECF-L) as a chitinase family protein. J Biol Chem. 2000 Jan 14;275(2):1279–1286. [PubMed]
  • Webb DC, McKenzie AN, Foster PS. Expression of the Ym2 lectin-binding protein is dependent on interleukin (IL)-4 and IL-13 signal transduction: identification of a novel allergy-associated protein. J Biol Chem. 2001 Nov 9;276(45):41969–41976. [PubMed]
  • Malinda KM, Ponce L, Kleinman HK, Shackelton LM, Millis AJ. Gp38k, a protein synthesized by vascular smooth muscle cells, stimulates directional migration of human umbilical vein endothelial cells. Exp Cell Res. 1999 Jul 10;250(1):168–173. [PubMed]
  • Chakravarthy MV, Abraha TW, Schwartz RJ, Fiorotto ML, Booth FW. Insulin-like growth factor-I extends in vitro replicative life span of skeletal muscle satellite cells by enhancing G1/S cell cycle progression via the activation of phosphatidylinositol 3'-kinase/Akt signaling pathway. J Biol Chem. 2000 Nov 17;275(46):35942–35952. [PubMed]
  • Wiesen J, Werb Z. Proteinases, cell cycle regulation, and apoptosis during mammary gland involution (minireview). Mol Reprod Dev. 2000 Aug;56(4):534–540. [PubMed]
  • Shakibaei M, Schulze-Tanzil G, de Souza P, John T, Rahmanzadeh M, Rahmanzadeh R, Merker HJ. Inhibition of mitogen-activated protein kinase kinase induces apoptosis of human chondrocytes. J Biol Chem. 2001 Apr 20;276(16):13289–13294. [PubMed]

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