|
1
|
Lähteenmäki H, Tervahartiala T, Räisänen IT, Pärnänen P, Mauramo M, Gupta S, Sampson V, Rathnayake N, Heikkinen AM, Alassiri S, Gieselmann DR, Frankenberger R, Sorsa T. Active MMP-8 point-of-care (PoC)/chairside enzyme-test as an adjunctive tool for early and real-time diagnosis of peri-implantitis. Clin Exp Dent Res 2022; 8:485-496. [PMID: 35118828 PMCID: PMC9033547 DOI: 10.1002/cre2.537] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Revised: 10/12/2021] [Accepted: 12/14/2021] [Indexed: 01/03/2023] Open
Abstract
Objective The aim of this study was to investigate the utility of the active matrix metalloproteinase (aMMP‐8)‐point‐of‐care (PoC) test as a quantitative real‐time chair‐side diagnostic tool for peri‐implant diagnosis, as well as assess the potentially developing and ongoing risk relative to the traditional clinical methods. Background Current peri‐implant and periodontal disease diagnoses rely on clinical and radiological examinations. This case‐control study investigated the applicability of aMMP‐8‐PoC immunotest for quantitative real‐time diagnosis and monitoring of dental implants in health and disease. Methods Sixty‐eight patients visiting a specialist clinic for maintenance following dental implant placement underwent assessment of their peri‐implant health. aMMP‐8‐PoC peri‐implant sulcular fluid (PISF) lateral‐flow immunotests were performed using ImplantSafe® technology quantitated by ORALyzer®. In addition, the PISF samples were analyzed for total MMP‐8, calprotectin, and interleukin (IL)‐6 by enzyme‐linked immunosorbent assays (ELISA), aMMP‐8 by western immunoblot, and MMP‐2 and MMP‐9 by gelatin zymography. Results The aMMP‐8‐PoC test promptly recorded and reflected peri‐implant disease, differentiating it clearly from health. X‐ray findings (bone loss > 2 mm), peri‐implant pocket depth ≥ 3 mm, and bleeding on probing were significantly more prevalent among implants positive for the aMMP‐8‐PoC test. aMMP‐8/ORALyzer analysis was more precise in recording disease than total MMP‐8, calprotectin, IL‐6, MMP‐2, and MMP‐9. Conclusions The aMMP‐8‐PoC test can be conveniently implemented to alert for and detect active collagenolysis affecting peri‐implant tissues, both in the early and advanced stages of the disease. Active and fragmented MMP‐8 exhibits a strong and significant association with peri‐implantitis as compared to total MMP‐8 and other biomarkers and can be utilized as the POC/chairside biomarker of choice in the new classification of peri‐implantitis.
Collapse
Affiliation(s)
- Hanna Lähteenmäki
- Department of Oral and Maxillofacial Diseases, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Taina Tervahartiala
- Department of Oral and Maxillofacial Diseases, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Ismo T Räisänen
- Department of Oral and Maxillofacial Diseases, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Pirjo Pärnänen
- Department of Oral and Maxillofacial Diseases, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Matti Mauramo
- Department of Oral and Maxillofacial Diseases, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.,Department of Pathology, Haartman Institute and HUSLab, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Shipra Gupta
- Unit of Periodontics, Oral Health Sciences Centre, Post Graduate Institute of Medical Education & Research (PGIMER), Chandigarh, India
| | - Victoria Sampson
- Department of Oral and Maxillofacial Diseases, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Nilminie Rathnayake
- Department of Oral and Maxillofacial Diseases, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Anna-Maria Heikkinen
- Department of Oral and Maxillofacial Diseases, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Saeed Alassiri
- Department of Oral and Maxillofacial Diseases, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.,Department of Periodontics and Community Dental Sciences, King Khalid University, Abha, Saudi Arabia
| | | | - Roland Frankenberger
- Department for Operative Dentistry, Endodontics, and Pediatric Dentistry, Philipps University Marburg and University Hospital Giessen and Marburg, Marburg, Germany
| | - Timo Sorsa
- Department of Oral and Maxillofacial Diseases, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.,Division of Periodontology, Department of Dental Medicine, Karolinska Institutet, Huddinge, Sweden
| |
Collapse
|
|
2
|
Neutrophil Adhesion and the Release of the Free Amino Acid Hydroxylysine. Cells 2021; 10:cells10030563. [PMID: 33807594 PMCID: PMC7999338 DOI: 10.3390/cells10030563] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Revised: 02/25/2021] [Accepted: 03/02/2021] [Indexed: 12/21/2022] Open
Abstract
During infection or certain metabolic disorders, neutrophils can escape from blood vessels, invade and attach to other tissues. The invasion and adhesion of neutrophils is accompanied and maintained by their own secretion. We have previously found that adhesion of neutrophils to fibronectin dramatically and selectively stimulates the release of the free amino acid hydroxylysine. The role of hydroxylysine and lysyl hydroxylase in neutrophil adhesion has not been studied, nor have the processes that control them. Using amino acid analysis, mass spectrometry and electron microscopy, we found that the lysyl hydroxylase inhibitor minoxidil, the matrix metalloproteinase inhibitor doxycycline, the PI3K/Akt pathway inhibitors wortmannin and the Akt1/2 inhibitor and drugs that affect the actin cytoskeleton significantly and selectively block the release of hydroxylysine and partially or completely suppress spreading of neutrophils. The actin cytoskeleton effectors and the Akt 1/2 inhibitor also increase the phenylalanine release. We hypothesize that hydroxylysine release upon adhesion is the result of the activation of lysyl hydroxylase in interaction with matrix metalloproteinase, the PI3K/Akt pathway and intact actin cytoskeleton, which play important roles in the recruitment of neutrophils into tissue through extracellular matrix remodeling.
Collapse
|
|
3
|
Sabbagh DK, Barmayehvar B, Nguyen T, Edgar RG, Turner AM. Managing panniculitis in alpha-1 antitrypsin deficiency: Systematic review of evidence behind treatment. World J Dermatol 2018; 7:1-8. [DOI: 10.5314/wjd.v7.i1.1] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2017] [Revised: 11/27/2017] [Accepted: 12/07/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To systematically review literature for management of alpha-1 antitrypsin deficiency (AATD) panniculitis.
METHODS Multiple databases were searched using combinations of pertinent terms. Articles were selected describing panniculitis treatment in patients with AAT < 11 μmol and/or PiZZ genotype, with no language limitation. All relevant articles were accessed in full text. Independent review of abstracts and full manuscripts was conducted by 2 reviewers, and quality assessment by one reviewer (checked by a second). Data extraction was conducted by one reviewer (checked by a second). Narrative synthesis only was conducted, as data were unsuitable for meta-analysis.
RESULTS Thirty-two case reports and 4 case series were found. Augmentation therapy (infusions of plasma-derived AAT) was the most successful, with complete resolution of symptoms in all patients. Dapsone is a less expensive option, and it achieved clinical resolution in 62% of patients, but it is very poorly tolerated. Among other single-agent antibiotics, doxycycline was the most successful with complete clinical resolution seen in 33% of patients. Immunosuppressants were largely unsuccessful; 80% of patients exhibited no response. Liver transplantation and therapeutic plasma exchange displayed complete resolution in 66% of patients. Other strategies, such as non-steroidal anti-inflammatory drugs or antibiotics other than dapsone did not show sufficient response rates to recommend their use. Authors note the risk of bias imposed by the type of evidence (case reports, case series) available in this field.
CONCLUSION Dapsone is the recommended first line therapy for AATD panniculitis, followed by augmentation therapy. Plasma exchange may be an alternative in the setting of rapidly progressive disease.
Collapse
Affiliation(s)
- Donah K Sabbagh
- the Medical Research Institute of New Zealand (MRINZ), CSB Building, Wellington Hospital, Newtown, Wellington 6021, New Zealand
| | - Behrad Barmayehvar
- Department of Colorectal Surgery, the Royal Wolverhampton Trust, Wolverhampton Road, West Midlands WV10 0QP, United Kingdom
| | - Thanh Nguyen
- Department of Intensive Care, United Lincolnshire Hospitals NHS Trust, Lincolnshire LN2 4AX, United Kingdom
| | - Ross G Edgar
- Therapy Services, University Hospitals Birmingham NHS Foundation Trust, Birmingham B15 2WG, United Kingdom
| | - Alice M Turner
- Institute of Applied Health Research, University of Birmingham, Birmingham B15 2TT, United Kingdom
| |
Collapse
|
|
4
|
Gaikwad SP, Gurav AN, Shete AR, Desarda HM. Effect of scaling and root planing combined with systemic doxycycline therapy on glycemic control in diabetes mellitus subjects with chronic generalized periodontitis: a clinical study. J Periodontal Implant Sci 2013; 43:79-86. [PMID: 23678391 PMCID: PMC3651941 DOI: 10.5051/jpis.2013.43.2.79] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2013] [Accepted: 03/05/2013] [Indexed: 12/16/2022] Open
Abstract
PURPOSE The purpose of study was to compare glycemic control using glycated hemoglobin levels (HbA1c) in diabetic patients with chronic generalized periodontitis (CGP) undergoing scaling and root planing (SRP) with and without systemic doxycycline. METHODS Fifty subjects with type 2 diabetes mellitus (T2DM) and CGP receiving antidiabetic therapy were selected for study. The selected subjects were randomly assigned to two groups (test group [TG] and control group [CG]) comprising 25 patients each. The TG received SRP followed by systemic doxycycline. The CG received treatment with SRP only. The periodontal parameters were recorded at baseline (day zero), and every 1 month for 4 months and included probing depth, clinical attachment level, plaque index, gingival index, and HbA1c level were recorded at baseline (day zero) and at the end of 4 months. RESULTS A statistically significant effect was demonstrated for the periodontal parameters for both the TG and CG. HbA1c values did not show a statistically significant difference in the treatment group as compared to the CG. CONCLUSIONS The authors concluded that nonsurgical periodontal therapy improved glycemic control in patients with T2DM in both groups, but no statistical difference was observed with adjunctive systemic doxycycline therapy. A further study with a larger sample size is required.
Collapse
Affiliation(s)
- Subodh P. Gaikwad
- Department of Periodontics, Tatyasaheb Kore Dental College and Research Centre, Kolhapur, India
| | - Abhijit N. Gurav
- Department of Periodontics, Tatyasaheb Kore Dental College and Research Centre, Kolhapur, India
| | - Abhijeet R. Shete
- Department of Periodontics, Tatyasaheb Kore Dental College and Research Centre, Kolhapur, India
| | - Hitesh M. Desarda
- Department of Periodontics, Tatyasaheb Kore Dental College and Research Centre, Kolhapur, India
| |
Collapse
|
|
5
|
Liu Y, Song F, Sun J, Yu H, Liu SSY. Suture compression induced bone resorption with intensified MMP-1 and 13 expressions. Bone 2012; 51:695-703. [PMID: 22819631 DOI: 10.1016/j.bone.2012.07.005] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2012] [Revised: 07/06/2012] [Accepted: 07/09/2012] [Indexed: 01/25/2023]
Abstract
UNLABELLED Suture compression is a widely used approach to inhibit maxillary growth; however, biological responses in sutures to compressive force are still unclear. The objective of this pilot study was to investigate the matrix metalloproteinase (MMP) expression and osteoclast activities during the midpalatal suture compression. METHODS 56 six-week old male C57BL/6 mice were randomly assigned to the control and compression groups. The mice in the compression and control groups received helix springs bonded to the maxillary molars delivering initial compressive forces of 0.20 and 0N (no activation), respectively. On Days 1, 4, 7 and 14, animals were sacrificed and scanned using micro-computed tomography to quantify suture width and bone mineral density. Serial histological sections were stained with HE, TRAP, and immunohistochemistry to observe changes in bone resorption, osteoclast activities, and MMP-1, 8, and 13 expressions. Bone volume/total volume (Bv/Tv) ratio, osteoclast count, osteoclast covering area, and MMP expression intensity were measured. The Mann-Whitney and the Kruskal-Wallis tests with Bonferroni post-hoc corrections were performed to compare differences between groups and between time points in the same group at significant level of P<0.05. RESULTS Compared to the control, suture width in the compression group was significantly reduced on Day 1, but continuously widened with reduced bone mineral density afterwards. With MMP-1 and -13 evidently intensified expressions, osteoclast number and activities significantly increased, leading to reduced Bv/Tv ratio and progressive bone resorption from Days 4 to 14. CONCLUSIONS Suture compression elevated the MMP-1 and 13 expressions, activated osteoclasts, reduced bone density, and induced bone resorption adjacent to the suture. It suggests that suture compression can be used for bone volume reduction.
Collapse
Affiliation(s)
- Yang Liu
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, PR China
| | | | | | | | | |
Collapse
|
|
6
|
Abstract
Tetracyclines were developed as a result of the screening of soil samples for antibiotics. The firstt of these compounds, chlortetracycline, was introduced in 1947. Tetracyclines were found to be highly effective against various pathogens including rickettsiae, as well as both gram-positive and gram-negative bacteria, thus becoming the first class of broad-spectrum antibiotics. Many other interesting properties, unrelated to their antibiotic activity, have been identified for tetracyclines which have led to widely divergent experimental and clinical uses. For example, tetracyclines are also an effective anti-malarial drug. Minocycline, which can readily cross cell membranes, is known to be a potent anti-apoptotic agent. Another tetracycline, doxycycline is known to exert anti-protease activities. Doxycycline can inhibit matrix metalloproteinases which contribute to tissue destruction activities in diseases such as periodontitis. A large body of literature has provided additional evidence for the “beneficial” actions of tetracyclines, including their ability to act as reactive oxygen species scavengers and anti-inflammatory agents. This review provides a summary of tetracycline's multiple mechanisms of action as a means to understand their beneficial effects.
Collapse
|
|
7
|
Griffin MO, Fricovsky E, Ceballos G, Villarreal F. Tetracyclines: a pleitropic family of compounds with promising therapeutic properties. Review of the literature. Am J Physiol Cell Physiol 2010; 299:C539-48. [PMID: 20592239 PMCID: PMC2944325 DOI: 10.1152/ajpcell.00047.2010] [Citation(s) in RCA: 288] [Impact Index Per Article: 19.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2010] [Accepted: 06/27/2010] [Indexed: 02/07/2023]
Abstract
There must be something unique about a class of drugs (discovered and developed in the mid-1940s) where there are more than 130 ongoing clinical trials currently listed. Tetracyclines were developed as a result of the screening of soil samples for antibiotic organisms. The first of these compounds chlortetracycline was introduced in 1948. Soon after their development tetracyclines were found to be highly effective against various pathogens including rickettsiae, Gram-positive, and Gram-negative bacteria, thus, becoming a class of broad-spectrum antibiotics. The mechanism of action of tetracyclines is thought to be related to the inhibition of protein synthesis by binding to the 30S bacterial ribosome. Tetracyclines are also an effective anti-malarial drug. Over time, many other "protective" actions have been described for tetracyclines. Minocycline, which can readily cross cell membranes, is known to be a potent anti-apoptotic agent. Its mechanism of action appears to relate to specific effects exerted on apoptosis signaling pathways. Another tetracycline, doxycycline is known to exert antiprotease activities. Doxycycline can inhibit matrix metalloproteinases, which contribute to tissue destruction activities in diseases such as gingivitis. A large body of literature has provided additional evidence for the "beneficial" actions of tetracyclines, including their ability to act as oxygen radical scavengers and anti-inflammatory agents. This increasing volume of published work and ongoing clinical trials supports the notion that a more systematic examination of their possible therapeutic uses is warranted. This review provides a summary of tetracycline's multiple mechanisms of action and while using the effects on the heart as an example, this review also notes their potential to benefit patients suffering from various pathologies such as cancer, Rosacea, and Parkinson's disease.
Collapse
Affiliation(s)
- Michael O Griffin
- 1Transitional Year Residency Program, Wheaton Franciscan Healthcare-St. Joseph, Milwaukee, Wisconsin, USA
| | | | | | | |
Collapse
|
|
8
|
Hypersensitivity vasculitis with leukocytoclastic vasculitis associated with alpha-1-proteinase inhibitor. Case Rep Med 2010; 2009:941258. [PMID: 20204065 PMCID: PMC2829622 DOI: 10.1155/2009/941258] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2009] [Accepted: 11/18/2009] [Indexed: 11/17/2022] Open
Abstract
Prolastin is a commercially available form of alpha-1-antitrypsin (AAT) that is derived from pooled human plasma and used for treatment of severe alpha-1-antitrypsin deficiency (AATD). We describe a patient with AATD who developed presumed hypersensitivity vasculitis (HV) following a Prolastin infusion. Hypersensitivity vasculitis (HV), or cutaneous vasculitis, is characterized by inflammation of the small vessels of the skin with resultant ischemia to the distally supplied areas. To our knowledge, this is the first reported case of presumed hypersensitivity vasculitis following Prolastin infusion.
Collapse
|
|
9
|
Abstract
There are many options for the treatment of acne rosacea, including topical and systemic therapies, laser and light-based therapies, and surgical procedures. A classification system for rosacea identifies 4 subtypes (ie, erythematotelangiectatic, papulopustular, phymatous, and ocular), which may help guide therapeutic decision making. Until recently, the pathophysiology of acne rosacea has been poorly understood and limited to descriptions of factors that exacerbate or improve this disorder. Recent molecular studies suggest that an altered innate immune response is involved in the pathogenesis of the vascular and inflammatory disease seen in patients with rosacea. These findings may help explain the benefits of current treatments and suggest new therapeutic strategies helpful for alleviating this disease. The goals of therapy include reduction of papules, pustules, erythema, physical discomfort, and an improvement in quality of life. Standard topical treatment agents include metronidazole, azelaic acid, and sodium sulfacetamide-sulfur. Second-line therapies include benzoyl peroxide, clindamycin, calcineurin inhibitors, and permethrin. There are also various systemic therapy options.
Collapse
Affiliation(s)
- Mohamed L Elsaie
- Department of Dermatology and Cutaneous Surgery, University of Miami, Miami, FL 33136, USA.
| | | |
Collapse
|
|
10
|
Yamasaki K, Gallo RL. The molecular pathology of rosacea. J Dermatol Sci 2009; 55:77-81. [PMID: 19481425 DOI: 10.1016/j.jdermsci.2009.04.007] [Citation(s) in RCA: 191] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2009] [Revised: 04/27/2009] [Accepted: 04/29/2009] [Indexed: 12/15/2022]
Abstract
Rosacea is a common and chronic inflammatory skin disease that affects over 10 million Americans. Although the phenotypes of rosacea are clinically heterogeneous, they are all related by the presence of chronic facial skin inflammation. Until recently, the pathophysiology of this disease has been poorly understood and limited to descriptions of factors that exacerbate or improve this disorder. Recent molecular studies suggest that an altered innate immune response is involved in the pathogenesis of the vascular and inflammatory disease seen in patients with rosacea. These findings may help explain the benefits of current treatments and suggest new therapeutic strategies helpful for alleviating this disease. This article discusses the possible molecular mechanisms for the pathogenesis of rosacea from current clinical observations and laboratory research.
Collapse
Affiliation(s)
- Kenshi Yamasaki
- Division of Dermatology, University of California, San Diego, CA 92161, USA.
| | | |
Collapse
|
|
11
|
Akkaya P, Onalan G, Haberal N, Bayraktar N, Mülayim B, Zeyneloglu HB. Doxycycline causes regression of endometriotic implants: a rat model. Hum Reprod 2009; 24:1900-8. [PMID: 19401321 DOI: 10.1093/humrep/dep106] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
BACKGROUND Doxycycline (Dox) has a number of non-antibiotic properties. One of them is the inhibition of matrix metalloproteinase (MMP) activity. The aim of this study was to assess the effects of Dox in a rat endometriosis model. METHODS Endometriosis was surgically induced in 40 rats by transplanting of endometrial tissue. After 3 weeks, repeat laparotomies were performed to check the implants and the animals were randomized into four groups: Group I, low-dose Dox (5 mg/kg/day); Group II, high-dose Dox (40 mg/kg/day); Group III, leuprolide acetate 1 mg/kg single dose, s.c.; and Group VI (controls), no medication. The treatment, initiated on the day of surgery and continuing for 3 weeks, was administered to the study groups. Three weeks later, the rats were euthanized and the implants were evaluated morphologically and histologically for immunoreactivity of MMP-2 and -9, and interleukin-6 (IL-6) concentration in the peritoneal fluid was assayed. RESULTS Treatment with leuprolide acetate, or high-dose or low-dose Dox caused significant decreases in the implant areas compared with the controls (P = 0.03, P = 0.006, and P = 0.001, respectively). IL-6 levels in peritoneal fluid decreased in Group I (P = 0.02) and Group III (P < 0.05). MMP H scores were significantly lower in the group that received low-dose Dox in both epithelial and stromal MMP-2 and -9 immunostaining when compared with the control group [P = 0.048, P = 0.002, P = 0.007 and P = 0.002, respectively, MMP-2 (epithelia), MMP-2 (stroma), MMP-9 (epithelia) and MMP-9 (stroma)]. CONCLUSIONS Low-dose Dox caused regression of endometriosis in this experimental rat model.
Collapse
Affiliation(s)
- Pinar Akkaya
- Obstetrics and Gynecology, Baskent University School of Medicine, Kubilay Sok no. 36 Maltepe, 06570 Ankara, Turkey
| | | | | | | | | | | |
Collapse
|
|
12
|
Cazalis J, Bodet C, Gagnon G, Grenier D. Doxycycline Reduces Lipopolysaccharide-Induced Inflammatory Mediator Secretion in Macrophage and Ex Vivo Human Whole Blood Models. J Periodontol 2008; 79:1762-8. [DOI: 10.1902/jop.2008.080051] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
|
|
13
|
Rossiter HB, Scadeng M, Tang K, Wagner PD, Breen EC. Doxycycline treatment prevents alveolar destruction in VEGF-deficient mouse lung. J Cell Biochem 2008; 104:525-35. [PMID: 18181212 DOI: 10.1002/jcb.21643] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
In vivo lung-targeted VEGF gene inactivation results in pulmonary cell apoptosis, airspace enlargement, and increased lung compliance consistent with an emphysema-like phenotype. The predominant hypothesis for the cause of lung destruction in emphysema is an imbalance between active lung protease and anti-protease molecules. Therefore, we investigated the role of protease (e.g., matrix metalloproteinases--MMPs) and anti-protease (e.g., tissue inhibitors of metalloproteinases--TIMPs) expression in contributing to the lung structural remodeling observed in pulmonary-VEGF-deficient mice. VEGFLoxP mice instilled through the trachea with an adeno-associated virus expressing Cre recombinase (AAV/Cre) manifest airspace enlargement and a greater (P < 0.05) mean linear intercept (MLI: 44.2 +/- 4.2 microm) compared to mice instilled with a control virus expressing LacZ (31.3 +/- 2.5 microm). Airspace enlargement was prevented by the continuous administration of the general MMP inhibitor, doxycycline (Dox) (Cre + Dox: 32.6 +/- 2.5 microm), and MLI values were not different from either control (LacZ + Dox: 30.5 +/- 1.2 microm). In situ magnetic resonance imaging of VEGF gene inactivated mouse lungs revealed uneven inflation, residual trapped gas volumes upon oxygen absorption deflation/re-inflation, and loss of parenchymal structure; effects that were largely prevented by Dox. Five weeks after AAV/Cre infection Western blot revealed a 9.9-fold increase in pulmonary MMP-3, and 2-fold increases in MMP-9 and TIMP-2. However, the increase in MMP-3 was prevented by Dox administration and was associated with a 2-fold increase in serpin b5 (Maspin) expression. These results suggest that doxycycline treatment largely prevents the aberrant lung remodeling response observed in VEGF-deficient mouse lungs and is associated with changes in protease and anti-protease expression.
Collapse
Affiliation(s)
- Harry B Rossiter
- Institute of Membrane and Systems Biology, University of Leeds, Leeds LS2 9JT, UK
| | | | | | | | | |
Collapse
|
|
14
|
DeLano FA, Schmid-Schönbein GW. Proteinase activity and receptor cleavage: mechanism for insulin resistance in the spontaneously hypertensive rat. Hypertension 2008; 52:415-23. [PMID: 18606910 DOI: 10.1161/hypertensionaha.107.104356] [Citation(s) in RCA: 82] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Arterial hypertension is associated with organ dysfunctions, but the mechanisms are uncertain. We hypothesized that enhanced proteolytic activity in the microcirculation of spontaneously hypertensive rats (SHRs) may be a pathophysiological mechanism causing cell membrane receptor cleavage and examine this for 2 different receptors. Immunohistochemistry of matrix-degrading metalloproteinases (matrix metalloproteinase [MMP]-9) protein shows enhanced levels in SHR microvessels, mast cells, and leukocytes compared with normotensive Wistar-Kyoto rats. In vivo microzymography shows cleavage by MMP-1 and -9 in SHRs that colocalizes with MMP-9 and is blocked by metal chelation. SHR plasma also has enhanced protease activity. We demonstrate with an antibody against the extracellular domain that the insulin receptor-alpha density is reduced in SHRs, in line with elevated blood glucose levels and glycohemoglobin. There is also cleavage of the binding domain of the leukocyte integrin receptor CD18 in line with previously reported reduced leukocyte adhesion. Blockade of MMPs with a broad-acting inhibitor (doxycycline, 5.4 mg/kg per day) reduces protease activity in plasma and microvessels; blocks the proteolytic cleavage of the insulin receptor, the reduced glucose transport; normalizes blood glucose levels and glycohemoglobin levels; and reduces blood pressure and enhanced microvascular oxidative stress of SHRs. The results suggest that elevated MMP activity leads to proteolytic cleavage of membrane receptors in the SHR, eg, cleavage of the insulin receptor-binding domain associated with insulin resistance.
Collapse
Affiliation(s)
- Frank A DeLano
- Department of Bioengineering, Whitaker Institute for Biomedical Engineering, University of California San Diego, La Jolla CA 92093-0412, USA
| | | |
Collapse
|
|
15
|
Burggraf D, Trinkl A, Dichgans M, Hamann GF. Doxycycline inhibits MMPs via modulation of plasminogen activators in focal cerebral ischemia. Neurobiol Dis 2007; 25:506-13. [PMID: 17166729 DOI: 10.1016/j.nbd.2006.10.013] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2006] [Revised: 10/20/2006] [Accepted: 10/29/2006] [Indexed: 10/23/2022] Open
Abstract
Tetracyclines inhibit matrix metalloproteinases (MMPs) and reduce infarction volume following cerebral ischemia. In this thesis an involvement of urokinase could be proven. Cerebral ischemia in rats was induced for 3 h followed by 24 h reperfusion (suture model). Each 6 animals received orally either doxycycline or water. Doxycycline treatment began 10 days before ischemia. MMP-2 and MMP-9 were substantially decreased. The possibility of involvement of the endogenous MMP inhibitors in the MMP inhibiting mechanisms was excluded. The plasminogen activator uPA was significantly decreased by doxycycline indicating an MMP inhibiting mechanism including the plasminogen/plasmin system. In the doxycycline group, this resulted in a decreased damage to the cerebral microvessels and less loss of the basal lamina antigen collagen type IV. Hemoglobin extravasation was also significantly reduced. Our results suggest that doxycycline may have a potential use as an anti-ischemic compound since it provides microvascular protection by inhibiting the plasminogen system.
Collapse
Affiliation(s)
- Dorothe Burggraf
- Department of Neurology, Ludwig-Maximilians University, Klinikum Grosshadern, Marchioninistr. 15, 81377 Munich, Germany
| | | | | | | |
Collapse
|
|
16
|
Llambés F, Silvestre FJ, Hernández-Mijares A, Guiha R, Caffesse R. Effect of non-surgical periodontal treatment with or without doxycycline on the periodontium of type 1 diabetic patients. J Clin Periodontol 2005; 32:915-20. [PMID: 15998278 DOI: 10.1111/j.1600-051x.2005.00736.x] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
AIM The present investigation was performed to study how type 1 diabetics responded to non-surgical periodontal treatment with and without adjunctive doxycycline. METHOD Sixty diabetic type 1 patients (mean age 35.3+/-9 years) with moderate-to-severe periodontal disease were selected and divided into two groups of 30 patients each. Both groups were sex and age matched and had similar amounts of periodontal destruction. Plaque index (PI), bleeding on probing (BOP), probing depth (PD) and clinical attachment levels (CAL) were recorded. Group 1 (30 patients) was treated with oral hygiene instruction, scaling and root planing, chlorhexidine rinses twice a day and doxycycline (100 mg/day for 15 days). Group 2 (30 patients) had the same treatment but without doxycycline. After 12 weeks their periodontal condition was reevaluated. RESULTS After treatment, both groups had a significant improvement in all periodontal parameters, since PI, BOP, probing pocket depth (PPD) and CAL were significantly reduced. However, the reduction in PD in pockets > or =6 mm and in BOP were more evident when doxycycline was used (group 1). Differences between groups for these parameters were statistically significant (p=0.03). CONCLUSION Although both periodontal treatment regimens are effective in type 1 diabetics, the use of doxycycline as an adjunct, provided more significant results when good plaque control was achieved.
Collapse
|
|
17
|
Griffin MO, Jinno M, Miles LA, Villarreal FJ. Reduction of myocardial infarct size by doxycycline: a role for plasmin inhibition. Mol Cell Biochem 2005; 270:1-11. [PMID: 15792348 DOI: 10.1007/s11010-005-2540-3] [Citation(s) in RCA: 37] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
Myocardial ischemia-reperfusion (I/R) is associated with the activation of matrix metalloproteinases (MMPs) and serine proteases. We hypothesized that activation of MMPs and the serine protease plasmin contribute to early cardiac myocyte death following I/R and that broad-spectrum protease inhibition with doxycycline (DOX) preserves myocyte viability. Rats treated daily with or without DOX beginning 48 h prior to experimentation were subjected to 30 min of coronary occlusion and 2 days of reperfusion. DOX pre-treatment reduced infarct size by 37%. DOX attenuated increases in MMP-9 and plasmin levels as determined by gelatin zymography and immunoblot, respectively. Neutrophil extravasation was unaltered by DOX as assessed by myeloperoxidase (MPO) activity. To examine the contribution of MMP-9 and plasmin to myocyte injury, cultures of neonatal rat ventricular myocytes (NRVMs) were treated for 48 h with 83 kDa MMP-9 or plasminogen in the presence or absence of DOX. MMP-9 treatment did not affect myocyte viability. Plasminogen treatment led to increased plasmin activity, resulting in loss of beta1-integrin, NRVM detachment and apoptosis. DOX co-treatment inhibited plasmin activity and preserved NRVM attachment, whereas co-treatment with the broad-spectrum MMP inhibitor GM6001 had no effect. These results indicate that plasmin causes disruption of myocyte attachment and viability independently of MMP activation in vitro and that inhibition of plasmin by DOX may reduce I/R-induced myocyte death in vivo through the inhibition of plasmin.
Collapse
Affiliation(s)
- Michael O Griffin
- Department of Medicine, University of California, San Diego, CA 2103-8412, USA
| | | | | | | |
Collapse
|
|
18
|
Gapski R, Barr JL, Sarment DP, Layher MG, Socransky SS, Giannobile WV. Effect of systemic matrix metalloproteinase inhibition on periodontal wound repair: a proof of concept trial. J Periodontol 2004; 75:441-52. [PMID: 15088883 PMCID: PMC2584373 DOI: 10.1902/jop.2004.75.3.441] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
BACKGROUND The adjunctive use of matrix metalloproteinase (MMP) inhibitors with scaling and root planing (SRP) promotes new attachment in patients with periodontal disease. This pilot study was designed to examine aspects of the biological response brought about by the MMP inhibitor low dose doxycycline (LDD) combined with access flap surgery (AFS) on the modulation of periodontal wound repair in patients with severe chronic periodontitis. METHODS Twenty-four subjects were enrolled into a 12-month, randomized, placebo-controlled, double-masked trial to evaluate clinical, biochemical, and microbial measures of disease in response to 6 months therapy of either placebo capsules + AFS or LDD (20 mg b.i.d.) + AFS. Clinical measures including probing depth (PD), clinical attachment levels (CAL), and bleeding on probing (BOP) as well as gingival crevicular fluid bone marker assessment (ICTP) and microbial DNA analysis (levels and proportions of 40 bacterial species) were performed at baseline and 3, 6, 9, and 12 months. RESULTS Patients treated with LDD + AFS showed more potent reductions in PD in surgically treated sites of >6 mm (P<0.05, 12 months). Furthermore, LDD + AFS resulted in greater reductions in ICTP levels compared to placebo + AFS. Rebounds in ICTP levels were noted when the drug was withdrawn. No statistical differences between the groups in mean counts were found for any pathogen tested. CONCLUSIONS This pilot study suggests that LDD in combination with AFS may improve the response of surgical therapy in reducing probing depth in severe chronic periodontal disease. LDD administration also tends to reduce local periodontal bone resorption during drug administration. The use of LDD did not appear to contribute to any significant shifts in the microbiota beyond that of surgery alone.
Collapse
Affiliation(s)
- R Gapski
- Center for Craniofacial Regeneration and Department of Periodontics/Prevention/ Geriatrics, School of Dentistry, University of Michigan, Ann Arbor, MI 48109-1078, USA
| | | | | | | | | | | |
Collapse
|
|
19
|
Grenier D, Plamondon P, Sorsa T, Lee HM, McNamara T, Ramamurthy NS, Golub LM, Teronen O, Mayrand D. Inhibition of proteolytic, serpinolytic, and progelatinase-b activation activities of periodontopathogens by doxycycline and the non-antimicrobial chemically modified tetracycline derivatives. J Periodontol 2002; 73:79-85. [PMID: 11846203 DOI: 10.1902/jop.2002.73.1.79] [Citation(s) in RCA: 43] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
BACKGROUND Tetracyclines, particularly doxycycline (Doxy), and their non-antimicrobial chemically-modified derivatives (CMTs) inhibit the activities of human matrix metalloproteinases (MMPs), and reduce the severity and progression of periodontal disease in animal models and humans. In this study, the effects of Doxy and CMT-1, -3, and -5 on proteolytic, serpinolytic, and progelatinase-B activation activities of potent periodontopathogens were studied. METHODS The effect of Doxy and CMTs (0.5 to 50 microM) on proteolytic activities were investigated by incubating bacteria with chromogenic substrates or human serum albumin. A collagenolytic fraction of Porphyromonas gingivalis was used to evaluate the effect of these substances on collagenolytic (type I collagen) and serpinolytic (alpha1-proteinase inhibitor) activities. Lastly, the effect of Doxy on progelatinase-B (pro-MMP-9) activation by purified proteinases from P. gingivalis and Treponema denticola was investigated by SDS-PAGE/Western immunoblotting. RESULTS Doxy and CMTs, except CMT-5 which lacks the structural elements required for cation chelation, inhibited Arg- and Lys-gingipain activities as well as collagenolytic activity of P. gingivalis. Doxy and CMTs did not markedly affect the chymotrypsin-like activity of T. denticola but inhibited its trypsin-like activity. In addition, degradation of human serum albumin by cells of P. gingivalis and T. denticola was strongly inhibited by Doxy and CMT-1. Doxy and CMT-1 also inhibited the inactivation of alpha1-proteinase inhibitor (serpinolytic activity) by a collagenolytic fraction of P. gingivalis. Lastly, Doxy prevented the latent to active conversion of human neutrophil progelatinase-B (pro-MMP-9) by Arg-gingipains A/B of P. gingivalis but not by the chymotrypsin-like proteinase of T. denticola. CONCLUSIONS Data from this study suggest that Doxy and CMTs have the potential to inhibit the periodontopathogenic bacterial proteinases, which contribute to tissue destruction cascades during periodontitis directly and indirectly by triggering the host response.
Collapse
Affiliation(s)
- D Grenier
- Groupe de Recherche en Ecologie Buccale, Faculté de Médecine Dentaire, Université Laval, Québec, Canada.
| | | | | | | | | | | | | | | | | |
Collapse
|
|
20
|
Frye CA, Yocum DE, Tuan R, Suyana E, Seftor EA, Seftor REB, Khalkhali-Ellis Z, Moore TL, Hendrix MJC. An in vitro Model for Studying Mechanisms Underlying Synoviocyte-Mediated Cartilage Invasion in Rheumatoid Arthritis. Pathol Oncol Res 2001; 2:157-166. [PMID: 11173599 DOI: 10.1007/bf02903519] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
Rheumatoid arthritis (RA) is a chronic inflammatory disease of joints involving the pathological development of an invasive and destructive pannus tissue which contributes to the loss of cartilage and bone. To further analyze the process of cartilage degradation and invasion, we have developed an in vitro model composed of cartilage matrix and synoviocytes (isolated from RA pannus tissue, as well as normal synovial membrane). The matrix is derived from pig articular cartilage and contains collagen type II and proteoglycans and is similar in composition to human cartilage. Data generated from this model reveal that synoviocytes isolated from RA pannus tissue invaded cartilage matrix in a manner which directly correlated with the severity of the disease. Analysis of mechanisms associated with the invasive process demonstrate that highly invasive RA synoviocytes maintain a round morphology during attachment and spreading on cartilage matrix, compared with their normal counterparts. Furthermore, the level of secretion of matrix metalloproteinase (MMP) activity was shown to correlate with the RA phenotype, which could be modulated with a novel MMP inhibitor. Normal synoviocytes could be "converted" to an RA phenotype by specific inflammatory cytokines, such that invasion of cartilage matrix was augmented by culturing these cells in the presence of 5 U/ml IL-1b or 18 U/ml TGFb. Invasion was inhibited by 150 U/ml TNFa, and unaffected by 100 ng/ml PDGF. In addition, synovial fluid from RA patients induced invasion of normal synoviocytes, in a concentration dependent manner, from 150% to 460%; however, synovial fluid from another inflammatory arthritidy (Crohn's) did not augment invasion to the same degree. Moreover, this "conversion effect" appears to be specific for synoviocytes, since similar effects could not be achieved with human skin fibroblasts. This in vitro model of synoviocyte-mediated cartilage invasion allows for further molecular characterization of the invasive properties of the synoviocyte which contribute to RA.
Collapse
Affiliation(s)
- Catherine A Frye
- University of Arizona, Department of Microbiology and Immunology, Tucson, USA
| | | | | | | | | | | | | | | | | |
Collapse
|
|
21
|
Abstract
PURPOSE To demonstrate the potential value of tetracyclines in the treatment of corneal ulceration after moderate to severe ocular chemical injuries. METHODS Review of published materials describing landmarks in the development of tetracyclines as matrix metalloproteinase inhibitors in ophthalmology and related disciplines. RESULTS Tetracyclines can protect the cornea against proteolytic degradation after moderate to severe ocular chemical injury. They inhibit matrix metalloproteinases by mechanisms independent of their antimicrobial properties, primarily through restriction of the gene expression of neutrophil collagenase and epithelial gelatinase, suppression of alpha1-antitrypsin degradation, and scavenging of reactive oxygen species. CONCLUSION Oral tetracyclines can be used along with topical tetracycline preparations and other therapeutic agents to inhibit collagenolytic degradation of the cornea after moderate to severe ocular chemical injuries.
Collapse
Affiliation(s)
- R A Ralph
- Wilmer Eye Institute, Johns Hopkins University, Rockville, Maryland, USA.
| |
Collapse
|
|
22
|
Myers SA, Wolowacz RG. Tetracycline-based MMP inhibitors can prevent fibroblast-mediated collagen gel contraction in vitro. Adv Dent Res 1998; 12:86-93. [PMID: 9972128 DOI: 10.1177/08959374980120012701] [Citation(s) in RCA: 23] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Collagen gels in vitro can be contracted by fibroblasts. The role of matrix metalloproteinases (MMPs) in the contraction of collagen lattices by human neonatal foreskin fibroblasts (HuFFs) was investigated in tissue culture media supplemented by various doses of known gelatinase inhibitors. Fluorescent assays with model gelatinase substrates and media conditioned by fibroblasts apparently confirmed the ability of chemically modified tetracyclines (CMTs) to act as inhibitors of MMP2, and zymography demonstrated that this was the major cell-derived MMP activity. There were no observable effects on the rate of contraction of attached FPCLs containing 6 x 10(4) HuFFs (passages 18-25) with either CMT-5 or CMT-2 at all concentrations tested (0-100 micrograms/mL). However, at greater than 20 micrograms/mL doxycycline and greater than 5 micrograms/mL CMT-3, FPCL contraction was completely abolished. Quantitative assessment of cell viability by means of the MTT assay in monolayer and qualitatively within the FPCLs with CalceinAM suggested that differences were not due to cytotoxic effects. Seeding FPCLs with lower-passage fibroblasts produced identical trends. These results may implicate the involvement of MMPs in the process of gel contraction, although tetracyclines have effects additional to their ability to inhibit MMPs directly.
Collapse
Affiliation(s)
- S A Myers
- Smith & Nephew Group Research Centre, York, United Kingdom
| | | |
Collapse
|
|
23
|
Golub LM, Lee HM, Ryan ME, Giannobile WV, Payne J, Sorsa T. Tetracyclines inhibit connective tissue breakdown by multiple non-antimicrobial mechanisms. Adv Dent Res 1998; 12:12-26. [PMID: 9972117 DOI: 10.1177/08959374980120010501] [Citation(s) in RCA: 466] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
A seminal experiment involving a germ-free rat model of connective tissue breakdown (followed soon thereafter by a series of in vitro studies) identified an unexpected non-antimicrobial property of tetracyclines (TCs). This ability of TCs to inhibit matrix metalloproteinases (MMPs) such as collagenase was found to reflect multiple direct and indirect mechanisms of action, and to be therapeutically useful in a variety of dental (e.g., adult periodontitis) and medical (e.g., arthritis, osteoporosis, cancer) diseases. The site on the TC molecule responsible for its MMP-inhibitory activity was identified which led to the development of a series of chemically modified non-antimicrobial analogs, called CMTs, which also have therapeutic potential but do not appear to induce antibiotic side-effects. Longitudinal double-blind studies on humans with adult periodontitis have demonstrated that a sub-antimicrobial dose of doxycycline (previously reported to suppress collagenase activity in the periodontal pocket) is safe and effective and has recently been approved by the FDA as an adjunct to scaling and root planing.
Collapse
Affiliation(s)
- L M Golub
- Department of Oral Biology and Pathology, School of Dental Medicine, SUNY at Stony Brook, USA
| | | | | | | | | | | |
Collapse
|
|
24
|
Bettany JT, Wolowacz RG. Tetracycline derivatives induce apoptosis selectively in cultured monocytes and macrophages but not in mesenchymal cells. Adv Dent Res 1998; 12:136-43. [PMID: 9972138 DOI: 10.1177/08959374980120010901] [Citation(s) in RCA: 48] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Evidence for a non-antibiotic activity displayed by certain tetracycline derivatives is presented. This activity is a selective cytotoxicity toward cells of the monocytic lineage (the human histiocytic lymphoma U937 cell line and the mouse macrophage line RAW264) but not toward various cells of a mesenchymal lineage (including primary ovine articular chondrocytes and meniscal cells, murine calvarial osteoblasts and MG-63 osteosarcoma cells, and primary human neonatal foreskin fibroblasts). Cells were incubated with various chemically modified tetracycline derivatives (CMTs) or doxycycline for 24 hrs at a range of concentrations between zero and 50 micrograms/mL in both serum-containing and serum-free culture conditions. Assessment of cell viability by means of the MTT assay demonstrated a potent dose-dependent cytotoxic effect induced by compound CMT-3 and a less potent effect induced by doxycycline, but no apparent cytotoxic effect in the presence of either CMT-2 or CMT-5. Cytospin preparations analyzed by the labeling of DNA fragments indicated the same trends and suggested that cell death was via an apoptotic mechanism. The cytotoxic potency of these tetracyclines toward cells of the monocytic lineage could be diminished but not abolished by either the presence of 10% fetal calf serum within the culture medium, or pre-treatment with phorbol esters to promote a more macrophage-like phenotype. These data provide evidence that, in addition to well-characterized antibiotic and MMP-inhibitory characteristics, tetracyclines may function by a novel mechanism to induce selective apoptosis.
Collapse
Affiliation(s)
- J T Bettany
- Smith and Nephew Group Research Centre, York, United Kingdom
| | | |
Collapse
|
|
25
|
Allaire E, Forough R, Clowes M, Starcher B, Clowes AW. Local overexpression of TIMP-1 prevents aortic aneurysm degeneration and rupture in a rat model. J Clin Invest 1998; 102:1413-20. [PMID: 9769334 PMCID: PMC508989 DOI: 10.1172/jci2909] [Citation(s) in RCA: 222] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
Although matrix metalloproteinases (MMPs) are expressed in abundance in arterial aneurysms, their contribution to arterial wall degeneration, dilation, and rupture has not been determined. We investigated MMP function in a rat model of aneurysm associated with arterial dilation, elastin loss, medial invasion by mononuclear inflammatory cells, and MMP upregulation. Rupture was correlated with increased gelatinase B (MMP-9) and activated gelatinase A (MMP-2). Syngeneic rat smooth muscle cells retrovirally transfected with tissue inhibitor of matrix metalloproteinases (TIMP)-1 cDNA (LTSN) or with the vector alone as a control (LXSN) were seeded onto the luminal surface of the vessels. The seeding of LTSN cells resulted in TIMP-1 local overexpression. The seeding with LTSN cells, but not LXSN cells, decreased MMP-9, activated MMP-2 and 28-kD caseinase and elastase activity, preserved elastin in the media, and prevented aneurysmal degeneration and rupture. We conclude that MMP overexpression is responsible for aneurysmal degeneration and rupture in this rat model and that local pharmacological blockade might be a reasonable strategy for controlling the formation of aneurysms in humans.
Collapse
MESH Headings
- Animals
- Aorta, Abdominal/pathology
- Aorta, Abdominal/physiology
- Aorta, Abdominal/transplantation
- Aortic Aneurysm, Abdominal/physiopathology
- Aortic Rupture/physiopathology
- Aortic Rupture/prevention & control
- Collagenases/metabolism
- Desmosine/analysis
- Elastin/analysis
- Gelatinases/metabolism
- Guinea Pigs
- Male
- Matrix Metalloproteinase 2
- Matrix Metalloproteinase 9
- Metalloendopeptidases/metabolism
- Muscle, Smooth, Vascular/pathology
- Muscle, Smooth, Vascular/physiology
- Muscle, Smooth, Vascular/transplantation
- Rats
- Rats, Inbred F344
- Recombinant Proteins/biosynthesis
- Tissue Inhibitor of Metalloproteinase-1/biosynthesis
- Tissue Inhibitor of Metalloproteinase-1/genetics
- Tissue Inhibitor of Metalloproteinase-2/biosynthesis
- Tissue Inhibitor of Metalloproteinase-3/biosynthesis
- Transfection
- Transplantation, Heterologous
Collapse
Affiliation(s)
- E Allaire
- Service de Chirurgie Vasculaire, Hôpital H. Mondor, 94010 Créteil, France
| | | | | | | | | |
Collapse
|
|
26
|
Koivunen AL, Maisi P, Konttinen YT, Prikk K, Sandholm M. Collagenolytic activity and its sensitivity to doxycycline inhibition in tracheal aspirates of horses with chronic obstructive pulmonary disease. Acta Vet Scand 1997. [PMID: 9129342 DOI: 10.1186/bf03548503] [Citation(s) in RCA: 21] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
The collagenolytic activity and its sensitivity to doxycycline inhibition in tracheal aspirates (TA) of horses with chronic obstructive pulmonary disease (COPD) was analyzed with SDS-PA gel electrophoresis (SDS-PAGE), using Type 1 collagen as the substrate. Both autoactive and total collagenase activities were significantly higher in TAs of horses with symptomatic COPD than in TAs of healthy horses. Doxycycline inhibition studies suggest that most of the TA collagenase is of the neutrophil type (MMP-8), but some is derived from other cells such as fibroblasts and monocyte/macrophages (MMP-1) and bacteria (bacterial collagenases). Drugs inhibiting collagenases in the respiratory tract might be worth a trial in the treatment of COPD in horses.
Collapse
|
|
27
|
Lee HM, Golub LM, Chan D, Leung M, Schroeder K, Wolff M, Simon S, Crout R. alpha 1-Proteinase inhibitor in gingival crevicular fluid of humans with adult periodontitis: serpinolytic inhibition by doxycycline. J Periodontal Res 1997; 32:9-19. [PMID: 9085238 DOI: 10.1111/j.1600-0765.1997.tb01377.x] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
The serum protein, alpha 1-proteinase inhibitor (alpha 1-PI), defends the host against serine proteinases, e.g. PMN elastase. Using a rabbit anti-serum against human alpha 1-PI, this protein in GCF was quantified from a standard curve constructed from dot-blot analysis and characterized by Western blot. GCF was collected on filter paper strips from healthy (H), gingivitis (G) and adult periodontitis (AP) patients, then extracted with Tris/NaCl/CaCl2 buffer, pH 7.6. alpha 1-PI concentration increased with G and was highest in AP subjects. H sites only showed intact alpha 1-PI (52 kDa); no degradation fragments (48 kDa) were detected. In G and AP subjects, alpha 1-PI degradation fragments were seen in 17% and 71% of GCF samples, respectively. Both collagenase and alpha 1-PI-degrading activities in GCF increased with severity of inflammation (GCF flow). Moreover, the alpha 1-PI degrading (or serpinolytic) activity was characterized as a matrix metalloproteinase, probably collagenase, based on its in vitro response to a panel of different proteinase inhibitors including doxycycline. We propose: (1) that collagenase promotes periodontal breakdown not only by degrading collagen, but also by depleting alpha 1-PI regulation of elastase and other serine-proteinases, thereby favoring a broader attack on extracellular matrix (ECM) constituents, and (2) based on a recent longitudinal double-blind study using the techniques described above for alpha 1-PI analysis, that low-dose doxycycline administration to humans with adult periodontitis can inhibit this broad cascade of ECM degradation.
Collapse
Affiliation(s)
- H M Lee
- Department of Oral Biology and Pathology, School of Dental Medicine, SUNY at Stony Brook 11794, USA
| | | | | | | | | | | | | | | |
Collapse
|
|
28
|
Koivunen AL, Maisi P, Konttinen YT, Prikk K, Sandholm M. Collagenolytic activity and its sensitivity to doxycycline inhibition in tracheal aspirates of horses with chronic obstructive pulmonary disease. Acta Vet Scand 1997; 38:9-16. [PMID: 9129342 PMCID: PMC8057019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
The collagenolytic activity and its sensitivity to doxycycline inhibition in tracheal aspirates (TA) of horses with chronic obstructive pulmonary disease (COPD) was analyzed with SDS-PA gel electrophoresis (SDS-PAGE), using Type 1 collagen as the substrate. Both autoactive and total collagenase activities were significantly higher in TAs of horses with symptomatic COPD than in TAs of healthy horses. Doxycycline inhibition studies suggest that most of the TA collagenase is of the neutrophil type (MMP-8), but some is derived from other cells such as fibroblasts and monocyte/macrophages (MMP-1) and bacteria (bacterial collagenases). Drugs inhibiting collagenases in the respiratory tract might be worth a trial in the treatment of COPD in horses.
Collapse
Affiliation(s)
- A.-L. Koivunen
- Department of Clinical Veterinary Sciences, Faculty of Veterinary Medicine, University of Helsinki, P.O. Box 57, Hämeentie 57, Helsinki, FIN-00014 Finland
| | - P. Maisi
- Department of Clinical Veterinary Sciences, Faculty of Veterinary Medicine, University of Helsinki, P.O. Box 57, Hämeentie 57, Helsinki, FIN-00014 Finland
| | - Y. T. Konttinen
- Division of Rheumatic Disease, Department of Medicine, University Central Hospital, Helsinki, Finland
| | - K. Prikk
- Division of Rheumatic Disease, Department of Medicine, University Central Hospital, Helsinki, Finland
| | - M. Sandholm
- Department of Clinical Veterinary Sciences, Faculty of Veterinary Medicine, University of Helsinki, P.O. Box 57, Hämeentie 57, Helsinki, FIN-00014 Finland
| |
Collapse
|
|
29
|
Pourtaghi N, Radvar M, Mooney J, Kinane DF. The effect of subgingival antimicrobial therapy on the levels of stromelysin and tissue inhibitor of metalloproteinases in gingival crevicular fluid. J Periodontol 1996; 67:866-70. [PMID: 8884643 DOI: 10.1902/jop.1996.67.9.866] [Citation(s) in RCA: 22] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
Recent investigations imply that a key mechanism in the pathogenesis of periodontal disease may be the ability of oral microorganisms to induce production and/or activation of matrix metalloproteinases (MMPs) in the host tissues. It has been suggested that the pharmacologic inhibition of MMP activity could play an important role in achieving a desirable outcome in periodontal therapy. The efficacy of locally delivered antibiotics on the level of gingival crevicular fluid (GCF) stromelysin (SL) and tissue inhibitor of metalloproteinases (TIMP) on sites with a history of a poor response to mechanical treatment was studied. Fifty-two patients with 4 periodontal pockets > or = 5 mm and bleeding on probing were randomized into four groups of 13 patients. One group received scaling and root planing alone and the other three groups received scaling and root planing plus a locally delivered antimicrobial system. These included 25% tetracycline fiber, 2% minocycline gel, and 25% metronidazole gel. The GCF samples taken at baseline and 6 weeks after treatments were analyzed using an enzyme linked immunosorbent assay (ELISA). GCF SL levels significantly decreased after adjunctive tetracycline fiber (paired t-test, P = 0.020) and minocycline gel (paired t-test, P = 0.023) treatments whereas it remained almost unchanged in the other two groups. While the GCF TIMP level did not change significantly in the scaling and root planing alone group, it significantly increased for all three adjunctive antimicrobial treatments (for tetracycline fiber P < 0.001, minocycline gel P = 0.005, metronidazole gel P < 0.001). The use of adjunctive locally delivered antimicrobial systems, particularly the tetracycline family, may offer an advantage in changing the metalloproteinase profile of the GCF to one more compatible with periodontal health.
Collapse
Affiliation(s)
- N Pourtaghi
- Periodontal Unit, Adult Dental Care Department, Glasgow Dental Hospital and School, UK
| | | | | | | |
Collapse
|
|
30
|
Crout RJ, Lee HM, Schroeder K, Crout H, Ramamurthy NS, Wiener M, Golub LM. The "cyclic" regimen of low-dose doxycycline for adult periodontitis: a preliminary study. J Periodontol 1996; 67:506-14. [PMID: 8724709 DOI: 10.1902/jop.1996.67.5.506] [Citation(s) in RCA: 75] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Specially-formulated low-dose doxycycline (LDD) regimens have been found to reduce collagenase activity in the gingival tissues and crevicular fluid (GCF) of adult periodontitis subjects in short-term studies. In the current, double-blind, placebo-controlled study, adult periodontitis patients were administered for 6 months a "cyclical" regimen of either LDD or placebo capsules; and various clinical parameters of periodontal disease severity, and both collagenase activity and degradation of the serum protein, alpha 1-PI, in the GCF were measured at different time periods. No significant differences between the LDD- and placebo-treated groups were observed for plaque index and gingival index. However, attachment levels, probing depth, and GCF collagenase activity and alpha 1-PI degradation were all beneficially and significantly (P < 0.05) affected by the drug regimen. We propose: 1) that LDD inhibits tissue destruction in the absence of either antimicrobial or significant anti-inflammatory efficacy; and 2) that long-term LDD could be a useful adjunct to instrumentation therapy in the management of the adult periodontitis patient.
Collapse
Affiliation(s)
- R J Crout
- Department of Periodontology, West Virginia University, Morgantown, USA
| | | | | | | | | | | | | |
Collapse
|
|
31
|
Nordstrom D, Lindy O, Konttinen YT, Lauhio A, Sorsa T, Friman C, Pettersson T, Santavirta S. Cathepsin G and elastase in synovial fluid and peripheral blood in reactive and rheumatoid arthritis. Clin Rheumatol 1996; 15:35-41. [PMID: 8929773 DOI: 10.1007/bf02231682] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
The purpose of the study was to evaluate the involvement of serine proteinases cathepsin G and elastase on pathomechanisms in synovial fluid (SF) of patients with reactive (ReA) and rheumatoid, (RA) arthritis. Cathepsin G, elastase, and their endogenous inhibitors alpha1-antichymotrypsin (alpha1-ACT) and alpha1-proteinase inhibitor (alpha1-PI) were identified immunohistochemically from SF and peripheral blood (PB) of patients with ReA and RA. Cathepsin G and elastase activities in SF and PB were measured spectrophotometrically. Dot-immunostaining was used to identify cathepsin G, elastase, but also alpha1-ACT and alpha1-PI from SF and PB. Cathepsin G and elastase-like activities (IU/I) were slightly elevated in ReA SF compared to the corresponding peripheral blood values (11.4 +/- 9.2 vs 4.8 +/- 1.7, NS, and 5.1 +/- 2.8 vs 2.3 +/- 2.2, NS), which was similar to what was seen in RA (16.4 +/- 6.2 vs 0.53 +/- 0.4, p < 0.05, and 6.51 +/- 1.8 vs 1.22 +/- 0.58, p < 0.05). Although some samples did not contain cathepsin G and/or elastase-like activities, all samples contained immunoreactive enzyme, but also alpha1-ACT and alpha1-PI. In ReA SF, in contrast to monocytes, all polymorphonuclear (PMN) cells contained cathepsin G and elastase. Cathepsin G and elastase activities correlated with each other (r = 0.78, p < 0.05) suggesting PMN / primary granules as their likely source. There was a closer association between the cathepsin G or elastase and SF leukocyte count in ReA than in RA. In ReA and RA SF elevated cathepsin G and elastase activities are detected compared to activity levels in PB suggesting local production mainly from PMNs. The co-existence of highly cellular SF and cathepsin G and elastase activity in the documented presence of endogenous inhibitors in ReA SF together with the, known, usually self-remitting clinical course of ReA, suggest a brisk and even exaggerated local PMN serine proteinase release; sparing of joints does not seem to be due to lack or inhibition of PMN responses but rather to a successful down-regulation or cessation of the responses initially elicited.
Collapse
Affiliation(s)
- D Nordstrom
- Department of Medicine, Helsinki University Central Hospital, Finland
| | | | | | | | | | | | | | | |
Collapse
|
|
32
|
Lauhio A, Salo T, Ding Y, Konttinen YT, Nordström D, Tschesche H, Lähdevirta J, Golub LM, Sorsa T. In vivo inhibition of human neutrophil collagenase (MMP-8) activity during long-term combination therapy of doxycycline and non-steroidal anti-inflammatory drugs (NSAID) in acute reactive arthritis. Clin Exp Immunol 1994; 98:21-8. [PMID: 7923879 PMCID: PMC1534162 DOI: 10.1111/j.1365-2249.1994.tb06601.x] [Citation(s) in RCA: 68] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
Abstract
We studied the in vivo effect of long-term doxycycline treatment combined with NSAID on human interstitial collagenases, other matrix metalloproteinases, serine proteinases, tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) and lactoferrin from saliva and serum during the course of acute reactive arthritis (ReA). Collagenase activity and serine proteases (elastase-like, cathepsin G-like and trypsin-like activities) of saliva (n = 10) and gelatinase, lactoferrin and TIMP-1 of saliva (n = 10) and serum (n = 10) samples before and after 2 months doxycycline treatment, combined with NSAID, were studied by quantitative SDS-PAGE assay, ELISA assay and by spectrophotometric assay. The cellular source and molecular forms of salivary collagenase were characterized by immunoblotting using specific antisera. We found that activities of total and endogenously active interstitial collagenase reduced significantly. The salivary collagenase was found to originate from neutrophils. No fragmentation of either pro 75-kD and active 65-kD MMP-8 was detected after 2 months doxycycline treatment. However, during 2 months doxycycline and NSAID treatment no reduction of salivary and serum gelatinase, lactoferrin and TIMP-1-levels and salivary serine protease activities were detected. The in vivo inhibition of collagenase (MMP-8) activity during long-term doxycycline therapy in human saliva containing inflammatory exudate of ReA patients may contribute to the reduced tissue destruction observed in recent clinical and animal model studies in arthritides during long-term doxycycline/tetracycline treatment.
Collapse
Affiliation(s)
- A Lauhio
- Department of Bacteriology, University of Helsinki, Finland
| | | | | | | | | | | | | | | | | |
Collapse
|
|
33
|
Golub LM, Evans RT, McNamara TF, Lee HM, Ramamurthy NS. A non-antimicrobial tetracycline inhibits gingival matrix metalloproteinases and bone loss in Porphyromonas gingivalis-induced periodontitis in rats. Ann N Y Acad Sci 1994; 732:96-111. [PMID: 7978855 DOI: 10.1111/j.1749-6632.1994.tb24728.x] [Citation(s) in RCA: 91] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Affiliation(s)
- L M Golub
- Department of Oral Biology & Pathology, School of Dental Medicine, State University of New York at Stony Brook 11794-8702
| | | | | | | | | |
Collapse
|
|
34
|
Mallya SK, Hall JE, Lee HM, Roemer EJ, Simon SR, Golub LM. Interaction of matrix metalloproteinases with serine protease inhibitors. New potential roles for matrix metalloproteinase inhibitors. Ann N Y Acad Sci 1994; 732:303-14. [PMID: 7978799 DOI: 10.1111/j.1749-6632.1994.tb24745.x] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Affiliation(s)
- S K Mallya
- Department of Biochemistry and Cell Biology, State University of New York at Stony Brook 11794
| | | | | | | | | | | |
Collapse
|
|
35
|
Sorsa T, Ding Y, Salo T, Lauhio A, Teronen O, Ingman T, Ohtani H, Andoh N, Takeha S, Konttinen YT. Effects of tetracyclines on neutrophil, gingival, and salivary collagenases. A functional and western-blot assessment with special reference to their cellular sources in periodontal diseases. Ann N Y Acad Sci 1994; 732:112-31. [PMID: 7978785 DOI: 10.1111/j.1749-6632.1994.tb24729.x] [Citation(s) in RCA: 128] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
The characterization and regulation of matrix metalloproteinases (MMPs) have been studied to determine their role(s) in periodontal tissue destruction. Progress in elucidating the roles of MMPs in periodontal tissue destruction has led to a new concept involving the chemotherapeutic inhibition on MMPs, a therapeutic strategy which less than a decade ago was considered "a difficult and perhaps impossible task." Tetracyclines/doxycycline (DOXY) and their chemically modified nonantimicrobial derivatives (CMTs) are known to inhibit the matrix metalloproteinases, especially preferring human neutrophil collagenase (MMP-8), and prevent the oxidative activation of procollagenases. We characterized by Western blotting the molecular forms and cellular sources of gingival tissue, dental plaque, gingival crevicular fluid (GCF), and salivary MMPs associated with periodontitis. Also the molecular forms of tissue inhibitors of matrix metalloproteinases (TIMP-1 and TIMP-2) in periodontitis were studied by Western blot. Neutrophil (PMN)-derived MMPs were found to predominate in periodontitis, and phospholipase C present in increased amounts in periodontitis sites was found to be a potential inducer of PMN degranulation. We further studied the effects of DOXY on molecular forms of different latent and active MMPs purified from different cellular sources (PMNs, fibroblasts, keratinocytes) and present in vivo in oral exudates (gingival extracts, GCF, and saliva). DOXY inhibition of activated (oxidatively or proteolytically) MMPs were not associated with MMP fragmentation. Michaelis-Menten plots of initial rates of degradation of soluble type I collagen revealed an apparent Km value of 0.3-0.6 microM for MMP-8, and 75 microM DOXY inhibited MMP-8 in a manner which did not result in changes in apparent Km value but did prevent the initial degradation reaching Vmax providing evidence for noncompetitive inhibition. Treatment of patients with long-term DOXY medication results in decreased MMP-8 activities/levels in gingival tissue, crevicular fluid, and saliva, but not fragmentation of MMP-8 in vivo. These data further support and extend the key role of PMN-MMPs in periodontitis, and the activities of these PMN MMPs can be inhibited directly by therapeutic levels of DOXY.
Collapse
Affiliation(s)
- T Sorsa
- Department of Periodontology, University of Helsinki, Finland
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
36
|
Lauhio A, Konttinen YT, Tschesche H, Nordström D, Salo T, Lähdevirta J, Golub LM, Sorsa T. Reduction of matrix metalloproteinase 8-neutrophil collagenase levels during long-term doxycycline treatment of reactive arthritis. Antimicrob Agents Chemother 1994; 38:400-2. [PMID: 8192476 PMCID: PMC284468 DOI: 10.1128/aac.38.2.400] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023] Open
Abstract
The aim of this work was to determine whether human polymorphonuclear neutrophilic interstitial collagenase (matrix metalloproteinase 8 [MMP-8]) levels are reduced during long-term doxycycline treatment in humans with reactive arthritis. Serum MMP-8 levels were reduced (mean +/- standard error of the mean, 678.9 +/- 185.6 versus 491.2 +/- 144.8 ng of MMP-8 per ml), but not statistically significantly. However, the reduction of salivary MMP-8 levels was statistically significant (3,729 +/- 1,905.3 versus 1,866 +/- 780.0 ng of MMP-8 per ml, P < 0.05). This study demonstrated that a 2-month regimen of doxycycline can reduce MMP-8 levels in serum and especially in body fluids (i.e., saliva) containing inflammatory exudates and thus may contribute to reduced tissue destruction.
Collapse
Affiliation(s)
- A Lauhio
- Department of Internal Medicine, Aurora Hospital, Helsinki, Finland
| | | | | | | | | | | | | | | |
Collapse
|
|
37
|
Lauhio A, Sorsa T, Lindy O, Suomalainen K, Saari H, Golub LM, Konttinen YT. The regulatory role of doxycycline/tetracycline in collagenolytic activity and tissue destruction in joint diseases: comment on the article by Yu et al. ARTHRITIS AND RHEUMATISM 1993; 36:1335-6. [PMID: 8216431 DOI: 10.1002/art.1780360924] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
|