transforming-growth-factor-alpha and Cachexia

Pain and cachexia are two of the most debilitating aspects of rheumatoid arthritis. Despite that, the mechanisms by which they are mediated are not well understood. We provide evidence that nerve growth factor (NGF), a secreted regulatory protein that controls neuronal survival during development, is a key mediator of pain and weight loss in auto-immune arthritis. Function blocking antibodies to NGF completely reverse established pain in rats with fully developed arthritis despite continuing joint destruction and inflammation. Likewise, these antibodies reverse weight loss while not having any effect on levels of the pro-cachectic agent tumor necrosis factor (TNF). Taken together, these findings argue that pathological joint pain and joint destruction are mechanistically independent processes and that NGF regulates an alternative cachexia pathway that is independent or downstream of TNF.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antibodies, Monoclonal; Arthritis, Experimental; Cachexia; Dose-Response Relationship, Drug; Escherichia coli Proteins; Humans; Hyperalgesia; Indomethacin; Male; Nerve Growth Factor; Pain Measurement; Rats; Rats, Inbred Lew; Severity of Illness Index; Time Factors; Transforming Growth Factor alpha; Weight Loss

At least 13 studies have shown that the ubiquitin-proteasome system mediates muscle wasting in weight-losing cancer subjects. We hypothesized that cancer itself may activate the ubiquitin-proteasome system, regardless of weight loss.. We utilized hybrid mice obtained by crossing Mouse Mammary Tumor Virus-Transforming Growth Factor-alpha (TGF-alpha) mice with the Lep(ob) strain. Five hybrid MMTV-TGF-alpha heterozygous Lep(+)Lep(ob) female mice with mammary tumors were used; 4 nontransgenic heterozygous Lep(+)Lep(ob) female mice served as controls. Ubiquitin conjugates were quantitated from hamstring and paraspinal muscles by Western blotting. Myocyte apoptosis was determined by a modified TUNEL assay.. All mice gained weight, even after tumor development. Higher concentrations of muscle ubiquitin conjugates were seen in the 5 tumor-bearing, TGF-alpha transgenic mice as compared with the 4 non-tumor-bearing mice: median (range) in arbitrary densitometric units: 0.67 (0.22-4.59) versus 0.18 (0.08-0.44) in hamstring muscle and 0.56 (0.23-20.15) versus 0.18 (0.08-0.25) in paraspinal muscle (p = 0.04 and p = 0.04, respectively; Mann-Whitney U test). Apoptosis was not seen in any muscle sample studied.. Ubiquitin conjugates are increased in the skeletal muscle of tumor-bearing mice in the absence of weight loss. Such activation is not seen in the skeletal muscle on non-tumor-bearing mice. Further studies might focus of whether this observation is relevant to cancer-associated wasting of lean tissue.

Topics: Adenocarcinoma; Animals; Apoptosis; Cachexia; Cysteine Endopeptidases; Disease Models, Animal; Female; Immunoblotting; In Situ Nick-End Labeling; Mammary Neoplasms, Experimental; Mice; Mice, Transgenic; Multienzyme Complexes; Muscle Proteins; Muscle, Skeletal; Proteasome Endopeptidase Complex; Transforming Growth Factor alpha; Ubiquitins; Weight Gain