Advances in the Use of Growth Factors for Treatment of Disorders of Soft Tissues

Abstract

Repair and healing of injured and diseased tendons have been traditionally fraught with apprehension and difficulties, and often lead to rather unsatisfactory results. The burgeoning research field of growth factors has opened new venues for treatment of tendon disorders and injuries, and possibly for treatment of disorders of the aorta and major arteries as well. Several chapters in this volume elucidate the role of transforming growth factor β in pathogenesis of several heritable disorders affecting soft tissues, such as aorta, cardiac valves, and tendons and ligaments. Several members of the bone morphogenetic group either have been approved by the FDA for treatment of non-healing fractures or have been undergoing intensive clinical and experimental testing for use in healing of bone fractures and tendon injuries. Because FGFs are involved in embryonic development of tendons and muscles among other tissues and organs the hope is that their testing would lead to the development of some new treatment strategies providing that we can control angiogenicity of these growth factors. The problem, or rather question regarding practical use of IGF-I in tendon repair is whether IGF-I acts independently or under the guidance of growth hormone. FGF2 or PDGF alone or in combination with IGF-I stimulated regeneration of periodontal ligament, a matter of importance in Marfan patients with periodontitis. In contrast, VEGF appears to have rather deleterious effect on experimental tendon healing, perhaps because of its angiogenic activity and stimulation of matrix metalloproteinases, proteases whose increased expression has been documented in a variety of ruptured tendons. Other modalities, such as local administration of platelet-rich plasma (PRP) and/or of mesenchymal stem cells have been explored extensively in tendon healing. Though treatment with PRP and mesenchymal stem cells has met with some success in horses (who experience a lot of tendon injuries and other tendon problems), the use of PRP and mesenchymal stem cells in people has been more problematic and requires more studies before PRP and mesenchymal stem cells can become reliable tools in management of soft tissue injuries and disorders.

Tendon development and diseases

“…Both TGF‐β and FGF signaling pathways, identified as being involved in tendon development, have been shown also to be important for tendon healing following injury . TGF‐β and FGF ligands are released at the tendon injury sites in animal models . The loss of the canonical intracellular component of TGF‐β pathway, Smad3 , leads to reduced Col1a1 transcription in healed tendons and to adhesion and scarring defects during tendon healing in Smad3 −/− mutant mice .…”

“…Collagens, such as the fibrillar collagens III and V and the non fibrillar FACITs (fibril‐associated collagens with interrupted triple helices) collagens XII and XIV, are important for collagen fibril formation, growth, and integrity in tendons (Table and references therein). In addition to fibrillar and FACIT collagens, small leucine‐rich proteoglycans (SLRPs) are also involved in type I collagen fibrillogenesis in tendons, mainly by regulating lateral collagen fibril growth . Mutations of one SLRP or combination of SLRPs systematically lead to a tendon phenotype in mice (Table and references therein).…”

“…The main structural and functional component of tendon, type I collagen, is not specific to tendon and is expressed in many other tissues such as bone, skin, and cornea. None of the ECM components involved in type I collagen fibrillogenis during tendon formation is specific to tendon; since they are also involved in collagen fibrillogenesis in other tissues . Tendons are characterized by the spatial and parallel organization of collagen fibrils.…”

Identification of Genes Differentially Expressed in Simvastatin‐Induced Alveolar Bone Formation

“…IGF‐1 has long been thought to be one of the major anabolic factors responsible for limiting or reversing periodontal bone destruction . IGF‐1 has been shown to enhance bone regeneration in human periodontal defects and to stimulate regeneration of periodontal ligament . To further investigate the SIM‐delivery and activation of IGF‐1 in ExP, protein expression confirmed that IGF‐1 expression was low in ExP samples and SIM‐PPi injected into the periodontitis lesion quickly increased IGF‐1 protein expression (Fig.…”

Lactoferrin and parathyroid hormone are not harmful to primary tenocytes in vitro, but PDGF may be

“…The potential of growth factor treatments to improve the poor healing capacity of tendon is a much studied area of research, with little clinical uptake to date 1,2 . Factors such as platelet-derived growth factor (PDGF), insulin-like growth factor 1 (IGF-1), basic fibroblast growth factor (bFGF) and members of the transforming growth factor beta (TGF-β) superfamily are all upregulated during the healing process, and have been extensively studied using tendon cells and explants in vitro, and using tendon defect models in vivo 3,4 .…”