Tendon structure is governed largely by factors regulating the anabolic and catabolic phases of tenocyte metabolism. Little is known about the mechanisms that regulate the synthesis, activation, and action of metalloproteinases, which are key enzymes in a multifactorial cascade controlling homeostasis of the extracellular matrix. In the present study, we investigated the effect of tension on collagenase-induced degradation of the tendon in vitro by assessing changes in structural and material properties measured during tensile failure tests. Devitalized right-left pairs of rabbit patella-patellar tendon-tibia units were maintained under culture conditions in the presence of 60 U/ml highly purified collagenase for 20 hours. One randomly selected unit from each animal was subjected to a tension that produced a constant 4% elongation or strain (n = 10); the contralateral unit served as a slack comparison (n = 10). In one series of experiments (immediate, n = 5), the tension was applied immediately prior to collagenase exposure. In a second series (delayed, n = 5), it was delayed for 4 hours to allow time for the collagenase to diffuse into the tendon. Additional devitalized and nonincubated units (n = 6) were used as normal controls. Collagenase exposure caused large decreases in stiffness and elongation to failure in slack units. This resulted in greater than 80% reductions in both maximum failure force and energy to failure. In contrast, the loaded unit in both experimental protocols had significantly greater stiffness than control units. In both the immediate and the delayed protocols, the loaded tendons had significantly higher stiffness and failed at significantly higher elongations and maximum forces than the slack tendons. Diffusion studies with and without tension showed the tension did not inhibit diffusion of collagenase into the tendon but did significantly decrease the water content from 64.6 to 57.8%. The data suggest that stresses and strains of the extracellular matrix may modify the kinetics of the bacterial collagenase-collagen interaction. Matrix stress and strain may be an important and overlooked factor that modulates the susceptibility of collagen to proteolytic degradation.

The antitumor activity of highly purified tumor necrosis factor (TNF) was tested against eight kinds of murine tumor and five kinds of human tumor heterotransplanted into nude mice. Mice were treated by intravenous or intratumoral injection of TNF, commencing when the tumors were well established. TNF showed an excellent curative effect against all kinds of murine and human tumors tested. Meth A sarcoma, Colon 26, Ehrlich, sarcoma 180, MM 46, MH 134, B16 melanoma, and Lewis lung tumors transplanted into mice underwent tumor necrosis and regression following a single injection of TNF. Sometimes a complete cure was observed in Meth A sarcoma, sarcoma 180, Ehrlich, and MM 46 tumors. Human cancers, SEKI, HMV-I, KATO-III, MKN 45, or KB, heterotransplanted into nude mice, also exhibited tumor necrosis and regression in size following several intratumoral injections of TNF. A great difference in curative effects of TNF was observed in Meth A sarcomas between those transplanted into BALB/c nu/+ and into BALB/c nu/nu mice: following a single intravenous administration the effect was stronger in BALB/c nu/+ than in nu/nu mice. In contrast, tumor necrosis was almost the same in nu/+ and nu/nu mice following intratumoral administration. The present results thus indicate that TNF from mice had an antitumor activity against not only murine tumors but also human tumors. In addition to direct cytotoxicity against tumor cells, TNF induced a host-mediated factor which contributed to the antitumor effects.

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Diabetic nephropathy (DN) is the major cause of end-stage renal failure and is associated with increased morbidity and mortality as compared to other causes of renal disease. Albuminuria is often the first clinical indicator of the presence of DN. However, albuminuria or proteinuria is a common symptom in patients with various renal disorders. Therefore, specific biomarkers for the diagnosis of DN are required. A primary hallmark of DN is the progressive damage and death of glomerular podocytes, resulting in the leaking of proteins into the urine. Urinary exosomes released by podocytes are microvesicles containing information of the originated cells. Podocyte-derived signal transduction factors (PDSTFs) are good candidates to assess podocyte injuries. The profile of PDSTFs in urinary exosomes from patients with DN is different from that from patients with minimal change nehrotic syndrome. In addition, PDSTFs molecules in exosomes were derived from primary murine podocytes under high glucose conditions. Among PDSTFs in urinary exosomes, Wilms tumor 1 (WT1) levels reflected damage of diabetic glomeruli in the patients. Urinary exosomal WT1 can predict the decline in eGFR for the following several years. In conclusion, urinary exosomal WT1 is a useful biomarker to improve risk stratification in patients with DN.