Expression of nitric oxide synthase and transforming growth factor‐beta in crush‐injured tendon and synovium

Abstract

This study examined the expression of inducible nitric oxide synthase (iNOS) and transforming growth factor-beta (TGF-beta) in macrophage infiltrates within crush-injured digital flexor tendon and synovium of control rats and rats treated with N(G)-nitro-1-arginine methyl ester (L-NAME) (5 mg/kg). Release of TGF-beta from organ cultures of tendon, muscle, and synovium, and the effects of L-NAME treatment (in vitro and in vivo), on adhesion of peritoneal macrophages to epitenon monolayers were also investigated. The results showed that during normal tendon healing the levels of TGF-beta are high at first and gradually decrease after 3 weeks of injury to slightly above control uninjured levels. However, when L-NAME was administered at the time of injury, the macrophage infiltrates were expressing high levels of TGF-beta even at 5 weeks after the injury, with no evidence of reduction. In the standard injury, iNOS activity was greatest at the acute phase of the inflammatory response and then gradually returned to normal. Treatment with L-NAME, however, resulted in inhibition of iNOS activity at 3 days and a reduction in the activity at the later time points examined after injury. We also found greatly increased levels of adhesion of peritoneal macrophages from L-NAME-treated rats to epitenon monolayers in vitro, which reflect a chronic imbalance in expression of TGF-beta, which is overexpressed, and nitric oxide, which is underexpressed. The results of the current study show that formation of nitric oxide is an important event in the course of tendon healing since its inhibition results in chronic inflammation and fibrosis due to an imbalance in TGF-beta expression in vivo.

Satellite Cells and the Muscle Stem Cell Niche

“…MMP-2 was demonstrated to be involved in this process (575). In addition, it was also suggested that NO may regulate satellite cell migration (104) and prevent fibrosis by inhibiting transforming growth factor-␤ signaling during muscle regeneration (126).…”

Spatiotemporal protein distribution of TGF‐βs, their receptors, and extracellular matrix molecules during embryonic tendon development

“…In contrast, most studies have focused mainly on the role of TGF-␤s in adult tendon and ligament pathology and wound healing. Thus, elevated protein and mRNA levels of TGF-␤ have been demonstrated in pathological Achilles tendons and during healing of injured tendons and ligaments (Natsu-ume et al, 1997;Fenwick et al, 2001;Darmani et al, 2004;Tsubone et al, 2004;Dahlgren et al, 2005). Exogenous application of TGF-␤1 and -␤2 significantly increased expression of collagen types I and III, and improved the mechanical properties of healing tendons or ligaments (Spindler et al, 2003;Kashiwagi et al, 2004;Anaguchi et al, 2005).…”

Effect of transforming growth factor beta 1 (TGF-beta 1) on nitric oxide production and lipid peroxidation in oral mucosal wound healing

“…TGF-beta has been reported to induce the inhibition of NO production by macrophages through decreasing the stability and translation of mRNA in the NOS and increasing its degradation (Gilbert and Herschman, 1993;Owens et al, 1996;Darmani et al, 2004). Bauer et al (1999) reported diminished NO production following administration of TGF-beta 1 using a noninflammatory wound repair model (Bauer et al, 1999).…”

“…It has been reported that TGF-beta induced the inhibition of nitric oxide production by macrophages through decreasing the stability and translation of mRNA for the NOS (Gilbert and Herschman, 1993;Darmani et al, 2004). However, there has been limited research into alterations such as those in lipid peroxidation and antioxidant status in oral mucosa which heals more quickly than skin wounds.…”