Osteoarthritis (OA) is a complex chronic progressive disease attacked by biological and mechanical factors and a result from the anabolic and catabolic imbalance in chondrocyte, subchondral bone and extracellular matrix(ECM). Etiology and pathological of OA are not yet entirely clear. The degradation and destruction of collagen II caused by matrix metalloproteinase -13 (MMP-13) is considered the core factor in the occurrence and development of OA. The research of MMP-13 inhibitor provide ideas and methods for the treatment of OA. In this article,the role and determination of MMP-13 in OA and the development prospect of MMP-13 inhibitor in the treatment of OA research progress were reviewed.
Animals ; Collagen ; metabolism ; Humans ; Matrix Metalloproteinase 13 ; analysis ; physiology ; Matrix Metalloproteinase Inhibitors ; therapeutic use ; Osteoarthritis ; drug therapy ; etiology

Continuing advances in dentin bonding technology and adhesives revolutionized bonding of resin-based composite restorations. However, hybrid layers created by contemporary dentin adhesives present imperfect durability, and degradation of collagen matrix by endogenous enzymes is a significant factor causing destruction of hybrid layers. Bond durability can be improved by using enzyme inhibitors to prevent collagen degradation and to preserve integrity of collagen matrix. This review summarizes progress on matrix metalloproteinase inhibitors (including chlorhexidine, ethylenediaminetetraacetic acid, quaternary ammonium salt, tetracycline and its derivatives, hydroxamic acid inhibitors, bisphosphonate derivative, and cross-linking agents) and suggests prospects for these compounds.
Acid Etching, Dental ; Bisphenol A-Glycidyl Methacrylate ; Collagen ; Dental Bonding ; Dentin ; Dentin-Bonding Agents ; Humans ; Matrix Metalloproteinase 2 ; Matrix Metalloproteinase Inhibitors

Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases that regulate cell-matrix composition and are also involved in processing various bioactive molecules such as cell-surface receptors, chemokines, and cytokines. Our group recently reported that MMP-3, -8, and -9 are upregulated during microglial activation and play a role as proinflammatory mediators (Lee et al., 2010, 2014). In particular, we demonstrated that MMP-8 has tumor necrosis factor alpha (TNF-alpha)-converting enzyme (TACE) activity by cleaving the prodomain of TNF-alpha and that inhibition of MMP-8 inhibits TACE activity. The present study was undertaken to compare the effect of MMP-8 inhibitor (M8I) with those of inhibitors of other MMPs, such as MMP-3 (NNGH) or MMP-9 (M9I), in their regulation of TNF-alpha activity. We found that the MMP inhibitors suppressed TNF-alpha secretion from lipopolysaccharide (LPS)-stimulated BV2 microglial cells in an order of efficacy: M8I>NNGH>M9I. In addition, MMP inhibitors suppressed the activity of recombinant TACE protein in the same efficacy order as that of TNF-alpha inhibition (M8I>NNGH>M9I), proving a direct correlation between TACE activity and TNF-alpha secretion. A subsequent pro-TNF-alpha cleavage assay revealed that both MMP-3 and MMP-9 cleave a prodomain of TNF-alpha, suggesting that MMP-3 and MMP-9 also have TACE activity. However, the number and position of cleavage sites varied between MMP-3, -8, and -9. Collectively, the concurrent inhibition of MMP and TACE by NNGH, M8I, or M9I may contribute to their strong anti-inflammatory and neuroprotective effects.
Chemokines ; Cytokines ; Endopeptidases ; Inflammation ; Matrix Metalloproteinase Inhibitors* ; Matrix Metalloproteinases ; Microglia* ; Neuroprotective Agents ; Tumor Necrosis Factor-alpha*

PURPOSE: Matrix metalloproteinases (MMPs) are capable of degrading extracellular matrix, and they are inducible enzymes depending on an inflammatory environment such as periodontitis and bacterial infection in periodontal tissue. Gingival inflammation has been postulated to be correlated with the production of MMP-2 and MMP-9. The objective of this study was to quantify the expression and activity of MMP-9 and -2, and to determine the correlation between activity and expression of these MMPs in human gingival tissues with periodontitis. METHODS: The gingival tissues of 13 patients were homogenized in 500 microL of phosphate buffered saline with a protease inhibitor cocktail. The expression and activity of MMP-2 and -9 were measured by enzyme-linked immunosorbent assay and Western blot analysis, and quantified by a densitometer. For the correlation line, statistical analysis was performed using the Systat software package. RESULTS: MMP-9 was highly expressed in all gingival tissue samples, whereas MMP-2 was underexpressed compared with MMP-9. MMP-9 activity increased together with the MMP-9 expression level, with a positive correlation (r=0.793, P=0.01). The correlation was not observed in MMP-2. CONCLUSIONS: The expression of MMP-2 and -9 might contribute to periodontal physiological and pathological processes, and the degree of MMP-9 expression and activity are predictive indicators relevant to the progression of periodontitis.
Bacterial Infections ; Blotting, Western ; Enzyme-Linked Immunosorbent Assay ; Extracellular Matrix ; Humans ; Inflammation ; Matrix Metalloproteinase 2 ; Matrix Metalloproteinase 9 ; Matrix Metalloproteinases ; Pathologic Processes ; Periodontitis ; Protease Inhibitors

A novel inhibitor series for matrix metalloproteinases (MMPs) were designed and synthesized. Using succinate and malonate as zinc binding groups and long hydrophobic substituents to bind with S1' pockets, the compounds showed micromolar inhibition and selectivity for MMP-2 over others. And we found a better activity compound. It is a chance to find a better precursor of MMP-2 inhibitors with activity and bioavailability by further optimization of compounds.
Drug Design ; Enzyme Inhibitors ; chemical synthesis ; chemistry ; Matrix Metalloproteinase Inhibitors ; Matrix Metalloproteinases ; chemical synthesis ; chemistry ; Molecular Structure ; Structure-Activity Relationship

1. Alkali burns of rabbit corneas were produced by 5.0 N NaOH swabbing the cornea and surrounding sclera. 2. Collagenolytic activity of alkali burned corneas, and the effectiveness of collagenase inhibitors (0.2 M cysteine sol. and 0.5% zinc sulfate sol.) in preventing the perforation of corneas were studied by pathology. 3. In control group, almost 85% of coreas were perforated, but in treated group, no corneal perforations were found. 4. In control group, epithelial and endothelial thickenings are evident and no neovascularization could be seen, in treated group neovascularization is evident and slight cellular reactions were visualized.
Alkalies* ; Burns* ; Cornea* ; Corneal Perforation ; Cysteine ; Matrix Metalloproteinase Inhibitors ; Pathology ; Sclera ; Zinc Sulfate

The possible role of collagenase in the development of corneal ulcers has been intensively studied and collagenase inhibitors have been successfully used to control some corneal ulcers. They are cysteine, EDTA, proteoglycan, serum, and medroxyprogesteron, However, most of them are limited in clinical use because of their toxicity and instability except serum, which is not toxic to the host. We carried out an experiment with serum upon alkali-burned rabbit cornea. Serum has potent anticollagenase effect, and prevents corneal ulceration.
Collagenases ; Cornea* ; Corneal Ulcer ; Cysteine ; Edetic Acid ; Matrix Metalloproteinase Inhibitors ; Proteoglycans ; Ulcer

BACKGROUND: Persistent facial telangiectasia, erythema and flushing are the major cosmetic problems in patients with rosacea. However various therapeutic treatments for rosacea papules and pustules are not effective in reducing telangiectasia and flushing reactions. Matrix-centered theory that dermal matrix degradation can cause telangiectasis, erythema and flushing, is one of the various theories of rosacea pathogenesis. Shark cartilage extracts are collagenase inhibitors and can inhibit dermal matrix degradation. OBJECTIVE: The purpose of this study was to evaluate the clinical effects of shark catilage extracts (Venatrix(R)) for erythematotelangiectatic rosacea patients. METHODS: Twenty three patients with erythematotelangiectatic rosacea applied shark cartilage extracts twice daily for up to 8 weeks. Efficacy was evaluated by erythema index using mexameter (MPA 5, CK, Germany) and clinical photography. RESULTS: Erythema index decreased from 525.7+/-114 to 413.9+/-101.7 (mean reduction: 21.3%) (p<0.1) after 8 weeks treatment. 16 patients (69%) showed excellent or good results by clinical photography. Transient stinging sensation was the most common adverse effect and these symptoms improved after the first few days. There were no other significant side effects. CONCLUSION: Shark cartilage extracts may be an effective treatment for mild erythematotelangiectatic rosacea.
Bites and Stings ; Cartilage* ; Erythema ; Flushing ; Humans ; Matrix Metalloproteinase Inhibitors ; Photography ; Rosacea* ; Sensation ; Sharks* ; Telangiectasis

OBJECTIVETo investigate the inhibitor of matrix metalloproteinase-2 (MMP-2) (2R)-2-[5-[4-[ ethyl-methylamino] phenyl [thiophene-2-sulfonylamino]-3-methylbutyric acid (TISAM) therapeutic effect on experimental autoimmune myocarditis (EAM) in Lewis rats.

METHODSTreatment protocol of oral administration of 5 mg/kg TISAM once a day for 14 days was performed on EAM Lewis rats. EAM Lewis rats were divided into 3 groups: treatment in early, middle and later stage respectively (n = 20). After experiment at the designate time point, the rats were euthanatized and hearts were harvested. Cardiac inflammatory score, fibrosis score and content, and infiltration of macrophages and T lyminflammatory score, fibrosis score and content, and infiltration of macrophages and T lymphocytes, message RNA (mRNA) expression of matrix metalloproteinase (MMP)-2 and MMP-9 and protein activity of gelatinase were determined.

RESULTSTISAM treatment in early phase was invalid (treatment started from the creation of the model), treatment in middle and later phase was effective (treatment started from 7 and 14 day after the creation of the model).

CONCLUSIONInhibitor of MMP-2 can block ventricular remodeling in middle stage in EAM Lewis rats. The mechanism maybe alleviate the inflammatory cell cardiac infiltration, decrease the mRNA expression of MMP-2 at transcript level and downregulate gelatinase activity at protein level.

Animals ; Autoimmune Diseases ; drug therapy ; Female ; Male ; Matrix Metalloproteinase 2 ; metabolism ; Matrix Metalloproteinase Inhibitors ; therapeutic use ; Myocarditis ; drug therapy ; Rats ; Rats, Inbred Lew ; Thiophenes ; therapeutic use

To investigate effects of verapamil on primary cultured human urethral scar fibroblasts (USFs) and to provide basis for protecting the formation of urethra scar.
 Methods: The cell proliferation was evaluated with the cell counting kit (CCK)-8 method after USFs were incubated various verapamil concentrations (50, 100, 150, 200, or 250 μmol/L) or solvent for 12, 24, or 48 h. The protein level of matrix metalloproteinase (MMP) was evaluated with ELISA after cells were incubated with verapamil (100 μmol/L) or solvent (control cells) for 24 h.
 Results: The proliferation of USFs was obviously suppressed after verapamil treatment, which was in a dose-dependent and time-dependent manner. Meanwhile, the protein levels of MMP-2 and MMP-9 in the verapamil treatment group increased obviously compared with those of the control groups (P<0.05).
 Conclusion: Calcium channel blockers may prevent the excessive formation of urethra scar by inhibiting the proliferation of urethral scar fibroblasts and enhancing the activity of MMP.
Calcium Channel Blockers ; pharmacology ; Cell Proliferation ; drug effects ; Cells, Cultured ; Cicatrix ; prevention & control ; Fibroblasts ; drug effects ; Humans ; Matrix Metalloproteinase 2 ; drug effects ; Matrix Metalloproteinase 9 ; drug effects ; Matrix Metalloproteinase Inhibitors ; pharmacology ; Up-Regulation ; drug effects ; Urethra ; cytology ; pathology ; Verapamil ; pharmacology