Neutralisation of TGFβ or binding of VLA-4 to fibronectin prevents rat tendon adhesion following transection

ATMU & Division of Cancer Sciences, University of Glasgow, Level 3 Queen Elizabeth Building, UK.
Cytokine (Impact Factor: 2.66). 06/2005; 30(4):195-202. DOI: 10.1016/j.cyto.2004.12.017
Source: PubMed


Following tendon injury, severe loss of function often occurs either as a result of obliteration of the synovial canal with fibrous scar tissue or from rupture of the repaired tendon. The role of cell engineering in tendon repair is to promote strong and rapid healing of tendon whilst at the same time facilitating rapid reconstitution of the synovial canal. Modification of the immediate inflammatory response around healing tendon has been found to be of value. Experimentally this has been achieved by neutralisation of transforming growth factor-beta over the first 3 days following injury, or by blockade of inflammatory cell binding to the CS-1 locus on fibronectin with an anti-VLA-4 antibody, or with the synthetic VLA-4 inhibitor, CS-1 peptide, in a rat model of tendon transection. It is concluded from this pilot study that the treatments described hold promise in improving outcomes of the common clinical problem of tendon injury in man.

1 Read
  • Source
    • "Transforming growth factor-Beta (TGF-β) is a potent fibrotic agent. Its inhibition with neutralizing antibodies has been shown to significantly reduce fibronectin concentrations and adhesion formation during early wound healing (Jorgensen et al., 2005). TGF-β1 has been shown to tilt gene expression in favour of ECM synthesis rather than matrix-remodelling matrix metalloproteinases , providing a mechanism for its promotion of adhesion formation (Farhat et al., 2012). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Tissue engineering of flexor tendons addresses a challenge often faced by hand surgeons: the restoration of function and improvement of healing with a limited supply of donor tendons. Creating an engineered tendon construct is dependent upon understanding the normal healing mechanisms of the tendon and tendon sheath. The production of a tendon construct includes: creating a three-dimensional scaffold; seeding cells within the scaffold; encouraging cellular growth within the scaffold while maintaining a gliding surface; and finally ensuring mechanical strength. An effective construct incorporates these factors in its design, with the ultimate goal of creating tendon substitutes that are readily available to the reconstructive hand surgeon.
    Full-text · Article · Nov 2013
  • Source
    • "Antagonism of TGF-β1 has been reported to reduce scarring and/or adhesion formation in animal models of tendon [7], [8], [9], abdominal [10], and skin [11], [12] injury and repair. Unfortunately, antagonizing TGF-β1 also led to the loss of mechanical strength within healing tendon [8], [9], suggesting that TGF-β1 mediated matrix production is essential to the strength of the repair. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Flexor tendon injuries are among the most challenging problems for hand surgeons and tissue engineers alike. Not only do flexor tendon injuries heal with poor mechanical strength, they can also form debilitating adhesions that may permanently impair hand function. While TGF-β1 is a necessary factor for regaining tendon strength, it is associated with scar and adhesion formation in the flexor tendons and other tissues as well as fibrotic diseases. The pleiotropic effects of TGF-β1 on tendon cells and tissue have not been characterized in detail. The goal of the present study was to identify the targets through which the effects of TGF-β1 on tendon healing could be altered. To accomplish this, we treated flexor tendon tenocytes cultured in pinned collagen gels with 1, 10 or 100 ng/mL of TGF-β1 and measured gel contraction and gene expression using RT-PCR up to 48 hours after treatment. Specifically, we studied the effects of TGF-β1 on the expression of collagens, fibronectin, proteoglycans, MMPs, MMP inhibitors, and the neotendon transcription factors, Scleraxis and Mohawk. Area contraction of the gels was not dose-dependent with the TGF-β1 concentrations tested. We observed dose-dependent downregulation of MMP-16 (MT3-MMP) and decorin, and upregulation of biglycan, collagen V, collagen XII, PAI-1, Scleraxis, and Mohawk by TGF-β1. Inter-gene analyses were also performed to further characterize the expression of ECM and MMP genes in the tenocyte-seeded collagen gels. These analyses illustrate that TGF-β1 tilts the balance of gene expression in favor of ECM synthesis rather than the matrix-remodeling MMPs, a possible means by which TGF-β1 promotes adhesion formation.
    Full-text · Article · Dec 2012 · PLoS ONE
  • [Show abstract] [Hide abstract]
    ABSTRACT: Hypertrophic scar and keloids are fibroproliferative disorders of the skin which occur often unpredictably, following trauma and inflammation that compromise cosmesis and function and commonly recur following surgical attempts for improvement. Despite decades of research in these fibrotic conditions, current non-surgical methods of treatment are slow, inconvenient and often only partially effective. Fibroblasts from these conditions are activated to produce extracellular matrix proteins such as collagen I and III, proteoglycans such as versican and biglycan and growth factors, including transforming growth factor-β and insulin like growth factor I. However, more consistently these cells produce less remodeling enzymes including collagenase and other matrix metalloproteinases, as well as the small proteoglycan decorin which is important for normal collagen fibrillogenesis. Recently, the systemic response to injury appears to influence the local healing process whereby increases in Th2 and possibly Th3 cytokines such as IL-2, IL-4 and IL-10 and TGF-β are present in the circulating lymphocytes in these fibrotic conditions. Finally, unique bone marrow derived cells including mesenchymal and endothelial stem cells as well as fibrocytes appear to traffic into healing wounds and influence the healing tissue. On this background, clinicians are faced with patients who require treatment and the pathophysiologic basis as currently understood is reviewed for a number of emerging modalities.
    No preview · Article · Aug 2007 · Wound Repair and Regeneration
Show more