Systemic MMP inhibition for periodontal wound repair: results of a multi‐centre randomized‐controlled clinical trial

Gapski, Ricardo; Hastürk, Hatice; Dyke, Thomas E. Van; Oringer, Richard J.; Wang, Shufang; Braun, Thomas; Giannobile, William V.

doi:10.1111/j.1600-051x.2008.01351.x

Cited by 43 publications

(27 citation statements)

References 44 publications

(44 reference statements)

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“…Therefore, MMPs may represent a potential therapeutic target to limit morbidity and mortality. Doxycycline is a licensed MMP inhibitor in the United States used to treat periodontal disease (30) and has been proposed as an agent to limit pathology in other infectious and inflammatory diseases (31)(32)(33)(34). Doxycycline suppressed multiple MMPs in cellular models (A) 7H11 agar impregnated with doxycycline 2 mg/ml completely suppresses growth of Mtb at 14 days.…”

Section: Discussionmentioning

confidence: 99%

“…Consequently, doxycycline may reduce pathology in human TB by effects on both MMP gene transcription and activity. Doxycycline is used in periodontal disease at a low dose of 20 mg twice daily (30) and so may also be effective at suppressing immunopathologic MMPs in TB with this regime. Doxycycline also suppressed TNF-a secretion, a key cytokine in the immune response to TB (7).…”

Section: Discussionmentioning

confidence: 99%

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Doxycycline and HIV Infection Suppress Tuberculosis-induced Matrix Metalloproteinases

Walker

Clark²,

Oni

et al. 2012

Am J Respir Crit Care Med

121

136

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Rationale: Tuberculosis kills more than 1.5 million people per year, and standard treatment has remained unchanged for more than 30 years. Tuberculosis (TB) drives matrix metalloproteinase (MMP) activity to cause immunopathology. In advanced HIV infection, tissue destruction is reduced, but underlying mechanisms are poorly defined and no current antituberculous therapy reduces host tissue damage. Objectives: To investigate MMP activity in patients with TB with and without HIV coinfection and to determine the potential of doxycycline to inhibit MMPs and decrease pathology. Methods: Concentrations of MMPs and cytokines were analyzed by Luminex array in a prospectively recruited cohort of patients. Modulation of MMP secretion and Mycobacterium tuberculosis growth by doxycycline was studied in primary human cells and TB-infected guinea pigs. Measurements and Main Results: HIV coinfection decreased MMP concentrations in induced sputum of patients with TB. MMPs correlated with clinical markers of tissue damage, further implicating dysregulated protease activity in TB-driven pathology. In contrast, cytokine concentrations were no different. Doxycycline, a licensed MMP inhibitor, suppressed TB-dependent MMP-1 and -9 secretion from primary human macrophages and epithelial cells by inhibiting promoter activation. In the guinea pig model, doxycycline reduced lung TB colony forming units after 8 weeks in a dose-dependent manner compared with untreated animals, and in vitro doxycycline inhibited mycobacterial proliferation. Conclusions: HIV coinfection in patients with TB reduces concentrations of immunopathogenic MMPs. Doxycycline decreases MMP activity in a cellular model and suppresses mycobacterial growth in vitro and in guinea pigs. Adjunctive doxycycline therapy may reduce morbidity and mortality in TB.Keywords: lung; mycobacteria; immunopathology; protease inhibitors Tuberculosis (TB) continues to kill more than 1.5 million people a year (1). Standard treatment for TB has remained unchanged for more than 30 years (2), and multidrug-and extensively drugresistant strains are progressively emerging (3, 4). Mortality rates remain high among patients even after they have commenced TB treatment (5, 6). A characteristic hallmark of TB is tissue destruction, causing morbidity, mortality, and transmission of infection. However, the mediators of this immunopathology are incompletely understood (7,8), preventing the design of rational therapies to reduce immunemediated host damage and improve outcomes in TB.TB is primarily a disease of the lung (9, 10). In advanced HIV infection, with severely reduced CD4 cell counts, TB infection is common, but there is reduced tissue destruction and cavitation rarely occurs (11). The underlying cause of divergent pathology in HIV-TB coinfection is poorly defined, and greater understanding of this tissue destruction may identify novel therapeutic approaches to limit morbidity and mortality. The biochemistry of the lung extracellular matrix predicts that matrix metalloproteinases (MMPs) will be ...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Doxycycline and HIV Infection Suppress Tuberculosis-induced Matrix Metalloproteinases

Walker

Clark²,

Oni

et al. 2012

Am J Respir Crit Care Med

121

136

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“…Doxycycline has been used in sub-antimicrobial doses to decrease the concentration of collagenases in periodontal disease (83). Its use has also been shown to improve pulmonary function in chronic obstructive pulmonary disease (84) and patients with asthma when added to standard therapies (85).…”

Section: Is There a Role For Immunotherapy In Tb?mentioning

confidence: 99%

Tuberculosis, Pulmonary Cavitation, and Matrix Metalloproteinases

Elkington

Friedland

2014

Am J Respir Crit Care Med

178

179

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Tuberculosis (TB), a chronic infectious disease of global importance, is facing the emergence of drug-resistant strains with few new drugs to treat the infection. Pulmonary cavitation, the hallmark of established disease, is associated with very high bacillary burden. Cavitation may lead to delayed sputum culture conversion, emergence of drug resistance, and transmission of the infection. The host immunological reaction to Mycobacterium tuberculosis is implicated in driving the development of TB cavities. TB is characterized by a matrix-degrading phenotype in which the activity of proteolytic matrix metalloproteinases (MMPs) is relatively unopposed by the specific tissue inhibitors of metalloproteinases. Proteases, in particular MMPs, secreted from monocyte-derived cells, neutrophils, and stromal cells, are involved in both cell recruitment and tissue damage and may cause cavitation. MMP activity is augmented by proinflammatory chemokines and cytokines, is tightly regulated by complex signaling paths, and causes matrix destruction. MMP concentrations are elevated in human TB and are closely associated with clinical and radiological markers of lung tissue destruction. Immunomodulatory therapies targeting MMPs in preclinical and clinical trials are potential adjuncts to TB treatment. Strategies targeting patients with cavitary TB have the potential to improve cure rates and reduce disease transmission.

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“…The only licensed MMP inhibitor in the USA is doxycycline, which is used in patients at sub-antimicrobial doses to reduce collagenase activity in periodontal disease [79]. Accumulating evidence demonstrates that doxycycline can suppress immunemediated tissue damage in a variety of inflammatory conditions, such as atherosclerosis [80,81], arthritis [82][83][84], neurocysticercosis [85] and Gram-positive infections [86,87].…”

Section: Regulation Of Mmp Expressionmentioning

confidence: 99%

Matrix metalloproteinases in tuberculosis

Elkington¹,

Ugarte-Gil²,

Friedland³

2011

European Respiratory Journal

110

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Tuberculosis (TB) remains a global health pandemic. Infection is spread by the aerosol route and Mycobacterium tuberculosis must drive lung destruction to be transmitted to new hosts. Such inflammatory tissue damage is responsible for morbidity and mortality in patients. The underlying mechanisms of matrix destruction in TB remain poorly understood but consideration of the lung extracellular matrix predicts that matrix metalloproteinases (MMPs) will play a central role, owing to their unique ability to degrade fibrillar collagens and other matrix components. Since we proposed the concept of a matrix degrading phenotype in TB a decade ago, diverse data implicating MMPs as key mediators in TB pathology have accumulated. We review the lines of investigation that have indicated a critical role for MMPs in TB pathogenesis, consider regulatory pathways driving MMPs and propose that inhibition of MMP activity is a realistic goal as adjunctive therapy to limit immunopathology in TB.

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Systemic MMP inhibition for periodontal wound repair: results of a multi‐centre randomized‐controlled clinical trial

Abstract: The results from this multi-centre study suggests that SDD in combination with surgery improves the short-term response of periodontal therapy by reducing PD, increasing CAL gain and inhibiting early stage bone resorption.

Cited by 43 publications

References 44 publications

Doxycycline and HIV Infection Suppress Tuberculosis-induced Matrix Metalloproteinases

Doxycycline and HIV Infection Suppress Tuberculosis-induced Matrix Metalloproteinases

Tuberculosis, Pulmonary Cavitation, and Matrix Metalloproteinases

Matrix metalloproteinases in tuberculosis

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