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Cutting-Edge Muscle Recovery

Using Antifibrosis Agents to Improve Healing

Yong Li, MD, PhD; Freddie H. Fu, MD; Johnny Huard, PhD

THE PHYSICIAN AND SPORTSMEDICINE - VOL 33 - NO. 5 - MAY 2022

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In Brief: Muscle injuries, the most frequent type of sports-related injury, present challenging problems in traumatology and sports medicine. Injured skeletal muscle can repair itself via spontaneous regeneration, but extracellular matrix overgrowth and collagen deposition can lead to fibrosis, resulting in incomplete functional recovery and a propensity for injury recurrence. Physicians may be able to improve skeletal muscle healing after injury when researchers understand more about the mechanisms involved in scar-tissue development. Techniques may be refined to prevent muscle fibrosis—specifically via the inactivation of transforming growth factor-beta-1—and, ultimately, improve muscle healing after injuries.

Professional and recreational athletes sustain many muscle injuries through a variety of mechanisms, including direct trauma (eg, lacerations, strains, and contusions) and indirect injuries related to ischemia and neurologic dysfunctions.19,20 Researchers have not yet identified the optimal treatment for these injuries, and the recommended treatment regimens vary widely depending on the severity of the injury.3,4 Suggested treatments currently include rest, ice, compression, and elevation (RICE), heat, water pool therapy, immobilization and mobilization (ie, aggressive full range of motion using passive-motion machines), nonsteroidal anti-inflammatory drugs (NSAIDs), and surgery.4-7

Significant morbidity, including early functional and structural deficits, reinjury, muscle atrophy, contracture, and pain, often occurs after muscle injuries.2-4 These unmet medical needs continue to motivate us to seek novel strategies to improve muscle healing.

Muscle strain, the most common type of muscle injury sustained by athletes, occurs in response to eccentric contractions and overstraining during acute exercise and physical training.8-10 Strains are especially common in sports that involve sprinting or jumping. Distraction strains occur in muscles subjected to overstretching caused by an excessive pulling force. Although strained skeletal muscle undergoes self-regeneration, the healing process is slow and often incomplete, resulting in strength loss and a high re-injury rate.3,8,11

Phases of Muscle Healing

The healing process in injured skeletal muscle occurs in several phases. The degeneration phase is characterized by the formation of a hematoma, the necrosis of muscle tissue, and an inflammatory-cell response. Next, a muscle regeneration phase activates satellite cells to proliferate and differentiate into multinucleated myotubes that eventually fuse into myofibers to promote the repair of injured skeletal muscle.7 In severe injuries to striated muscle, another phase is characterized by the overproduction of extracellular matrix (ECM) and connective tissues and by capillary ingrowth. During a final remodeling phase, the regenerated muscle fibers mature and contract while displaying reorganization of the fibrous scar tissue.

We have researched the occurrence of fibrosis in skeletal muscle and the use of a novel technique to improve the healing of injured skeletal muscle by preventing fibrosis during muscle healing. The overall goal of our research is to develop approaches to improve muscle healing after injury and to identify ways that may improve muscle regeneration and inhibit the fibrosis that frequently occurs in injured muscle. Our findings also could contribute to the development of innovative therapies for muscle diseases, such as Duchenne's and Becker's muscular dystrophies.

Muscle Regeneration

Injured skeletal muscle can eventually heal itself through spontaneous muscle regeneration.1,2,9,12 Mononucleated satellite cells, located between the basal lamina and plasma membrane of the muscle fiber,4,13,14 are released when muscle injury disrupts the basal lamina and plasma membrane.14,15 During muscle regeneration, trophic substances, including growth factors and cytokines, are released by lymphocytes infiltrating the injured muscle. These substances can activate the satellite cells16 to self-renew, proliferate, and fuse with either local myogenic cells or with one another to support muscle regeneration. The growth of these regenerating myofibers at the injury site promotes muscle healing; however, the injured area is usually filled with a hematoma. Growing granulation tissue slowly replaces the hematoma, eventually resulting in the formation of scar tissue.17 These events not only interfere with the repair process but also inhibit muscle tissue regeneration and contribute to the incomplete functional recovery of injured muscle (figure 1).1,3

Investigators studying the effects of different growth factors on muscle healing found that insulin-like growth factor 1 (IGF-1), basic fibroblast growth factor (bFGF), and nerve growth factor (NGF) can improve muscle cell differentiation both in vitro and in vivo.10,18 However, improvement in muscle regeneration does not appear to restore muscle to near-complete recovery levels. Fibrous scar-tissue formation is one of the major factors that can slow muscle healing. Because muscle regeneration and the development of fibrous scar tissue occur concurrently in injured skeletal muscle, they may compete with one another during the healing process.

Fibrosis in Injured Skeletal Muscle

Some research suggests that a persistent imbalance between collagen biosynthesis and degradation contributes to hypertrophic scars and fibrosis in different tissues.19,20 High levels of collagens have been observed in the injured area of skeletal muscle,21-23 and inhibiting collagen deposition reduces the amount of scar tissue that forms.21-26 A greater understanding of the mechanism behind fibrous scar-tissue formation in injured skeletal muscle would benefit many patients.

Normal wound repair after tissue injury follows a closely regulated sequence that includes inflammation; recruitment, activation, and proliferation of fibroblasts; and secretion of ECM. Signaling by repair cells terminates the proliferation and secretion process and results in healing.27-29

In pathologic fibrosis, however, the normal termination and resolution stages do not occur, and unabated fibroblast activity continues. Excessive ECM containing a large amount of fibrillar collagens accumulates, and its presence results in the disruption of normal tissue architecture and function.29

Pathologic fibrosis can occur in almost any organ, but it is most common in the liver, kidneys, lungs, and skin. In severely injured skeletal muscle, fibrosis seems to be the limiting factor for full recovery.1,2,4 We have observed time-dependent formation of fibrous scar tissue in all the animal models of muscle injury tested in our laboratory (ie, models of contusion, laceration, and strain).17,30

Fibrosis also represents a problem for patients who have Duchenne's muscular dystrophy whose muscles often become replete with fibrous scar tissue—and thus very weak—by the teenage years.31 The formation of scar tissue within injured skeletal muscle impairs muscle regeneration, hinders the functional recovery of muscle, and appears to contribute to injury recurrence.

Cytokines and Growth Factors

The release of cytokines and growth factors in response to injury is a central event in tissue repair. Several lines of evidence point to transforming growth factor-beta (TGF-beta) as a key cytokine that initiates and terminates tissue repair and whose sustained production underlies the development of fibrous scar tissue.32 TGF-beta is a multifunctional cytokine that was first identified more than 20 years ago. The name derives from the observation that TGF-beta stimulates normal cells to grow on soft agar as though they had been virally transformed. The biological properties of the three isoforms found in mammals (ie, TGF-beta-1, -beta-2, and -beta-3) are nearly identical. TGF-beta-1 is up-regulated in response to injury and is the most strongly implicated isoform in fibrosis.33,34

TGF-beta-1 is synthesized as a 391-amino-acid precursor molecule that is proteolytically cleaved to yield peptide fragments and a 112-amino-acid subunit. The active TGF-beta-1 is a 25-Kd dimeric protein composed of two subunits linked by a disulfide bond. TGF-beta-1 is secreted in an inactive (ie, latent) form and is stored at the cell surface and in the ECM. In response to stimulation, inactive TGF-beta-1 at these sites becomes activated via an unknown mechanism.33 TGF-beta binds to at least three membrane proteins (ie, receptor types 1, 2, and 3) that exist in virtually all types of cells. The type 1 and 2 receptors are transmembrane serine-threonine kinases that interact with one another and facilitate each other's signaling.35 The type 3 receptor, also called betaglycan, is a membrane-anchored proteoglycan that has no signaling structure but presents TGF-beta to the other receptors.33 The type 1 receptor mediates the effect of TGF-beta on the synthesis and deposition of ECM, whereas the type 2 receptor mediates the effect of TGF-beta on cell growth and proliferation.35,36

Platelet-derived growth factor, (PDGF), endothelial growth factor (EGF), tumor necrosis factor, and interleukin-1 are other cytokines that interact with TGF-beta during tissue remodeling after injury.32,37,38 Each of these cytokines has a specific role in the repair process. PDGF stimulates cell migration and proliferation, EGF induces the formation of new blood vessels, and tumor necrosis factor and interleukin-1 promote inflammation, cell migration, and proliferation.

TGF-b, in contrast, is unique in its widespread effect on the deposition of ECM and its potent regulation of muscle repair while coordinating and suppressing the action of other cytokines.37,39,40 TGF-beta induces ECM deposition by simultaneously stimulating cells to increase the synthesis of most matrix proteins by several fold, decrease the production of matrix-degrading proteases, increase the production of protease inhibitors, modulate the expression of integrins to increase cellular adhesion to the matrix, and, finally, promote myofibroblast survival by preventing them from undergoing apoptosis.34,41-43 For all these reasons, the excessive and sustained production of TGF-beta leads to tissue fibrosis in skeletal muscle and various other tissues, including tissues of the kidneys, liver, lungs, skin, arteries, and central nervous system.33,34,44

TGF-beta and Fibrosis

In skeletal muscle, TGF-beta is found in high levels and is associated with the fibrosis observed in the skeletal muscle of patients who have Duchenne's muscular dystrophy.31 Excess TGF-beta also is present in muscle biopsies of patients with dermatomyositis, which leads to chronic inflammation, fibrosis, and accumulation of ECM.45 In injured skeletal muscle, inflammatory reactions at the injured site appear to stimulate the focal release of TGF-b, which in turn triggers fibrosis via the activation of ECM and connective tissue overgrowth.

We have begun to explore the possible relationships among TGF-beta-1 expression, the extent of muscle injury, and fibrous scar formation during muscle healing. We have demonstrated that muscle-derived stem cells and more highly differentiated muscle cells can differentiate into fibrotic cells after muscle laceration injury.30 We have also observed that TGF-beta-1 can induce autocrine expression in myogenic cells and that TGF-beta-1 gene transfection can trigger myoblast (ie, C2C12) differentiation into fibrotic cells both in vitro and in vivo. Additionally, we have reported that TGF-beta-1 is expressed at high levels and in a time-dependent manner in injured skeletal muscle.26 These results suggest that TGF-beta-1 plays a significant role in the initiation of a fibrosis cascade in skeletal muscle.26

Inefficient Muscle Healing

After muscle injury, infiltrating lymphocytes release initial TGF-beta-1 within the injured muscle to induce autocrine expression of TGF-beta-1 in local myogenic cells, including the regenerating myofibers. This positive feedback cycle appears to hinder muscle healing, because increasing amounts of TGF-beta-1 secreted within the injured area prevent myogenic cells from regenerating skeletal muscle and promote fibrosis.

Members of our laboratory have extensively documented the natural healing process of animal muscles injured via contusion, laceration, or strain.17,21-23,25,46,47 We have used these data, particularly the muscle laceration studies, as a baseline for evaluating the ability of various therapeutic interventions to enhance muscle healing. Using histology and immunohistochemistry, we have shown that injured muscle undergoes regeneration that peaks 5 to 10 days after injury and slows over time. Fibrosis, however, begins 10 to 14 days after injury, and large formations of fibrous scar tissue are visible 3 weeks after injury and remain within the injured muscle indefinitely. Because muscle regeneration slows significantly 10 to 14 days after injury, we hypothesize that fibrosis in the injured muscle interferes with muscle regeneration.

The time-dependent formation of fibrous scar tissue interferes with muscle regeneration and gradually slows muscle healing.1,2,12,21-23,25 The presence of many centronucleated myofibers at the injured site within 10 days of injury indicates that regeneration has begun within the injured muscle. The diameters of many centronucleated myofibers decrease 10 to 20 days after injury, which suggests some sort of interference with the regeneration process. Researchers also have observed ECM overgrowth during this period.

Fibrous scar tissue, which begins to form 2 weeks after injury, appears to hinder the development of regenerated myofibers, as demonstrated by the unorganized arrangement of centronucleated myofibers. Thus, it seems plausible that fibrous scar tissue interferes with muscle regeneration and results in slower and incomplete muscle healing.

To sum up, the interaction between fibrosis and regeneration influences the outcome of muscle healing: If more fibrous scar tissue is present, fewer regenerated myofibers are visible within the injured muscle (figure 2).

Preventing Fibrosis

Although administering exogenous growth factors (eg, IGF-1, bFGF, or NGF) can enhance muscle regeneration, it does not prevent fibrosis in injured muscle. In contrast, biological approaches designed to directly block muscle fibrosis can improve muscle healing.10,18,21,22 Although not all the steps necessary for efficient muscle healing are fully understood, preliminary results strongly suggest that researchers should focus their efforts on eliminating fibrosis to enhance healing within injured skeletal muscle.

An increased understanding of the cellular and molecular events that lead to fibrosis in various tissues, including skeletal muscle, should facilitate the development of effective therapies to prevent fibrosis and improve healing. In muscles, both myogenic cells and regenerating myofibers residing in the tissue differentiate into fibroblastic cells after injury. TGF-beta-1 triggers this pathologic process, which ultimately leads to muscle fibrosis.26,30 Because TGF-beta-1 plays a crucial role in fibrous scar-tissue formation, this molecule is a key target for our ongoing research on a functional antifibrosis therapy based on the neutralization of TGF-beta-1.

Antifibrosis Agents

In our efforts to minimize the effects of TGF-beta-1 in injured muscle, we have histologically and physiologically evaluated the capacity of several different antifibrosis agents to block fibrosis and promote improved functional recovery of injured skeletal muscle. Using different animal models of muscle injury, we have demonstrated that decorin, suramin, and interferon-gamma (IFN-g) can antagonize the effect of TGF-beta-1 in different ways. Decorin works by directly combining with TGF-beta-1, suramin competes with TGF-beta-1 receptors, and IFN-g interferes with TGF-beta-1 signal transduction.21-23,25,26 All these antifibrosis agents block the action of TGF-beta-1, inhibit skeletal muscle fibrosis induced by traumatic injury, enhance muscle regeneration, and improve the functional recovery of injured muscle (see figure 2).21-23,25,26

Decorin, a proteoglycan that has beneficial effects on muscle healing in laceration and strain models,23,25,26,48 impedes fibrosis by counteracting the effects of TGF-beta by combining with it. Decorin is a small dermatan sulfate proteoglycan that helps constitute the ECM in all collagen-containing tissues.49,50 Decorin plays a pivotal role in regulating the proper assembly of collagenous matrices and in controlling cell proliferation.51 Because decorin binds to fibrillar collagen and delays in vitro fibrillogenesis, it is a key modulator of matrix assembly.52 Decorin modulates the bioactivities of growth factors and acts as a direct signaling molecule to different cells. Decorin can prevent the fibrotic activity of TGF-beta-1 by direct conjugation with the TGF-beta-1 active protein and by blocking the transfer of TGF-beta-1 mRNA in the cells.52,53

High levels of decorin are found in skeletal muscle during early development,54,55 when it interferes with muscle cell differentiation and migration and may prevent the overgrowth of connective tissues. Direct injection of decorin into lacerated muscles results in nearly complete functional recovery within 2 weeks of injection.25,55 Injecting decorin (0, 5, 25, or 50 µg per muscle) improves muscle healing in a dose-dependent manner.25 Higher doses of decorin lead to better muscle healing, as assessed both histologically and physiologically.25 The mechanism by which decorin blocks fibrosis is likely related to its inhibitory effect on TGF-beta activity. Members of our laboratory are also investigating the possible association between decorin and muscle-cell differentiation.

Suramin is a polysulphonated naphthyl-urea originally designed as an antiparasitic drug. Because suramin can inhibit TGF-beta expression by competitively binding to the growth factor receptor,56-58 it is a good candidate for possible clinical applications.59-61 TGF-beta-1, beta-2, and the A and B chains of PDGF all have strong stimulatory effects on fibroblast proliferation. Suramin blocks the effects of these growth factors by competitively binding to their receptors.56,57,62

In a study of dermal wound healing in rats,63 suramin injections decreased ECM deposition. Suramin also has proven highly effective in preventing scar-tissue formation in the ciliary epithelium of leaf-monkeys without toxic effects.64 We used animal models of laceration and strain injury to investigate the possible antifibrosis effects of suramin during muscle healing.22,65 We found that suramin (50 µg/mL) can inhibit the proliferation of fibroblasts and the expression of fibrotic proteins (ie, alpha-SMA and vimentin) effectively in vitro. Our in vivo studies22,65 demonstrated that the injection of 2.5 mg of suramin 2 weeks after injury can efficiently prevent muscle fibrosis, enhance muscle regeneration, and enable more complete functional recovery of injured muscles (figure 3).

Interferon-gamma, a TGF-beta-1 pathway inhibitor, can disrupt TGF-beta-1 signal transduction.66 IFN-g down-regulates endogenous collagen expression and blocks TGF-beta-1-mediated increases in collagen protein levels.67 Furthermore, IFN-g inhibits TGF-beta-1 signaling by inducing the expression of Smad7, which participates in a negative feedback loop in the TGF-beta-1 signal transduction pathway.66

Research shows that IFN-g can inhibit TGF beta-1-induced adoption of the myofibroblast phenotype by palatal fibroblasts in animal models of liver and kidney fibrosis.68-70 We therefore hypothesized that IFN-g might also block the effects of TGF-beta-1 in skeletal muscle. Our studies have shown that IFN-g treatment down-regulated the level of TGF-beta-1-induced fibrotic protein expression by muscle-derived fibroblasts in vitro. To conduct in vivo studies, we used a muscle laceration model to induce fibrosis in the skeletal muscles of mice. We found that the intramuscular injection of 250 U of IFN-g into the injured (lacerated) site 1 or 2 weeks after injury resulted in improved functional recovery (in terms of fast-twitch and tetanic strength) of the treated muscle when compared with control muscle (injured muscle not treated with IFN-g). These findings demonstrate that IFN-g can be used to prevent muscle fibrosis in lacerated muscles and, consequently, can improve muscle healing.21

Ongoing Research Parameters

Severe injuries in skeletal muscle induce the formation of fibrous scar tissue, and TGF-beta-1 is a key stimulator of fibrosis during the muscle healing process. Prevention of fibrosis via neutralization of TGF-beta-1 action can reduce scar tissue formation and enhance muscle regeneration and improve muscle healing. However, because the fibrous scar tissue forms in a time-dependent manner, researchers must identify the optimal time for therapeutic application and correlate the appropriate dose of antifibrosis agents with the injury severity to improve muscle healing. More clinical data are needed before therapeutic rules can be established. To ensure the best therapeutic outcome in injured patients, we continue to search for a clinically available antifibrosis agent that effectively prevents fibrosis in injured muscle while having minimal (if any) side effects. After additional characterization, this sort of antifibrosis approach could become a common therapeutic method in sports medicine for treatment of exercise-related muscle injuries.

The authors wish to thank Ryan Sauder, MA, University of Pittsburgh, for editorial assistance and are grateful for funding from the National Institutes of Health (NIH 1 R01 AR47973-01 to J.H.), the Department of Defense, the William F. and Jean W. Donaldson Chair at Children's Hospital of Pittsburgh, and the Henry J. Mankin Chair at the University of Pittsburgh.

References

  1. Li Y, Cummins J, Huard J: Muscle injury and repair. Curr Opin Orthop 2001;12:409-415
  2. Huard J, Li Y, Fu FH: Muscle injuries and repair: current trends in research. J Bone Joint Surg Am 2002;84(5):822-832
  3. Garrett WE Jr: Muscle strain injuries: clinical and basic aspects. Med Sci Sports Exerc 1990;22(4):436-443
  4. Lehto MU, Jarvinen MJ: Muscle injuries, their healing process and treatment. Ann Chir Gynaecol 1991;80(2):102-108
  5. Levine WN, Bergfeld JA, Tessendorf W, et al: Intramuscular corticosteroid injection for hamstring injuries: a 13-year experience in the National Football League. Am J Sports Med 2000;28(3):297-300
  6. Jarvinen MJ, Lehto MU: The effects of early mobilisation and immobilisation on the healing process following muscle injuries. Sports Med 1993;15(2):78-89
  7. Hurme T, Kalimo H, Lehto M, et al: Healing of skeletal muscle injury: an ultrastructural and immunohistochemical study. Med Sci Sports Exerc 1991;23(7):801-810
  8. Garrett WE Jr: Muscle strain injuries. Am J Sports Med 1996;24(6 suppl):S2-S8
  9. Huard J, Li Y, Peng H, et al: Gene therapy and tissue engineering for sports medicine. J Gene Med 2003;5(2):93-108
  10. Kasemkijwattana C, Menetrey J, Bosch P, et al: Use of growth factors to improve muscle healing after strain injury. Clin Orthop 2000;370(Jan):272-285
  11. Nikolaou PK, Macdonald BL, Glisson RR, et al: Biomechanical and histological evaluation of muscle after controlled strain injury. Am J Sports Med 1987;15(1):9-14
  12. Carlson BM, Faulkner JA: The regeneration of skeletal muscle fibers following injury: a review. Med Sci Sports Exerc 1983;15(3):187-198
  13. Alameddine HS, Dehaupas M, Fardeau M: Regeneration of skeletal muscle fibers from autologous satellite cells multiplied in vitro: an experimental model for testing cultured cell myogenicity. Muscle Nerve 1989;12(7):544-555
  14. Bischoff R: The satellite cell and muscle regeneration, in Engel AG, Franzini-Armstrong C (eds): Myology: Basic and Clinical, ed 2. New York City, McGraw-Hill, 1994, pp 97-118
  15. Schultz E, Jaryszak DL, Valliere CR: Response of satellite cells to focal skeletal muscle injury. Muscle Nerve 1985;8(3):217-222
  16. Grounds MD: Towards understanding skeletal muscle regeneration. Pathol Res Pract 1991;187(1):1-22
  17. Menetrey J, Kasemkijwattana C, Fu FH, et al: Suturing versus immobilization of a muscle laceration: a morphological and functional study in a mouse model. Am J Sports Med 1999:27(2):222-229
  18. Menetrey J, Kasemkijwattana C, Day CS, et al: Growth factors improve muscle healing in vivo. J Bone Joint Surg Br 2000;82(1):131-137
  19. Trojanowska M, LeRoy EC, Eckes B, et al: Pathogenesis of fibrosis: type 1 collagen and the skin. J Mol Med 1998;76(3-4):266-274
  20. Schmid P, Itin P, Cherry G, et al: Enhanced expression of transforming growth factor-beta type I and type II receptors in wound granulation tissue and hypertrophic scar. Am J Pathol 1998;152(2):485-493
  21. Foster W, Li Y, Usas A, et al: Gamma interferon as an antifibrosis agent in skeletal muscle. J Orthop Res 2003;21(5):798-804
  22. Chan YS, Li Y, Foster W, et al: Antifibrotic effects of suramin in injured skeletal muscle after laceration. J Appl Physiol 2003;95(2):771-780
  23. Sato K, Li Y, Foster W, et al: Improvement of muscle healing through enhancement of muscle regeneration and prevention of fibrosis. Muscle Nerve 2003;28(3):365-372
  24. Velleman SG: The role of the extracellular matrix in skeletal muscle development. Poult Sci 1999;78(5):778-784
  25. Fukushima K, Badlani N, Usas A, et al: The use of an antifibrosis agent to improve muscle recovery after laceration. Am J Sports Med 2001;29(4):394-402
  26. Li Y, Foster W, Deasy BM, et al: Transforming growth factor-beta1 induces the differentiation of myogenic cells into fibrotic cells in injured skeletal muscle: a key event in muscle fibrogenesis. Am J Pathol 2004;164(3):1007-1019
  27. Verrecchia F, Mauviel A: Transforming growth factor-beta signaling through the Smad pathway: role in extracellular matrix gene expression and regulation. J Invest Dermatol 2002;118(2):211-215
  28. Eming SA, Morgan JR, Berger A: Gene therapy for tissue repair: approaches and prospects. Br J Plast Surg 1997;50(7):491-500
  29. Mutsaers SE, Bishop JE, McGrouther G, et al: Mechanisms of tissue repair: from wound healing to fibrosis. Int J Biochem Cell Biol 1997;29(1):5-17
  30. Li Y, Huard J: Differentiation of muscle-derived cells into myofibroblasts in injured skeletal muscle. Am J Pathol 2002;161(3):895-907
  31. Bernasconi P, Di Blasi C, Mora M, et al: Transforming growth factor-beta1 and fibrosis in congenital muscular dystrophies. Neuromuscul Disord 1999;9(1):28-33
  32. Border WA, Noble NA: Cytokines in kidney disease: the role of transforming growth factor-beta. Am J Kidney Dis 1993;22(1):105-113
  33. Border WA, Noble NA: Transforming growth factor beta in tissue fibrosis. N Engl J Med 1994;331(19):1286-1292
  34. Branton MH, Kopp JB: TGF-beta and fibrosis. Microbes Infect 1999;1(15):1349-1365
  35. Choi ME: Mechanism of transforming growth factor-beta1 signaling. Kidney Int Suppl 2000;77:S53-S58
  36. Gold LI, Sung JJ, Siebert JW, et al: Type I (RI) and type II (RII) receptors for transforming growth factor-beta isoforms are expressed subsequent to transforming growth factor-beta ligands during excisional wound repair. Am J Pathol 1997;150(1):209-222
  37. Ketteler M, Border WA, Noble NA: Cytokines and L-arginine in renal injury and repair. Am J Physiol 1994;267(2 pt 2):F197-F207
  38. Messadi DV, Le A, Berg S, et al: Effect of TGF-beta-1 on PDGF receptors expression in human scar fibroblasts. Front Biosci 1998;3:A16-A22
  39. Grande JP, Warner GM, Walker HJ, et al: TGF-beta1 is an autocrine mediator of renal tubular epithelial cell growth and collagen IV production. Exp Biol Med (Maywood) 2002;227(3):171-181
  40. Moulin V: Growth factors in skin wound healing. Eur J Cell Biol 1995;68(1):1-7
  41. Zhang HY, Phan SH: Inhibition of myofibroblast apoptosis by transforming growth factor beta(1). Am J Respir Cell Mol Biol 1999;21(6):658-665
  42. Border WA, Ruoslahti E: Transforming growth factor-beta-1 induces extracellular matrix formation in glomerulonephritis. Cell Differ Dev 1990;32(3):425-431
  43. Terrell TG, Working PK, Chow CP, et al: Pathology of recombinant human transforming growth factor-beta-1 in rats and rabbits. Int Rev Exp Pathol 1993;34(pt B):43-67
  44. Border WA, Noble NA: Targeting TGF-beta for treatment of disease. Nat Med 1995;1(10):1000-1001
  45. Amemiya K, Semino-Mora C, Granger RP, et al: Downregulation of TGF-beta1 mRNA and protein in the muscles of patients with inflammatory myopathies after treatment with high-dose intravenous immunoglobulin. Clin Immunol 2000;94(2):99-104
  46. Kasemkijwattana C, Menetrey J, Somogyl G, et al: Development of approaches to improve the healing following muscle contusion. Cell Transplant 1998;7(6):585-598
  47. Kasemkijwattana C, Menetrey J, Goto H, et al: The use of growth factors, gene therapy and tissue engineering to improve meniscal healing. Materials Sci Eng 2000;13:19-28
  48. Isaka Y, Brees DK, Ikegaya K, et al: Gene therapy by skeletal muscle expression of decorin prevents fibrotic disease in rat kidney. Nat Med 1996;2(4):418-423
  49. Andrade W, Brandan E: Isolation and characterization of rat skeletal muscle proteoglycan decorin and comparison with the human fibroblast decorin. Comp Biochem Physiol B 1991;100(3):565-570
  50. Imai K, Hiramatsu A, Fukushima D, et al: Degradation of decorin by matrix metalloproteinases: identification of the cleavage sites, kinetic analyses and transforming growth factor-beta1 release. Biochem J 1997;322(pt 3):809-814
  51. Westergren-Thorsson G, Hernnas J, Sarnstrand B, et al: Altered expression of small proteoglycans, collagen, and transforming growth factor-beta-1 in developing bleomycin-induced pulmonary fibrosis in rats. J Clin Invest 1993;92(2):632-637
  52. Harper JR, Spiro RC, Gaarde WA, et al: Role of transforming growth factor beta and decorin in controlling fibrosis. Methods Enzymol 1994;245:241-254
  53. Giri SN, Hyde DM, Braun RK, et al: Antifibrotic effect of decorin in a bleomycin hamster model of lung fibrosis. Biochem Pharmacol 1997;54(11):1205-1216
  54. Brandan E, Fuentes ME, Andrade W: The proteoglycan decorin is synthesized and secreted by differentiated myotubes. Eur J Cell Biol 1991;55(2):209-216
  55. Nishimura T, Futami E, Taneichi A, et al: Decorin expression during development of bovine skeletal muscle and its role in morphogenesis of the intramuscular connective tissue. Cells Tissues Organs 2002;171(2-3):199-214
  56. Kloen P, Jennings CL, Gebhardt MC, et al: Suramin inhibits growth and transforming growth factor-beta-1 (TGF-beta-1) binding in osteosarcoma cell lines. Eur J Cancer 1994;30A(5):678-682
  57. Coffey RJ Jr, Leof EB, Shipley GD, et al: Suramin inhibition of growth factor receptor binding and mitogenicity in AKR-2B cells. J Cell Physiol 1987;132(1):143-148
  58. Zumkeller W, Schofield PN: Growth factors, cytokines and soluble forms of receptor molecules in cancer patients. Anticancer Res 1995;15(2):343-348
  59. Mietz H, Krieglstein GK: Suramin to enhance glaucoma filtering procedures: a clinical comparison with mitomycin. Ophthalmic Surg Lasers 2001;32(5):358-369
  60. Levine AM, Gill PS, Cohen J, et al: Suramin antiviral therapy in the acquired immunodeficiency syndrome: clinical, immunological, and virologic results. Ann Intern Med 1986;105(1):32-37
  61. Cheson BD, Levine AM, Mildvan D, et al: Suramin therapy in AIDS and related disorders: report of the US Suramin Working Group. JAMA 1987;258(10):1347-1351
  62. Wade TP, Kasid A, Stein CA, et al: Suramin interference with transforming growth factor-beta inhibition of human renal cell carcinoma in culture. J Surg Res 1992;53(2):195-198
  63. Chamberlain J, Shah M, Ferguson MW: The effect of suramin on healing adult rodent dermal wounds. J Anat 1995;186(pt 1):87-96
  64. Mak JW: Lam PL, Choong MF, et al: Antifilarial activity of intravenous suramin and oral diethylcarbamazine citrate on subperiodic Brugia malayi in the leaf-monkey, Presbytis cristata. J Helminthol 1990;64(2):96-99
  65. Chan YS, Li Y, Foster W, et al: The use of suramin, an antifibrotic agent, to improve muscle recovery after strain injury. Am J Sports Med 2005;33(1):43-51
  66. Ulloa L, Doody J, Massague J: Inhibition of transforming growth factor-beta/SMAD signalling by the interferon-gamma/STAT pathway. Nature 1999;397(6721):710-713
  67. Ghosh AK, Yuan W, Mori Y, et al: Antagonistic regulation of type I collagen gene expression by interferon-gamma and transforming growth factor-beta: integration at the level of p300/CBP transcriptional coactivators. J Biol Chem 2001;276(14):11041-11048
  68. Baroni GS, D'Ambrosio L, Curto P, et al: Interferon gamma decreases hepatic stellate cell activation and extracellular matrix deposition in rat liver fibrosis. Hepatology 1996;23(5):1189-1199
  69. Yokozeki M, Baba Y, Shimokawa H, et al: Interferon-gamma inhibits the myofibroblastic phenotype of rat palatal fibroblasts induced by transforming growth factor-beta1 in vitro. FEBS Lett 1999;442(1):61-64
  70. Oldroyd SD, Thomas GL, Gabbiani G, et al: Interferon-gamma inhibits experimental renal fibrosis. Kidney Int 1999;56(6):2116-2127

Dr Li is an assistant professor and Dr Huard is the director of the Growth and Development Laboratory at Children's Hospital of Pittsburgh. Dr Fu is a professor and chair, Dr Huard is an associate professor, and Dr Li is an assistant professor in the department of orthopedic surgery at the University of Pittsburgh. Dr Huard is also an associate professor in the departments of molecular genetics and biochemistry and bioengineering at the University of Pittsburgh. Address correspondence to Johnny Huard, PhD, 4100 Rangos Research Center, 3460 Fifth Ave, Pittsburgh, PA 15213-2583; e-mail to [email protected].

Disclosure information: Drs Li, Fu, and Huard disclose no significant relationship with any manufacturer of any commercial product mentioned in this article. No drug is mentioned in this article for an unlabeled use.


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