Table 1.
Growth Factors, Cytokines, Chemokines, and/or Other Signaling Molecules Involved in Tendon Development and Healing
| Role in Tendon Development | Role in Tendon Healing | |
|---|---|---|
| TGF-βs | Tenogenesis27,28,75,76,88; up-regulation of SCX and Col1a1 expression27 | Involved in initial inflammatory response66,67; repair site and sheath increase expression of TGF-β receptors after injury and repair70; collagen synthesis66,68–71; angiogenesis66; TGF-B1 expressed by tenocytes and infiltrating fibroblasts and inflammatory cells72,73; up-regulated initially after injury and elevated levels persist until at least 3 wk after injury106 |
| VEGF | Angiogenesis92 | Increased in early healing, neovascularization42,94,95; marker of chronic overuse92,93; up-regulation peaks at 10 days after injury96 |
| IGF-1 | Requires further investigation | Up-regulated expression in inflammatory cells66; stimulation of ECM synthesis107; involved in muscle hypertrophy108; up-regulated immediately after injury and peaks at 4–8 wk109 |
| FGF2 | Requires further investigation; FGF4 and FGF8 are expressed on muscle and tendon boundary regions during limb development87; equivocal evidence on ability to induce cells to express scleraxis during somite development28,29,88 | Increased expression in inflammatory cells66,84; neovascularization84; proliferation3,38,85,86; collagen synthesis3,38; down-regulated after injury until at least 3 wk after injury106 |
| PDGF | When inhibited suppresses mechanically cued tendon tissue growth100 | Synthesis of ECM68,110; angiogenesis66; PDGF-B up-regulated persist for over 6 mo after tendon injury,111 though has also been shown to be minimally expressed after injury106 |
| CTGF | Requires further investigation | Exogenous and endogenous stem cell tenogenic differentiation112; increased expression in fibroblasts113; increased collagen type I deposition113; up-regulated gene expression persisting over 21 days after injury106 |
| MMPs | MMP-1 involved in the processing of native collagen I, II, III, and X, which are also components of the tendon fibers114; MMP-2/MT3-MMP are involved in initiation of and progression of fibril growth, matrix assembly, and tendon development115 | MMP-1 MMP-8, MMP-13, and MMP-18 degrade collagens, a critical component of the tendon ECM116; MMP-2 and MMP-9 cleave smaller collagen fragments and gelatin116; MMP-3, MMP-10, MMP-11, MMP-7, MMP-26, and MMP-12 degrade glycoproteins and proteoglycans116; MMP-9 and MMP-13 help degrade the ECM shortly after injury whereas MMP-3, MMP-4 and MMP-14 participate in both matrix degradation and matrix remodeling throughout the healing process42,117–120 |
| TIMPs | Regulates MMPs; constant low TIMP-2 expression seen in tendon development115 | MMP endogenous antagonists117; increased TIMP-1 mRNA expression in tendon and tendon sheath after acute injury117; TIMPs mRNA expression levels decrease in overuse tendon injuries121 |
| ADAMTS | Removes the respective propeptides from procollagen, within the secretory pathway in tendon fibroblasts122 | Lower mRNA 1 levels of ADAMTS-7, ADAMTS-13 seen in overuse injuries123; requires further investigation in acute injuries |
| IL-1β | Requires further investigation | Increased level of IL-1β mRNA expression in tendon42 and tendon-sheath117; promotes inflammation and degradation of the ECM118; alters glucose metabolism in tendon progenitors124 |
| IL-6 | Requires further investigation | Inhibitory effect on fibroblast cellular proliferation125; increases proliferation capability and induced cell cycle of tendon-derived stem cells, but may inhibit their tenogenic differentiation (inhibited gene expression of inhibited gene expression of scleraxis, collagen I, tenomodulin, collagen III, early growth response protein 1 decorin, lumican, biglycan and fibromodulin)126 |
| EGF | Requires further investigation | Increased expression on inflammatory cells66 |
| TNFα | Requires further investigation | Increased level of mRNA expression in tendon after injury42 |
| BMP-2 | BMP-2 requires further investigation; BMP-4 secretion facilitates limb tendon formation18 | Role within physiologic tendon healing requires further investigation; exogenous delivery augments bone ingrowth within tendon-to-bone junctions127 |
SCX, scleraxis; ECM, extracellular matrix; CTGF, connective tissue growth factor; MMP, matrix metalloproteinase; TIMP, tissue inhibitor of metalloproteinase; ADAMTS, a disintegrin and metalloproteinase with thrombospondin motifs; EGF, epidermal growth factor; TNFα, tissue necrosis factor alpha; BMP-2, bone morphogenetic protein 2; IL, interleukin.