The role of nitric oxide in tendon healing

Nitric oxide (NO) is a small free radical that is generated by a family of enzymes called the nitric oxide synthases (NOS). There are 3 isoforms of NOS: endothelial NOS (eNOS), brain or neuronal NOS (bNOS), and inducible NOS (iNOS). In experiments performed during the last 20 years, we have shown that NO is induced by all 3 isoforms of NOS after tendon injury and that NOS activity is upregulated in tendinopathy. In normal uninjured tendons, there is very little NOS activity. In injured rat and human tendons, NOS activity was found in healing fibroblasts in a temporal fashion. In animal models, competitive inhibition of NOS resulted in reduced tendon healing, whereas the addition of NO resulted in enhanced tendon healing. In cultured human cells, the addition of NO via chemical means and adenovirus transfection resulted in enhanced collagen synthesis. We performed 3 randomized, double-blinded clinical trials that demonstrated a significant positive beneficial effect of NO treatment on clinical symptoms and function in patients with Achilles tendinopathy, tennis elbow, and supraspinatus tendonitis. NO was delivered via glyceryl trinitrate (GTN) patches. We also conducted a 3-year prospective follow-up that demonstrated significant long-term efficacy of GTN patches in treating noninsertional Achilles tendinopathy. In a 5-year prospective comparison treating lateral epicondylitis, we found no additional benefits of GTN vs placebo at 5 years. The use of a new GTN patch, OrthoDerm, demonstrated no evidence for efficacy in treating chronic lateral epicondylitis.