GP130 cytokines and bone remodelling in health and disease
1
조회
0
다운로드
1
인용
0
참고문헌
키워드
초록
Cytokines that bind to and signal through the gp130 co-receptor subunit include interleukin (IL)-6, IL-11, oncostatin M (OSM), leukemia inhibitory factor (LIF), cardiotrophin-1 (CT-1),and ciliary neutrophic factor (CNTF). Apart from contributing to inflammation, gp130 signalling cytokines also function in the maintenance of bone homeostasis. Expression of each of these cytokines and their ligand-specific receptors is observed in bone and joint cells, and bone-active hormones and inflammatory cytokines regulate their expression. gp130 signalling cytokines have been shown to regulate the differentiation and activity of osteoblasts, osteoclasts and chondrocytes. Furthermore,cytokine and receptor specific gene-knockout mouse models have identified distinct roles for each of these cytokines in regulating bone resorption, bone formation and bone growth. This review will discuss the current models of paracrine and endocrine actions of gp130-signalling cytokines in bone remodelling and growth, as well as their impact in pathologic bone remodelling evident in periodontal disease, rheumatoid arthritis, spondylarthropathies and osteoarthritis.
Abstract
Cytokines that bind to and signal through the gp130 co-receptor subunit include interleukin (IL)-6, IL-11, oncostatin M (OSM), leukemia inhibitory factor (LIF), cardiotrophin-1 (CT-1),and ciliary neutrophic factor (CNTF). Apart from contributing to inflammation, gp130 signalling cytokines also function in the maintenance of bone homeostasis. Expression of each of these cytokines and their ligand-specific receptors is observed in bone and joint cells, and bone-active hormones and inflammatory cytokines regulate their expression. gp130 signalling cytokines have been shown to regulate the differentiation and activity of osteoblasts, osteoclasts and chondrocytes. Furthermore,cytokine and receptor specific gene-knockout mouse models have identified distinct roles for each of these cytokines in regulating bone resorption, bone formation and bone growth. This review will discuss the current models of paracrine and endocrine actions of gp130-signalling cytokines in bone remodelling and growth, as well as their impact in pathologic bone remodelling evident in periodontal disease, rheumatoid arthritis, spondylarthropathies and osteoarthritis.
참고문헌 (120)
- Bravo, J., "Receptor recognition by gp130 cytokines", Embo J., 19, pp.2399~2411 (2000)
- Yamasaki, K., "Cloning and expression of the human interleukin-6 (BSF-2", IFN beta 2) receptor, 1988, pp.241, 825~828
- Hilton, D. J., "Cloning of a murine IL-11 receptor alpha-chain; requirement for gp130 for high affinity binding and signal transduction", Embo J., 13, pp.4765~4775 (1994)
- Elson, G. C., "CLF associates with CLC to form a functional heteromeric ligand for the CNTF receptor complex", Nat. Neurosci., 3, pp.867~872 (2000)
- Plun-Favreau, H., "The ciliary neurotrophic factor receptor alpha component in duces the secretion of and is required for functional responses to cardiotrophin-like cytokine", Embo J., 20, pp.1692~1703 (2001)
- Hibi, M., "Molecular cloning and expression of an IL-6 signal transducer, gp130", Cell, 63, pp.1149~1157 (1990)
- Gearing, D. P., "Leukemia inhibitory factor receptor is structurally related to the IL-6 signal transducer, gp130", Embo J., 10, pp.2839~2848 (1991)
- Mosley, B., "Dual oncostatin M (OSM) receptors. Cloning and characterization of an alternative signaling subunit conferring OSM-specific receptor activation", J. Biol. Chem., 271, pp.32635~32643 (1996)
- Lindberg, R. A., "Cloning and characterization of a specific receptor for mouse oncostatin M", Mol. Cell Biol., 18, pp.3357~3367 (1998)
- Pflanz, S., "IL-27, a heterodimeric cytokine composed of EBI3 and p28 protein, induces proliferation of naive CD4(+) T cells", Immunity, 16, pp.779~790 (2002)
- Hashimoto, Y., "Humanin inhibits neuronal cell death by interacting with a cytokine receptor complex or complexes involving CNTF receptor alpha", WSX-1, Mol. Biol. Cell, pp.2009, 20[DOI]
- Sims, N. A., "Bone remodeling: multiple cellular interactions required for coupling of bone formation and resorption", Semin. Cell Dev. Biol., 19, pp.444~451 (2008)
- Martin, T. J., "Bone remodeling: cellular and molecular events; in The Skeletal System", pp.297~316 (2009), Cold Spring Harbor Press
- Walker, E. C., "Cardiotrophin-1 is an osteoclast-derived stimulus of bone formation required for normal bone remodeling", J. Bone Miner Res., 23, pp.2025~2032 (2008)
- Pederson, L., "Regulation of bone formation by osteoclasts involves Wnt", BMP signaling and the chemokine sphingosine-1-phosphate, 2008, pp.통권 : 105, 20764~20769
- van Bezooijen, R. L., "SOST", sclerostin, an osteocyte- derived negative regulator of bone formation, 2005, pp.16, 319~327
- Kogianni, G., "Apoptotic bodies convey activity capable of initiating osteoclastogenesis and localised bone destruction", J. Bone Miner Res., 23, pp.915~927 (2008)
- Laaksovirta, H., "Serum level of CNTF is elevated in patients with amyotrophic lateral sclerosis and correlates with site of disease onset", Eur. J. Neurol., 15, pp.355~359 (2008)
- Waring, P., "Leukemia inhibitory factor levels are elevated in septic shock and various inflammatory body fluids", J. Clin. Invest, 90, pp.2031~2037 (1992)
- Talwar, S., "An immunoluminometric assay for cardiotrophin-1: a newly identified cytokine is present in normal human plasma and is increased in heart failure", Biochem. Biophys. Res. Commun., 261, pp.567~571 (1999)
- Daynes, R. A., "Altered regulation of IL-6 production with normal aging. Possible linkage to the age-associated decline in dehydroepiandrosterone and its sulfated derivative", J. Immunol., 150, pp.5219~5230 (1993)
- Romas, E., "The role of gp130-mediated signals in osteoclast development: regulation of interleukin 11 production by osteoblasts and distribution of its receptor in bone marrow cultures", J. Exp. Med., 183, pp.2581~2591 (1996)
- Manolagas, S. C., "The role of IL-6 type cytokines and their receptors in bone", Ann. N. Y. Acad. Sci., 840, pp.194~204 (1998)
- Greenfield, E. M., "Adenyl cyclase and interleukin 6 are downstream effectors of parathyroid hormone resulting in stimulation of bone resorption", J. Clin. Invest., 96, pp.1238~1244 (1995)
- Liang, J. D., "Immunohistochemical localization of selected early response genes expressed in trabecular bone of young rats given hPTH 1-34", Calcif. Tissue Int., 65, pp.369~373 (1999)
- Tamura, T., "Soluble interleukin-6 receptor triggers osteoclast formation by interleukin 6", Proc. Natl. Acad. Sci. U.S.A., 통권 : 90, pp.11924~11928 (1993)
- Richards, C. D., "Stimulation of osteoclast differentiation in vitro by mouse oncostatin M, leukaemia inhibitory factor, cardiotrophin-1 and interleukin 6: synergy with dexamethasone", Cytokine, 12, pp.613~621 (2000)
- McGregor, N. E., "Ciliary neurotrophic factor inhibits bone formation and plays a sex-specific role in bone growth and remodeling", Calcif Tissue Int., 86, pp.261~270 (2010)
- Horwood, N. J., "Osteotropic agents regulate the expression of osteoclast differentiation factor and osteoprotegerin in osteoblastic stromal cells", Endocrinology, 139, pp.4743~4746 (1998)
- Fu, Q., "Parathyroid hormone controls receptor activator of NFkappaB ligand gene expression via a distant transcriptional enhancer", Mol. Cell Biol., 26, pp.6453~6468 (2006)
- Atkins, G. J., "Coordinated cytokine expression by stromal and hematopoietic cells during human osteoclast formation", Bone, 26, pp.653~661 (2000)
- Shin, H. I., "Gp130-mediated signaling is necessary for normal osteoblastic function in vivo and in vitro", Endocrinology, 145, pp.1376~1385 (2004)
- Girasole, G., "Interleukin-11: a new cytokine critical for osteoclast development", J. Clin. Invest., 93, pp.1516~1524 (1994)
- Gorny, G., "IL-6, LIF, and TNF-alpha regulation of GM-CSF inhibition of osteoclastogenesis in vitro", Exp. Cell Res., 294, pp.149~158 (2004)
- Sims, N. A., "Glycoprotein 130 regulates bone turnover and bone size by distinct downstream signaling pathways", J. Clin. Invest, 113, pp.379~389 (2004)
- Sims, N. A., "Interleukin-11 receptor signaling is required for normal bone remodeling", J. Bone Miner Res., 20, pp.1093~1102 (2005)
- Kamiya, S., "Effects of IL-23 and IL-27 on osteoblasts and osteoclasts: inhibitory effects on osteoclast differentiation", J. Bone Miner Metab., 25, pp.277~285 (2007)
- Kawasaki, K., "Osteoclasts are present in gp130-deficient mice", Endocrinology, 138, pp.4959~4965 (1997)
- Poli, V., "Interleukin-6 deficient mice are protected from bone loss caused by estrogen depletion", Embo J., 13, pp.1189~1196 (1994)
- Grey, A., "A role for interleukin-6 in parathyroid hormone-induced bone resorption in vivo", Endocrinology, 140, pp.4683~4690 (1999)
- Bozec, A., "Osteoclast size is controlled by Fra-2 through LIF", LIF-receptor signalling and hypoxia, 2008, pp.454, 221~225
- Ware, C. B., "Targeted disruption of the low-affinity leukemia inhibitory factor receptor gene causes placental, skeletal, neural and metabolic defects and results in perinatal death", Development, 121, pp.1283~1299 (1995)
- Walker, E. C., "Oncostatin M promotes bone formation independently of resorption when signaling through leukemia inhibitory factor receptor in mice", J. Clin. Invest, 120, pp.582~592 (2010)
- Bellido, T., "Activation of the Janus kinase", STAT (signal transducer and activator of transcription) signal transduction pathway by interleukin-6-type cytokines promotes osteoblast differentiation, 1997, pp.138, 3666~3676
- Kitamura, H., "Bone marrow neutrophilia and suppressed bone turnover in human interleukin-6 transgenic mice. A cellular relationship among hematopoietic cells, osteoblasts, and osteoclasts mediated by stromal cells in bone marrow", Am. J. Pathol., 147, pp.1682~1692 (1995)
- De Benedetti, F., "Impaired skeletal development in interleukin-6-transgenic mice: a model for the impact of chronic inflammation on the growing skeletal system", Arthritis. Rheum., 54, pp.3551~3563 (2006)
- Li, X., "Sclerostin antibody treatment increases bone formation, bone mass, and bone strength in a rat model of postmenopausal osteoporosis", J. Bone Miner Res., 24, pp.578~588 (2009)
- Keller, H., "SOST is a target gene for PTH in bone", Bone, 37, pp.148~158 (2005)
- Robling, A. G., "Mechanical stimulation in vivo reduces osteocyte expression of sclerostin", J. Musculoskelet Neuronal Interact, 6, pp.354~ (2006)
- Jenkins, B. J., "Imbalanced gp130-dependent signaling in macrophages alters macrophage colony-stimulating factor responsiveness via regulation of c-fms expression", Mol. Cell Biol., 24, pp.1453~1463 (2004)
- Dagoneau, N., "Null leukemia inhibitory factor receptor (LIFR) mutations in Stuve-Wiedemann", Schwartz-Jampel type 2 syndrome, 2004, pp.74, 298~305
- Sims, N. A., "gp130 signaling in bone cell biology: multiple roles revealed by analysis of genetically altered mice", Mol. Cell Endocrinol., 310, pp.30~39 (2009)
- Qi, L., "Interleukin-6 genetic variability and adiposity: associations in two prospective cohorts and systematic review in 26,944 individuals", J. Clin. Endocrinol. Metab., 92, pp.3618~3625 (2007)
- Takacs, I., "Sib pair linkage and association studies between bone mineral density and the interleukin-6 gene locus", Bone, 27, pp.169~173 (2000)
- Tsukamoto, K., "Association of radial bone mineral density with CA repeat polymorphism at the interleukin 6 locus in postmenopausal Japanese women", J. Hum. Genet., 44, pp.148~151 (1999)
- Ogura, N., "Stimulation of interleukin-6 production of periodontal ligament cells by Porphyromonas endodontalis lipopolysaccharide", Biochem. Med. Metab. Biol., 53, pp.130~136 (1994)
- Barkhordar, R. A., "Detection of interleukin-6 in human dental pulp and periapical lesions", Endod. Dent. Traumatol., 15, pp.26~27 (1999)
- Johnson, R. B., "Interleukin-11 and IL-17 and the pathogenesis of periodontal disease", J. Periodontol., 75, pp.37~43 (2004)
- Kawashima, N., "Expression of bone-resorptive and regulatory cytokines in murine periapical inflammation", Arch. Oral. Biol., 44, pp.55~66 (1999)
- Tsai, C. H., "Immunohistochemical localization of oncostatin M in epithelialized apical periodontitis lesions", Int. Endod. J., 41, pp.772~776 (2008)
- Lin, S. J., "Measurement of gp130 cytokines oncostatin M and IL-6 in gingival crevicular fluid of patients with chronic periodontitis", Cytokine, 30, pp.160~167 (2005)
- Pradeep, A. R., S, T. M, "Serum levels of oncostatin M (a gp 130 cytokine): an inflammatory biomarker in periodontal disease", Biomarkers, 15, pp.277~282 (2010)
- Gravallese, E. M., "Identification of cell types responsible for bone resorption in rheumatoid arthritis and juvenile rheumatoid arthritis", Am. J. Pathol., 152, pp.943~951 (1998)
- Romas, E., "Expression of osteoclast differentiation factor at sites of bone erosion in collagen-induced arthritis", Arthritis Rheum, 43, pp.821~826 (2000)
- Scott, D. L., "Prognostic factors in early rheumatoid arthritis", Rheumatology (Oxford), 39(1), pp.24~29 (2000)
- Pettit, A. R., "RANKL protein is expressed at the pannus-bone interface at sites of articular bone erosion in rheumatoid arthritis", Rheumatology (Oxford), 45, pp.1068~1076 (2006)
- Horwood, N. J., "Activated T lymphocytes support osteoclast formation in vitro", Biochem. Biophys. Res. Commun., 265, pp.144~150 (1999)
- Crotti, T. N., "Receptor activator NF-kappaB ligand (RANKL) expression in synovial tissue from patients with rheumatoid arthritis, spondyloarthropathy, osteoarthritis, and from normal patients: semiquantitative and quantitative analysis", Ann. Rheum. Dis., 61, pp.1047~1054 (2002)
- Walsh, N. C., "Osteoblast function is compromised at sites of focal bone erosion in inflammatory arthritis", J. Bone Miner Res., 24, pp.1572~1585 (2009)
- Okamoto, H., "The synovial expression and serum levels of interleukin-6, interleukin-11, leukemia inhibitory factor, and oncostatin M in rheumatoid arthritis", Arthritis. Rheum., 40, pp.1096~1105 (1997)
- Kotake, S., "Interleukin-6 and soluble interleukin-6 receptors in the synovial fluids from rheumatoid arthritis patients are responsible for osteoclast-like cell formation", J. Bone Miner Res., 11, pp.88~95 (1996)
- Nowell, M. A., "Soluble IL-6 receptor governs IL-6 activity in experimental arthritis: blockade of arthritis severity by soluble glycoprotein 130", J. Immunol., 171, pp.3202~3209 (2003)
- Al-Awadhi, A., "Serum concentrations of interleukin 6, osteocalcin, intact parathyroid hormone, and markers of bone resorption in patients with rheumatoid arthritis", J. Rheumatol., 26, pp.1250~1256 (1999)
- Walsh, N. C., "Rheumatic diseases: the effects of inflammation on bone", Immunol. Rev., 208, pp.228~251 (2005)
- Fonseca, J. E., "Interleukin-6 as a key player in systemic inflammation and joint destruction", Autoimmun. Rev., 8, pp.538~542 (2009)
- Takagi, N., "Blockage of interleukin-6 receptor ameliorates joint disease in murine collagen-induced arthritis", Arthritis. Rheum., 41, pp.2117~2121 (1998)
- Kato, A., "Early effects of tocilizumab on bone and bone marrow lesions in a collagen-induced arthritis monkey model", Exp. Mol. Pathol., 84, pp.262~270 (2008)
- Jones, G., "Comparison of tocilizumab monotherapy versus methotrexate monotherapy in patients with moderate to severe rheumatoid arthritis: The AMBITION study", Ann. Rheum. Dis., 69, pp.88~96 (2010)
- Plater-Zyberk, C., "Amelioration of arthritis in two murine models using antibodies to oncostatin M", Arthritis. Rheum., 44, pp.2697~2702 (2001)
- Field, M., "Interleukin-6 localisation in the synovial membrane in rheumatoid arthritis", Rheumatol. Int., 11, pp.45~50 (1991)
- Chu, C. Q., "Detection of cytokines at the cartilage", pannus junction in patients with rheumatoid arthritis: implications for the role of cytokines in cartilage destruction and repair, 1992, pp.31, 653~661
- Wong, P. K., "Interleukin-6 modulates production of T lymphocytederived cytokines in antigen-induced arthritis and drives inflammation-induced osteoclastogenesis", Arthritis. Rheum., 54, pp.158~168 (2006)
- Mihara, M., "Evidence for the role of Th17 cell inhibition in the prevention of autoimmune diseases by anti-interluekin-6 receptor antibody", Biofactors, 35, pp.47~51 (2009)
- Fujimoto, M., "Interleukin-6 blockade suppresses autoimmune arthritis in mice by the inhibition of inflammatory Th17 responses", Arthritis. Rheum., 58, pp.3710~3719 (2008)
- Benjamin, M., "The "enthesis organ" concept: why enthesopathies may not present as focal insertional disorders", Arthritis. Rheum., 50, pp.3306~3313 (2004)
- McGonagle, D., "Imaging the joint and enthesis: insights into pathogenesis of psoriatic arthritis", Ann. Rheum. Dis., 64(2), pp.ii58~ii60 (2005)
- McGonagle, D., "The concept of a "synovio-entheseal complex" and its implications for understanding joint inflammation and damage in psoriatic arthritis and beyond", Arthritis. Rheum., 56, pp.2482~2491 (2007)
- Benjamin, M., "Histopathologic changes at "synovio-entheseal complexes" suggesting a novel mechanism for synovitis in osteoarthritis and spondylarthritis", Arthritis. Rheum., 56, pp.3601~3609 (2007)
- Lories, R. J., "Modulation of bone morphogenetic protein signaling inhibits the onset and progression of ankylosing enthesitis", J. Clin. Invest., 115, pp.1571~1579 (2005)
- Diarra, D., "Dickkopf-1 is a master regulator of joint remodeling", Nat. Med., 13, pp.156~163 (2007)
- Appel, H., "Altered skeletal expression of sclerostin and its link to radiographic progression in ankylosing spondylitis", Arthritis. Rheum., 60, pp.3257~3262 (2009)
- Partsch, G., "Highly increased levels of tumor necrosis factor-alpha and other proinflammatory cytokines in psoriatic arthritis synovial fluid", J. Rheumatol., 24, pp.518~523 (1997)
- Gratacos, J., "Serum cytokines (IL-6, TNF-alpha, IL-1 beta and IFN-gamma) in ankylosing spondylitis: a close correlation between serum IL-6 and disease activity and severity", Br. J. Rheumatol., 33, pp.927~931 (1994)
- Hayer, S., "Interleukin 6 is not a crucial regulator in an animal model of tumour necrosis factor-mediated bilateral sacroiliitis", Ann. Rheum. Dis., 69, pp.1403~1406 (2010)
- Dieppe, P. A., "Pathogenesis and management of pain in osteoarthritis", Lancet, 365, pp.965~973 (2005)
- Sakao, K., "Osteoblasts derived from osteophytes produce interleukin-6, interleukin-8, and matrix metalloproteinase-13 in osteoarthritis", J. Bone Miner Metab., 27, pp.412~423 (2009)
- Durigova, M., "Mechanism of proteoglycan aggregate degradation in cartilage stimulated with oncostatin M", Osteoarthritis Cartilage, 16, pp.98~104 (2008)
- Langdon, C., "Murine oncostatin M stimulates mouse synovial fibroblasts in vitro and induces inflammation and destruction in mouse joints in vivo", Am. J. Pathol., 157, pp.1187~1196 (2000)
- de Hooge, A. S., "Adenoviral transfer of murine oncostatin M elicits periosteal bone apposition in knee joints of mice, despite synovial inflammation and up-regulated expression of interleukin-6 and receptor activator of nuclear factor-kappa B ligand", Am. J. Pathol., 160, pp.1733~1743 (2002)
- Karsdal, M. A., "Cartilage degradation is fully reversible in the presence of aggrecanase but not matrix metalloproteinase activity", Arthritis. Res. Ther., 10, pp.R63~ (2008)
- de Hooge, A. S., "Male IL-6 gene knock out mice developed more advanced osteoarthritis upon aging", Osteoarthritis. Cartilage., 13, pp.66~73 (2005)
- Upadhyay, A., "Role of a LIF antagonist in LIF and OSM induced MMP-1, MMP-3, and TIMP-1 expression by primary articular chondrocytes", Cytokine, 46, pp.332~338 (2009)
- Fan, Z., "IL-1beta induction of IL-6 and LIF in normal articular human chondrocytes involves the ERK, p38 and NFkappaB signaling pathways", Cytokine, 28, pp.17~24 (2004)
- Rowan, A. D., "Synergistic effects of glycoprotein 130 binding cytokines in combination with interleukin-1 on cartilage collagen breakdown", Arthritis. Rheum., 44, pp.1620~1632 (2001)
- Gao, Y., "Expression of IL-6 receptor and GP130 in mouse bone marrow cells during osteoclast differentiation", Bone, 22, pp.487~493 (1998)
- Allan, E. H., "Osteoblasts display receptors for and responses to leukemia-inhibitory factor", J. Cell Physiol., 145, pp.110~119 (1990)
- Udagawa, N., "Interleukin (IL)-6 induction of osteoclast differentiation depends on IL-6 receptors expressed on osteoblastic cells but not on osteoclast progenitors", J. Exp. Med., 182, pp.1461~1468 (1995)
- Bellido, T., "Detection of receptors for interleukin-6, interleukin-11, leukemia inhibitory factor, oncostatin M, and ciliary neurotrophic factor in bone marrow stromal", osteoblastic cells, 1996, pp.97, 431~437
- Dame, J. B., "The distribution of receptors for the pro-inflammatory cytokines interleukin (IL)-6 and IL-8 in the developing human fetus", Early Hum. Dev., 58, pp.25~39 (2000)
- Legendre, F., "JAK", STAT but not ERK1, soluble IL-6R down-regulation of Type II collagen, aggrecan core, and link protein transcription in articular chondrocytes. Association with a down-regulation of SOX9 expression, pp.J. Biol. Chem., 2003[DOI]
- Nowell, M. A., "Regulation of pre-B cell colony-enhancing factor by STAT-3-dependent interleukin-6 trans-signaling: implications in the pathogenesis of rheumatoid arthritis", Arthritis. Rheum., 54, pp.2084~2095 (2006)
- Hashizume, M., "IL-6 trans-signalling directly induces RANKL on fibroblast-like synovial cells and is involved in RANKL induction by TNF-alpha and IL-17", Rheumatology (Oxford), 47, pp.1635~1640 (2008)
- Wong, C., "Effects of inflammatory cytokine IL-27 on the activation of fibroblast-like synoviocytes in rheumatoid arthritis", Arthritis Res. Ther., 12 (2010)
- Ishimi, Y., "IL-6 is produced by osteoblasts and induces bone resorption", J. Immunol., 145, pp.3297~3303 (1990)
- Ishimi, Y., "Leukemia inhibitory factor", differentiation-stimulating factor (LIF, J. Cell Physiol., pp.1992, 152[DOI]
- Liu, F., "Expression of leukemia inhibitory factor (LIF)", interleukin-6 family cytokines and receptors during in vitro osteogenesis: differential regulation by dexamethasone and LIF, 2002, pp.31, 212~219
- Guerne, P. A., "IL-6 production by human articular chondrocytes. Modulation of its synthesis by cytokines, growth factors, and hormones in vitro", J. Immunol., 144, pp.499~505 (1990)
- Maier, R., "Interleukin-11, an inducible cytokine in human articular chondrocytes and synoviocytes, stimulates the production of the tissue inhibitor of metalloproteinases", J. Biol. Chem., 268, pp.21527~21532 (1993)
- Grimaud, E., "Leukaemia inhibitory factor (lif) is expressed in hypertrophic chondrocytes and vascular sprouts during osteogenesis", Cytokine, 20, pp.224~230 (2002)
- Sheng, Z., "Cardiotrophin-1 displays early expression in the murine heart tube and promotes cardiac myocyte survival", Development, 122, pp.419~428 (1996)
