Cysteine Cathepsins and Matrix Metalloproteases Among Breast Cancer Patients.

BACKGROUND: Cellular proteases are thought to increase the likelihood of cancer cell infiltration and metastasis by degrading constituents of the extracellular matrix (ECM). Measuring activities of these proteases may be used as tumor markers for early diagnosis, prognosis, and as a possible target for treatment plan. OBJECTIVE: The aim of the current study is to evaluate cysteine cathepsins (CTSK and CTSL) and matrix metalloproteases-2 (MMP-2) and 9 (MMP-9) activities in human breast tumor tissue. METHODS: A comparative cross-sectional study plan was devised to study the enzymatic activities ofCTSK and CTSL andMMP-2 and MMP-9 via zymographic detection method. Sites of tissue sample collection were St Paul's Millennium Medical College, Menelik II Hospital and Zewditu Memorial Hospital, Addis Ababa, Ethiopia. A total of 36 breast cancer patients were recruited and tissue samples were collected for the study. RESULTS: Activities of CTSK and CTSL were significantly elevated in cancerous tissue than the adjacent normal non-cancerous breast tissue of the same patients (n = 36, p ≤ 0.05). Also, activities ofMMP-2 and MMP-9 were increased significantly in tumor tissues than normal tissues (n = 36, P ≤ 0.05). CONCLUSION: It is found that there are different patterns of protease enzymatic activity expression between normal and tumor tissue using zymography. Compared with normal tissue samples, the protease enzymatic activity in cancerous tissue is higher. Thus, tissue proteases can be used in conjunction with histological techniques to identify patients in the same clinical group.

TMT-labelled quantitative proteomic analysis to predict the target promoting human odontogenic inflammatory granulation tissue transform into reparative granulation tissue.

OBJECTIVES: Odontogenic inflammatory diseases are main causes for alveolar bone breakdown and teeth loss, leaving great difficulties in denture restoration. Local inflammatory granulation tissue (IGT) is considered as pathological tissue and required to be removed. However, there are many evidences supporting that under appropriate intervention, IGT in alveolar bone maybe transformed into reparative granulation tissue (RGT), followed by ossification. Therefore, this study aimed to discover a specific target to promote this transformation. MATERIALS AND METHODS: After drawing out histological differences between IGT and RGT with haematoxylin and eosin (H&E) and immunohistochemical (IHC) assay staining, TMT-labelled quantitative proteomic analysis was applied to identify potential targets. RESULTS: The most striking histological property of RGT was found to be ECM deposition, which significantly decreased inflammatory cells, prominently increased fibroblasts as well as triggered changes of vascular types. Combined with histological findings and proteomic analysis, five KEGG pathways were associated with ECM, inflammation and angiogenesis and 49 pathways involved in differentially expressed proteins. COL1A1 was not only the most up-regulated protein, but also one of main hubs in protein-protein interaction regulatory network. Specific protease cathepsin K (CTSK) was identified. Level of CTSK in RGT was down-regulated to 69.10-76.97% (p < .05), with significantly up-regulated COL1A1, COL1A2, FN1 and TGFB1 included in focal adhesion, PI3K-Akt signalling pathways and angiogenesis. CTSK involved in transformation from IGT to RGT. CONCLUSIONS: CTSK might be a target to regulate transformation from IGT to RGT in alveolar bone through ECM, stem cells and angiogenesis mechanisms. However, further research is also clearly required.

AP-1 and Mitf interact with NFATc1 to stimulate cathepsin K promoter activity in osteoclast precursors.

Cathepsin K (CTSK) is a secreted protease that plays an essential role in osteoclastic bone resorption and osteoporotic bone loss. We have previously shown that activator protein 1 (AP-1) stimulates CTSK promoter activity and that proximal nuclear factor of activated T cells cytoplasmic 1 (NFATc1)-binding sites play a major role in the stimulation of CTSK gene expression by receptor activator of NFκB ligand (RANKL). In the present study, we have extended these observations and further dissected the effects of transcription factors involved in the regulation of CTSK gene expression. Our aim was to investigate the cooperative interplay among transcription factors AP-1, microphthalmia-associated transcription factor (Mitf), and NFATc1, and the consequent regulatory effects on CTSK transcription. Experiments were carried out in RAW 264.7 cells, which can be readily differentiated to osteoclasts upon RANKL stimulation. Our data show that AP-1, Mitf, and NFATc1 are capable of independently stimulating CTSK promoter activity. A combination of any two factors further enhances CTSK promoter activity, with the combination of AP-1 (c-fos/c-jun) and NFATc1 inducing the largest increase. We further identify a synergistic effect when all three factors cooperate intimately at the proximal promoter region, yielding maximal transcriptional upregulation of the CTSK promoter. RANKL induces temporal localization of AP-1 and NFATc1 to the CTSK promoter. These results suggest that the interaction of multiple transcription factors mediate a maximal response to RANKL-induced CTSK gene expression.

Role of odanacatib in reducing bone loss due to endodontic disease: An overview.

AIMS AND OBJECTIVES: Through a comprehensive literature review, this article provides an overview of the potential role of odanacatib (ODN) in reducing bone loss due to endodontic disease. MATERIALS AND METHODS: A literature review was performed in PubMed Central, MEDLINE, Cochrane Library, and EBSCO databases. The articles identified included those published between 2002 and 2016. Based on the predetermined inclusion and exclusion criteria, out of 237 articles found, 50 were selected for this review. RESULTS: Cathepsin K (CstK), which is indispensible to the immune system, also plays an important role in osteoclastic bone resorption. ODN, which is an orally active, selective, and effective inhibitor of CstK, decreases bone resorption by selectively inhibiting proteolysis of matrix proteins by CstK, without affecting other osteoclastic activity or osteoblast viability. CONCLUSION: The goal of endodontic treatment is to achieve a clinically asymptomatic state along with formation of reparative bone. This process could take 6 months or longer, hence, an earlier reversal of the resorption process could lead to faster healing and resolution of the periapical lesion. Use of ODN can be of help in achieving this goal.