Cytokines regulate nerve growth factor (NGF) synthesis during inflammatory processes. Since cytokmes are also involved in the inflammatory processes of autoimmune rheumatic diseases, we examined levels of NGF in patients with rheumatoid or other types of chronic arthritis. NGF was present in the synovial fluid and synovium of patients with chronic arthritis, but was undetectable in control fluids. We conclude that NGF might be involved in the pathogenesis of arthritis.Nerve growth factor (NGF) is a well-characterized neurotrophic protein which plays an essential role in the development and differentiation of sympathetic and sensory nerve cells and the cholinergic neurons of the central nervous system (1). Studies published in recent years have shown that lymphocytes express NGF receptors (2) and that during inflammatory processes, cells of the immune system lineage are able to synthesize and/or release NGF (3,4). More recently, it has been shown that cytokines, such as interleukin-1 (IL-1) and tumor necrosis factor (TNF), elicit a significant increase in levels of NGF in the peripheral and This observation prompted us to examine levels of NGF in synovial fluid from patients with rheumatoid arthritis (RA) and other forms of chronic arthritis, and to determine whether NGF is present in their synovial tissues.The synovium is a type of connective tissue that is densely vascularized and innervated by fibers that originate in the sympathetic and sensory nervous systems. These fibers release neuropeptides, including substance P (SP) and calcitonin gene-related peptide, the levels of which increase during inflammatory disease (6). Since it has been reported that the synthesis and/or release of these neuropeptides is also regulated by NGF (7), the possibility of NGF involvement in the pathogenesis of joint inflammation was considered. We present here our findings regarding the levels of NGF and SP in synovial fluid and synovium from patients with various forms of chronic inflammatory arthritis.
PATIENTS AND METHODSSynovial Ruids. Synovial fluid samples were collected from the knees of 22 outpatients of the Department of Rheumatology, University "La Sapienza" (Rome, Italy). Six of these 22 patients (3 women and 3 men) had osteoarthritis (OA). Their mean age was 66 years (range 5!9-76), and their mean duration of disease was 10.5 years (range 1-20 years). Eight patients (6 women and 2 men) had RA. Their mean age was 49 years (range 24-83), and their mean duration of disease was 7.5 years (range 1-20 years). Eight patients had other types of chronic arthritis: 4 had psoriatic arthritis (PA), 3 had ankylosing spondylitis (AS), and 1 had juvenile chronic arthritis (JCA). Their mean age was 33 years (range 1443), and their mean duration of disease was 6.3 years (range 3-10 years). The diagnoses of OA and RA were
Recent studies effected by our Institute indicate that various forms of human arthritis express both immunohistochemically and biologically active nerve growth factor (NGF) in the synovium. In the present study, we used a model of carrageenan-induced arthritis to further evaluate the effects of joint inflammation on NGF level. These studies showed that experimentally-induced arthritis in rats caused a significant increase in NGF in the perivascular area of the synovium. We also showed that injection into the synovium of purified NGF did not cause inflammation per se and that the destruction of peripheral sympathetic innervation significantly reduced both the inflammation and the level of NGF following carrageenan injection.
Three diabetic patients with leg or foot ulcers unresponsive to conventional therapies were treated with topical application of Nerve Growth Factor (NGF). The results showed that NGF promotes healing after 5-14 weeks of treatment. This study suggests that the use of topical application of NGF may represent a new useful tool for the management of difficult diabetic ulcers.
Numerous studies reported in recent years have shown that withdrawal from chronic consumption of drugs induces high levels of anxiety, both in humans and in animal models. In the present study, we demonstrated that withdrawal from chronic consumption of either ethanol or heroin causes a significant increase in plasma nerve growth factor, suggesting that the resulting anxiety condition triggers the release of this molecule. Although the functional significance of this phenomenon needs to be better defined, it is hypothesized that the increased levels of circulating nerve growth factor might be involved in homeostatic adaptive and/or reparative mechanisms.
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