Abstract
Tendon healing is a complex and highly-regulated process that is initiated, sustained and eventually terminated by a large number and variety of molecules. Growth factors represent one of the most important of the molecular families involved in healing, and a considerable number of studies have been undertaken in an effort to elucidate their many functions. This review covers some of the recent investigations into the roles of five growth factors whose activities have been best characterised during tendon healing: insulin-like growth factor-I (IGF-I), transforming growth factor β (TGFβ), vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and basic fibroblast growth factor (bFGF). All five are markedly up-regulated following tendon injury and are active at multiple stages of the healing process. IGF-I has been shown to be highly expressed during the early inflammatory phase in a number of animal tendon healing models, and appears to aid in the proliferation and migration of fibroblasts and to subsequently increase collagen production. TGFβ is also active during inflammation, and has a variety of effects including the regulation of cellular migration and proliferation, and fibronectin binding interactions. VEGF is produced at its highest levels only after the inflammatory phase, at which time it is a powerful stimulator of angiogenesis. PDGF is produced shortly after tendon damage and helps to stimulate the production of other growth factors, including IGF-I, and has roles in tissue remodelling.
In vitro and in vivo studies have shown that bFGF is both a powerful stimulator of angiogenesis and a regulator of cellular migration and proliferation. This review also covers some of the most recent studies into the use of these molecules as therapeutic agents to increase the efficacy and efficiency of tendon and ligament healing. Studies into the effects of the exogenous application of TGFβ, IGF-I, PDGF and bFGF into the wound site singly and in combination have shown promise, significantly decreasing a number of parameters used to define the functional deficit of a healing tendon. Application of IGF-I has been shown to increase in the Achilles Functional Index and the breaking energy of injured rat tendon. TGFβ and PDGF have been shown separately to increase the breaking energy of healing tendon. Finally, application of bFGF has been shown to promote cellular proliferation and collagen synthesis in vivo.
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References
Albright JA. The scientific basis of orthopaedics. 2nd ed. Norwalk (CT): Appleton & Lange, 1987
Mast BA. Healing in other tissues. Surg Clin North Am 1997; 77(3): 529–47
Hyman J, Rodeo SA. Injury and repair of tendons and ligaments. Phys Med Rehabil Clin N Am 2000; 11(2): 267–88
Woo SL, Hildebrand K, Watanabe N, et al. Tissue engineering of ligament and tendon healing. Clin Orthop 1999; 367S: S312–23
Klein MB, Pham H, Yalamanchi N, et al. Flexor tendon wound healing in vitro: the effect of lactate on tendon cell proliferation and collagen production. J Hand Surg [Am] 2001; 26A: 847–54
Braddock M, Campbell C, Zuder D. Current therapies for wound healing: electrical stimulation, biological therapeutics and the potential for gene therapy. Int J Dermatol 1999; 38: 808–17
Braddock M. The transcription factor Egr-1: a potential drug in wound healing and tissue repair. Ann Med 2001; 33(5): 313–8
Sciore P, Boykiw R, Hart DA. Semi-quantitive reverse transcriptase polymerase chain reaction analysis of mRNA for growth factors and growth factor receptors from normal and healing rabbit medial collateral ligament tissue. J Orthop Res 1998; 16: 429–37
Hansson HA, Dahlin L, Lundborg G, et al. Transiently increased insulin-like growth factor I immunoreactivity in tendons after vibration trauma: an immunohistochemical study on rats. Scand J Plast Reconstr Surg Hand Surg 1988; 22(1): 1–6
Lynch SE, Colvin R, Antoniades HN. Growth factors in wound healing: single and synergistic effects on partial thickness porcine skin wounds. J Clin Invest 1989; 84(2): 640–6
Jones JI, Clemmons D. Insulin-like growth factors and their binding proteins: biological actions. Endocr Rev 1995; 16(1): 3–34
Abrahamsson SO. Similar effects of recombinant human insulin-like growth factor-I and II on cellular activities in flexor tendons of young rabbits: experimental studies in vitro. J Orthop Res 1997; 15(2): 256–62
McCarthy TL, Centrella M, Canalis E. Regulatory effects of insulin-like growth factors I and II on bone collagen synthesis in rat calvarial cultures. Endocrinology 1989; 124(1): 301–9
Chang J, Thunder R, Most D, et al. Studies in flexor tendon wound healing: neutralizing antibody to TGF-B1 increases postoperative range of motion. Plast Reconstr Surg 2000; 105(1): 148–55
Bennett NT, Schultz G. Growth factors and wound healing: biochemical properties of growth factors and their receptors. Am J Surg 1993; 165(6): 728–37
Wojciak B, Crossan J. The effects of T cells and their products on in vitro healing of epitenon cell microwounds. Immunology 1994; 83(1): 93–8
Zhu X, Hu C, Zhang Y, et al. Expression of cyclin-dependent kinase inhibitors p21 (cip1) and p27 (kip1), during wound healing in rats. Wound Repair Regen 2001; 9: 205–12
Marui T, Niyibizi C, Georgescu HI, et al. Effect of growth factors on matrix synthesis by ligament fibroblasts. J Orthop Res 1997; 15(1): 18–23
Natsu-ume T, Nakamura N, Shino K, et al. Temporal and spatial expression of transforming growth factor-beta in the healing patellar ligament of the rat. J Orthop Res 1997; 15(6): 837–43
Boyer MI, Watson J, Lou J, et al. Quantitative variation in vascular endothelial growth factor mRNA expression during early flexor tendon healing: an investigation in a canine model. J Orthop Res 2001; 19(5): 869–72
Gelberman RH, Khabie V, Cahill CJ. The revascularization of healing flexor tendons in the digital sheath: a vascular injection study in dogs. J Bone Joint Surg Am 1991; 73(6): 868–81
Pierce GF, Mustoe T, Lingelbach J, et al. Platelet-derived growth factor and transforming growth factor-beta enhance tissue repair activities by unique mechanisms. J Cell Biol 1989; 109(1): 429–40
Folkman J, Klagsbrun M. Angiogenic factors. Science 1987; 235(4787): 442–7
Chan BP, Fu S, Qin L, et al. Effects of basic fibroblast growth factor (bFGF) on early stages of tendon healing: a rat patellar tendon model. Acta Orthop Scand 2000; 71(5): 513–8
Chang J, Most D, Thunder R, et al. Molecular studies in flexor tendon wound healing: the role of basic fibroblast growth factor gene expression. J Hand Surg [Am] 1998; 23A(6): 1052–9
Winston BW, Krein P, Mowat C, et al. Cytokine-induced macrophage differentiation: a tale of 2 genes. Clin Invest Med 1999; 22(6): 236–55
Le Rorth D. Insulin-like growth factors. N Engl J Med 1997; 336(9): 633–9
Cohick WS, Clemmons DR. The insulin-like growth factors. Annu Rev Physiol 1993; 55: 131–53
Steenfos H, Hunt T. Insulin-like growth factor has a major role in wound healing. Surg Forum 1989; 40: 68–70
Tsuzaki M, Brigman B, Yamamoto J, et al. Insulin-like growth factor-I is expressed by avian flexor tendon cells. J Orthop Res 2000; 18(4): 546–56
Edwall D, Schalling M, Jennische E, et al. Induction of insulinlike growth factor I messenger ribonucleic acid during regeneration of rat skeletal muscle. Endocrinology 1989; 124: 820–5
Fortier LA, Balkman C, Sandell LJ, et al. Insulin-like growth factor-I gene expression patterns during spontaneous repair of acute articular cartilage injury. J Orthop Res 2001; 19(4): 720–8
Bos PK, van Osch G, Frenz DA, et al. Growth factor expression in cartilage wound healing: temporal and spatial immunolocalization in a rabbit auricular cartilage wound model. Osteoarthritis Cartilage 2001; 9(4): 382–9
Vogt PM, Lehnhardt M, Wagner D, et al. Growth factors and insulin-like growth factor binding proteins in acute wound fluid. Growth Horm IGF Res 1998; 8Suppl B: 107–9
Rubini M, Werner H, Gandini E, et al. Platelet-derived growth factor increases the activity of the promoter of the insulin-like growth factor-I (IGFI) receptor gene. Exp Cell Res 1994; 211: 374–9
Bottinger EP, Letterio J, Roberts AB. Biology of TGF-Beta in knockout and transgenic mouse models. Kidney Int 1997; 51: 1355–60
Ngo M, Pham H, Longaker MT, et al. Differential expression of transforming growth factor-beta receptors in a rabbit zone II flexor tendon wound healing model. Plast Reconstr Surg 2001; 108: 1260–7
Klein MB. Flexor tendon healing in vitro: effects of TGF-(beta) on tendon cell collagen production. J Hand Surg [Am] 2002; 27A(4): 615–21
Centrella M, McCarthy T, Canalis E. Transforming growth factor-beta and remodeling of bone. J Bone Joint Surg Am 1991; 73A: 1418–28
Jackson JR, Minton J, Ho ML, et al. Expression of vascular endothelial growth factor in synovial fibroblasts is induced by hypoxia and interleukin 1beta. J Rheumatol 1997; 24(7): 1253–9
Ellis LM, Takahashi Y, Liu W, et al. Vascular endothelial growth factor in human colon cancer: biology and therapeutic implications. Oncologist 2000; 5Suppl. 1: 11–5
Clauss M, Weich H, Breier G. The vascular endothelial growth factor receptor Flt-1 mediates biological activities: implications for a functional role of placenta growth factor in monocyte activation and chemotaxis. J Biol Chem 1996; 271: 17629–34
Deroanne CF, Hajitou A, Calberg-Bacq CM, et al. Angiogenesis by fibroblast growth factor 4 is mediated through an autocrine up-regulation of vascular endothelial growth factor expression. Cancer Res 1997; 57(24): 5590–7
Duffy Jr FJ, Seiler J, Gelberman RH, et al. Growth factors and canine flexor tendon healing: initial studies in uninjured and repair models. J Hand Surg [Am] 1995; 20(4): 645–9
Ronnstrand L, Heldin C. Mechanisms of platelet-derived growth factor-induced chemotaxis. Int J Cancer 2001; 91(6): 757–62
Yoshikawa Y, Abrahamsson S. Dose-related cellular effects of platelet-derived growth factor-BB differ in various types of rabbit tendons in vitro. Acta Orthop Scand 2001; 72(3): 287–92
Hildebrand KA, Woo SL, Smith DW, et al. The effects of platelet-derived growth factor-BB on healing of the rabbit medial collateral ligament: an in vivo study. Am J Sports Med 1998; 26(4): 549–54
Nugent MA, Iozzo R. Fibroblast growth factor-2. Int J Biochem Cell Biol 2000; 23: 115–20
Chan BP, Chan K, Maffulli N, et al. Effect of basic fibroblast growth factor: an in vitro study of tendon healing. Clin Orthop 1997; 342: 239–47
Kurtz CA, Loebig T, Anderson DD, et al. Insulin-like growth factor 1 accelerates functional recovery from Achilles tendon injury in a rat model. Am J Sports Med 1999; 27(3): 363–9
Letson AK, Dahners L. The effect of combinations of growth factors on ligament healing. Clin Orthop 1994; 308: 207–12
Forslund C, Aspenberg P. Tendon healing stimulated by injected CDMP-2. Med Sci Sports Exerc 2001; 33(5): 685–7
Aspenberg P, Forslund C. Bone morphogenetic proteins and tendon repair. Scand J Med Sci Sports 2000; 10(6): 372–5
Fukui N, Katsuragawa Y, Sakai H, et al. Effect of local application of basic fibroblast growth factor on ligament healing in rabbits. Rev Rhum Engl Ed 1998; 65(6): 406–14
Kobayashi D, Kurosaka M, Yoshiya S, et al. Effect of basic fibroblast growth factor on the healing of defects in the canine anterior cruciate ligament. Knee Surg Sports Traumatol Arthrose 1997; 5(3): 189–94
Hefti FL, Kress A, Fasel J, et al. Healing of the transacted anterior cruciate ligament in the rabbit. J Bone Joint Surg Am 1991; 73: 373–83
Tischler M. Platelet rich plasma: the use of autologous growth factors to enhance bone and soft tissue grafts. N Y State Dent J 2002 Mar; 68(3): 22–4
Bouletreau PJ, Warren SM, Spector JA, et al. Hypoxia and VEGF up-regulate BMP-2 mRNA and protein expression in microvascular endothelial cells: implications for fracture healing. Plast Reconstr Surg 2002 Jun; 109(7): 2384–97
Yeung HY, Lee KM, Fung KP, et al. Sustained expression of transforming growth factor-betal by distraction during distraction osteogenesis. Life Sci 2002 May 24; 71(1): 67–79
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The authors would like to acknowledge support provided by St George Hospital and South Eastern Area Health Service.
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Molloy, T., Wang, Y. & Murrell, G.A.C. The Roles of Growth Factors in Tendon and Ligament Healing. Sports Med 33, 381–394 (2003). https://doi.org/10.2165/00007256-200333050-00004
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DOI: https://doi.org/10.2165/00007256-200333050-00004