Matrix metalloproteinases (MMPs) have been implicated in numerous tissue-remodeling processes. The finding that mice deficient in collagenase-2 (MMP-8) are more susceptible to develop skin cancer, prompted us to investigate the role of this protease in cutaneous wound healing. We have observed a significant delay in wound closure in MMP8-/- mice and an altered inflammatory response in their wounds, with a delay of neutrophil infiltration during the first days and a persistent inflammation at later time points. These changes were accompanied by alterations in the TGF-beta1 signaling pathway and by an apoptosis defect in MMP8-/- mice. The delay in wound healing observed in MMP8-/- mice was rescued by bone marrow transplantation from wild-type mice. Analysis of other MMPs showed that MMP8-/- mice had a significant increase in the expression of MMP-9, suggesting that both proteases might act coordinately in this process. This possibility was further supported by the novel finding that MMP-8 and MMP-9 form specific complexes in vivo. Taken together, these data indicate that MMP-8 participates in wound repair by contributing to the resolution of inflammation and open the possibility to develop new strategies for treating wound healing defects.

A large subset of patients with chronic renal failure showed PBMC resistance to cyclosporine and prednisolone. Hyperresistant patients have a high risk of being refractory to immunosuppressive therapy with one of these drugs. Alternative treatment should be considered according to the individual drug-sensitivity data.

Extracellular matrix metalloproteinase inducer (EMMPRIN) participates in the breakdown of the extracellular matrix (ECM) by augmenting matrix metalloproteinase (MMP) expression. In the present study, we identified and characterized the menstrual cycle-dependent expression of EMMPRIN in human endometrium in vivo. At the proliferative phase of the menstrual cycle, EMMPRIN was detected in glandular epithelium of the basal layer in endometrium. In addition, at the superficial region of the functional layer, EMMPRIN was expressed in stroma but not glandular epithelium. At the secretory phase, EMMPRIN was found in both stroma and glandular epithelium of the functional layer and glandular epithelium of the basal layer. Furthermore, EMMPRIN colocalized with MMP-1/collagenase-1 in the glandular epithelium in vivo. Western blot analysis of tissue from the functional layer showed that EMMPRIN species with molecular weights of approximately 35 and 47 kDa were detected at the proliferative phase, whereas approximately 35- and 51-kDa EMMPRIN species were predominantly expressed at the secretory phase. In addition, the variant EMMPRIN molecules were found to differ in glycosylation. On the other hand, EMMPRIN was constitutively produced in primary cultured endometrial stromal and glandular epithelial cells. The production and glycosylation of EMMPRIN in the stromal cells were augmented by progesterone at the posttranscriptional and posttranslational stages, respectively. These results suggest for the first time that EMMPRIN is expressed in human endometrium during the menstrual cycle and that its expression and glycosylation are augmented by progesterone. Moreover, EMMPRIN may be involved in ECM breakdown at the interface between endometrial cells and ECM by using EMMPRIN-bound MMP-1.

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The results showed that we could use PBMCs to pharmacodynamically predict the patients with a poor response to cyclosporine therapy. These patients may require larger doses of cyclosporine or alternative approaches to treatment. The patients with PBMCs sensitive to cyclosporine should be evaluated for treatment with smaller doses of the drug to avoid serious side effects.

Abstract. Nobiletin, a polymethoxy flavonoid, prevents cancer and inflammation, but the roles of nobiletin in bone are unclear. We examined the effects of nobiletin on bone resorption in vitro and on bone mass in ovariectomized (OVX) mice in vivo. In vitro, nobiletin suppressed osteoclast formation and bone resorption induced by interleukin (IL)-1. Nobiletin suppressed the expression of cyclooxygenase-2, NFκB-dependent transcription, and prostaglandin E (PGE) production induced by IL-1 in osteoblasts. OVX mice showed severe bone loss in the femur by increased bone resorption due to estrogen deficiency, and nobiletin significantly restored the bone mass. Nobiletin could be beneficial to bone health in postmenopausal women.

Spaceflight is known to induce severe systemic bone loss and muscle atrophy of astronauts due to the circumstances of microgravity. We examined the influence of artificially produced 2G hypergravity on mice for bone and muscle mass with newly developed centrifuge device. We also analyzed the effects of microgravity (mostly 0G) and artificial produced 1G in ISS (international space station) on mouse bone mass. Experiment on the ground, the bone mass of humerus, femur and tibia was measured using micro-computed tomography (μCT), and the all bone mass was significantly increased in 2G compared with 1G control. In tibial bone, the mRNA expression of bone formation related genes such as Osx and Bmp2 was elevated. The volume of triceps surae muscle was also increased in 2G compared with 1G control, and the mRNA expression of myogenic factors such as Myod and Myh1 was elevated by 2G. On the other hand, microgravity in ISS significantly induced the loss of bone mass on humerus and tibia, compared with artificial 1G induced by centrifugation. Here, we firstly report that bone and muscle mass are regulated by the gravity with loaded force in both of positive and negative on the ground and in the space.

An acyl-CoA hydrolase, referred to as hBACH, was purified from human brain cytosol. The enzyme had a molecular mass of 100 kDa and 43-kDa subunits, and was highly active with long-chain acyl-CoAs, e.g. a maximal velocity of 295 micromol/min/mg and K(m) of 6.4 microM for palmitoyl-CoA. Acyl-CoAs with carbon chain lengths of C(8-18) were also good substrates. In human brain cytosol, 85% of palmitoyl-CoA hydrolase activity was titrated by an anti-BACH antibody, which accounted for over 75% of the enzyme activity found in the brain tissue. The cDNA isolated for hBACH, when expressed in Escherichia coli, directed the expression of palmitoyl-CoA hydrolase activity and a 44-kDa protein immunoreactive to the anti-BACH antibody, which in turn neutralized the hydrolase activity. The hBACH cDNA encoded a 338-amino acid sequence which was 95% identical to that of a rat homolog. The hBACH gene spanned about 130 kb and comprised 9 exons, and was mapped to 1p36.2 on the cytogenetic ideogram. These findings indicate that the long-chain acyl-CoA hydrolase present in the brain is well conserved between man and the rat, suggesting a conserved role for this enzyme in the mammalian brain, and enabling genetic studies on the functional analysis of acyl-CoA hydrolase.