Understanding resolution of inflammation in periodontal diseases: Is chronic inflammatory periodontitis a failure to resolve?

Periodontitis is an infectious-inflammatory disease that results from loss of balance between the commensal microbiome and the host response. The hyper-inflammatory, uncontrolled inflammatory immune lesion promotes tissue damage and impedes effective bacterial clearance. In this review, the relationship between the microbiome and the inflammatory/immune response is explored in the context of a bi-directional pathogenesis; bacteria induce inflammation and inflammation modifies the growth environment causing shifts in the composition of the microbiome. Resolution of inflammation is an active, receptor-mediated process induced by specialized pro-resolving lipid mediators. Inflammatory disease may, therefore, be the result of failure of resolution. Failure to resolve inflammation coupled with resultant microbiome changes is hypothesized to drive development of periodontitis. Re-establishment of microbiome/host homeostasis by specialized pro-resolving lipid mediator therapy suggests that microbiome dysbiosis, the host hyperinflammatory phenotype, and periodontitis can be reversed.

Development and validation of a predictive model for periodontitis using NHANES 2011-2012 data.

AIM: To develop and validate a predictive model for moderate-to-severe periodontitis in the adult USA population, with data from the 2011-2012 National Health and Nutrition Examination Survey (NHANES) cycle. MATERIAL AND METHODS: A subset of 3017 subjects aged >30 years, with >14 teeth present and having received a periodontal examination in addition to data collected on cardio-metabolic risk measures (smoking habit, body mass index [BMI], blood pressure, total cholesterol and glycated haemoglobin [HbA1c]) were used for model development by multivariable logistic regression. RESULTS: The prevalence of moderate and severe periodontitis using CDC/AAP classification was 37.1% and 13.2%, respectively. A multivariable logistic regression model revealed that HbA1c ≥5.7% was significantly associated with moderate-to-severe periodontitis (odds ratio, OR = 1.29; p < 0.01). A predictive model including age, gender, ethnicity, HbA1c and smoking habit as variables had 70.0% sensitivity and 67.6% specificity in detecting moderate-to-severe periodontitis in US adults. CONCLUSIONS: Periodontitis is a common disease in North American adults, and its prevalence is significantly higher in individuals with pre-diabetes or diabetes. The present study demonstrates that a model including age, gender, ethnicity, HbA1c and smoking habit could be used as a reliable screening tool for periodontitis in primary medical care settings to facilitate referral of patients at risk for periodontal examination and diagnosis.

Lack of p47(phox) in Akita Diabetic Mice Is Associated with Interstitial Pneumonia, Fibrosis, and Oral Inflammation.

Excess reactive oxygen species production is central to the development of diabetic complications. The contribution of leukocyte reactive oxygen species produced by the NADPH oxidase to altered inflammatory responses associated with uncontrolled hyperglycemia is poorly understood. To get insight into the role of phagocytic superoxide in the onset of diabetic complications, we used a model of periodontitis in mice with chronic hyperglycemia and lack of leukocyte p47(phox) (Akita/Ncf1) bred from C57BL/6-Ins2(Akita)/J (Akita) and neutrophil cytosolic factor 1 knockout (Ncf1) mice. Akita/Nfc1 mice showed progressive cachexia starting at early age and increased mortality by six months. Their lungs developed infiltrative interstitial lesions that obliterated air spaces as early as 12 weeks when fungal colonization of lungs also was observed. Neutrophils of Akita/Ncf1 mice had normal degranulation and phagocytic efficiency when compared with wild-type mice. Although Akita/Ncf1 mice had increased prevalence of oral infections and more severe periodontitis compared with wild-type mice, bone loss was only marginally higher compared with Akita and Ncf1 null mice. Altogether these results indicate that lack of leukocyte superoxide production in mice with chronic hyperglycemia results in interstitial pneumonia and increased susceptibility to infections.

Nuclear Factor Erythroid 2-Related Factor 2 Down-Regulation in Oral Neutrophils Is Associated with Periodontal Oxidative Damage and Severe Chronic Periodontitis.

The balance between reactive oxygen species and antioxidants plays an important role in periodontal health. We previously demonstrated that high reactive oxygen species production by oral polymorphonuclear neutrophils (oPMNs) in chronic periodontitis (CP) refractory to conventional therapy is associated with severe destruction of periodontium. Herein, we show that inhibition of antioxidant production through down-regulation of nuclear factor erythroid 2-related factor 2 (Nrf2) pathway in oPMN, despite enhanced recruitment in the oral cavity, is associated with severe CP. Twenty-four genes in the Nrf2-mediated oxidative stress response pathway were down-regulated in PMNs of diseased patients. Downstream of Nrf2, levels of oPMN superoxide dismutase 1 and catalase were decreased in severe CP, despite increased recruitment. Nrf2(-/-) mice had more severe loss of periodontium in response to periodontitis-inducing subgingival ligatures compared with wild-types. Levels of 8-hydroxy-deoxyguanosine were increased in periodontal lesions of Nrf2(-/-) mice, indicating high oxidative damage. We report, for the first time, Nrf2 pathway down-regulation in oPMNs of patients with severe CP. PMNs of CP patients may be primed for low antioxidant response in the context of high recruitment in the oral cavity, resulting in increased oxidative tissue damage.

Adseverin plays a role in osteoclast differentiation and periodontal disease-mediated bone loss.

Osteoclast differentiation and function are highly dependent on the assembly and turnover of actin filaments, but little is known about the roles of actin binding proteins in these processes. Adseverin (Ads), a member of the gelsolin superfamily of actin capping and severing proteins, regulates actin filament turnover and can regulate the turnover of cortical actin filaments of chromaffin cells during exocytosis. Using a conditional Ads knockout mouse model, we confirmed our previous finding in cultured cells that Ads plays a role in osteoclastogenesis (OCG) and actin cytoskeletal organization in osteoclasts. Here we show that Ads is required for osteoclast formation and that when alveolar bone resorption is experimentally induced in mice, genetic deletion of Ads prevents osteoclast-mediated bone loss. Further, when Ads-null osteoclasts are cultured, they exhibit defective OCG, disorganized podosome-based actin filament superstructures, and decreased bone resorption. Reintroduction of Ads into Ads-null osteoclast precursor cells restored these osteoclast defects. Collectively, these data demonstrate a unique and osteoclast-specific role for Ads in OCG and osteoclast function.

Rac-null leukocytes are associated with increased inflammation-mediated alveolar bone loss.

Periodontitis is characterized by altered host-biofilm interactions that result in irreversible inflammation-mediated alveolar bone loss. Genetic and epigenetic factors that predispose to ineffective control of biofilm composition and maintenance of tissue homeostasis are not fully understood. We elucidated how leukocytes affect the course of periodontitis in Rac-null mice. Mouse models of acute gingivitis and periodontitis were used to assess the early inflammatory response and patterns of chronicity leading to loss of alveolar bone due to inflammation in Rac-null mice. Leukocyte margination was differentially impaired in these mice during attachment in conditional Rac1-null (granulocyte/monocyte lineage) mice and during rolling and attachment in Rac2-null (all blood cells) mice. Inflammatory responses to subgingival ligatures, assessed by changes in peripheral blood differential leukocyte numbers, were altered in Rac-null compared with wild-type mice. In response to persistent subgingival ligature-mediated challenge, Rac-null mice had increased loss of alveolar bone with patterns of resorption characteristic of aggressive forms of periodontitis. These findings were partially explained by higher osteoclastic coverage of the bone-periodontal ligament interface in Rac-null compared with wild-type mice. In conclusion, this study demonstrates that leukocyte defects, such as decreased endothelial margination and tissue recruitment, are rate-limiting steps in the periodontal inflammatory process that lead to more aggressive forms of periodontitis.

Diabetes mellitus and periodontal diseases.

A bidirectional relationship between diabetes mellitus (DM) and periodontal diseases (PDs) has been established. It is estimated that patients with poorly controlled DM are 3 times more likely to develop chronic PD compared with normoglycemic individuals despite similar composition in subgingival biofilms. Furthermore, these patients present with increased severity and rapid progression of attachment loss around teeth resulting in edentulism. Treatment of PD results in a modest but significant improvement in glycemic control in patients with DM reflected by a 0.4 % reduction in HbA1c-glycated hemoglobin levels. Compelling evidence from in vitro and animal studies supports a plausible biological explanation for the relationship between the 2 conditions centered on systemic low-grade inflammation. However, the limited number of comparable large randomized clinical trials is reflected in the limited specific guidelines offered by the international organizations for DM and PD regarding the management of the 2 diseases in an individual.

Macrophage subsets and osteoimmunology: tuning of the immunological recognition and effector systems that maintain alveolar bone.

Chronic and aggressive periodontal diseases are characterized by the failure to resolve local inflammation against periodontopathogenic bacteria in the subgingival biofilm. Alveolar bone resorption is associated with altered innate and adaptive immune responses to periodontal pathogens. Macrophage-derived cytokines, chemokines and growth factors, present in both destructive and reparative phases of periodontitis, are elevated in numerous animal and human studies. Macrophage polarization to either a predominantly pro-inflammatory or anti-inflammatory phenotype may be a critical target for monitoring disease activity, modulating immune responses to subgingival biofilms in patients at risk and reducing alveolar bone loss.

Oral Neutrophil Free Fatty Acid Receptors Expression May Link Oral Host and Microbiome Lipid Metabolism.

In health, commensal bacteria from oral biofilms stimulate polymorphonuclear neutrophil (PMN) recruitment in gingival sulci and the oral cavity. Oral PMN (oPMN) is short-lived cells with low prosurvival gene expression. In periodontitis, oPMN accumulates in higher numbers, has extended lifespan, and sustains nonresolving inflammation. We hypothesize that short- and long-chain free fatty acids (SCFAs and LCFAs) and lipid mediator resolvin E1 (RvE1) modulate host ability to control biofilms and resolve inflammation. Our objective was to measure oPMN surface expression of receptors FFAR2 (binds bacteria-derived SCFA), FFAR4 (binds LCFA, EPA, and DHA), and ERV1 (binds RvE1) in health and to assess sex differences. We included 20 periodontally healthy individuals aged 20-80 years (10 males, 10 females), who were asked to (1) answer a targeted health nutritional questionnaire and (2) provide an oral saline rinse. oPMN isolated by sequential filtration was labeled with fluorophore-conjugated antibodies against CD11b, CD14, CD16, CD66b, ERV1, FFAR2, and FFAR4 and analyzed by flow cytometry. Statistical analyses were the following: two-way ANOVA, Tukey's test, and Pearson's correlation. Oral rinses contained 80% oPMN of which 60% were ERV1+ and FFAR2+, and 10% FFAR4+, with no sex differences. Females had more oPMN ERV1 compared to males. Both sexes had higher ERV1 compared to FFAR2 and FFAR4. CD66b+CD16high oPMN expressed less ERV1 and FFAR2 compared to CD66b+CD16low. There were positive correlations between oPMN ERV1 and FFAR2 expression and between ERV1+ and FFAR2+ oPMN and fish intake. These findings will help to better understand how oral host and microbiome interactions maintain periodontal health.

Evaluation of Comprehensive COVID-19 Testing Program Outcomes in a US Dental Clinical Care Academic Setting.

Importance: Although many academic institutions have implemented infection control and prevention protocols, including regular asymptomatic self-testing, in response to the COVID-19 pandemic, the outcomes of mandatory surveillance testing programs at academic dental institutions that offer direct patient-facing clinical care has not yet been reported. Objective: To report the findings of a comprehensive surveillance COVID-19 testing program at an academic dental institution by assessing SARS-CoV-2 positivity rates and the potential association of test positivity with individual-level characteristics such as age, sex, and role. Design, Setting, and Participants: A retrospective cohort study was conducted using SARS-CoV-2 self-testing data from a mandatory surveillance program at the Harvard School of Dental Medicine. Test results obtained between August 24, 2020, and February 28, 2022, from students, faculty, and staff members were analyzed. Testing cadence varied from 1 to 3 times per week depending on risk status. The association of individual characteristics with test positivity was evaluated with univariate analyses and a bayesian multilevel logistic regression model. Exposures: Age by decade, sex, and role or position category (staff members, faculty, and students stratified by their involvement in clinical care activities), testing cadence, and testing date. Main Outcomes and Measures: Positive results from SARS-CoV-2 real-time reverse transcription-polymerase chain reaction self-tests were assessed. Results: Of the 390 study participants, 210 (53.8%) were women. Participants were grouped by age as follows: 20 to 29 years (190 [48.7%]), 30 to 39 years (88 [22.6%]), 40 to 49 years (44 [11.3%]), 50 to 59 years (42 [10.8%]), and 60 years or older (26 [6.7%]). Test results demonstrated an overall 0.27% positivity rate (61 test-positive cases), with a peak weekly positivity rate of 5.12% in the first week of January 2022. The mean (SD) test positivity rate among those involved in clinical activities was 0.25% (0.04) compared with 0.36% (0.09) among nonclinical participants. When adjusting for all considered covariates, test positivity was significantly associated with testing frequency (3 times vs 1 time per week: odds ratio [OR], 1.51 [95% credible interval (CrI), 1.07-3.69]) and timing of the test (after vs during the Alpha wave: OR, 0.33 [95% CrI, 0.11-0.88]; and Omicron vs Alpha: OR, 11.59 [95% CrI, 6.49-22.21]) but not with individual characteristics (age, sex, and role). Conclusions and Relevance: These findings suggest that implementing an adaptive testing cadence based on the risk status of individuals may be effective in reducing the risk of SARS-CoV-2 infection within an institution. In this study, involvement in clinical activities did not pose additional risk of SARS-CoV-2 infection compared with other in-person activities in the presence of these control measures.

Raman microspectroscopy/micro-optical coherence tomography approach for chairside diagnosis of periodontal diseases: A pilot study.

BACKGROUND: Our objective was to develop and test a combined Raman microspectroscopy (RMS) and micro-optical coherence tomography (µOCT) approach for chairside quantification of gingival collagen, DNA, epithelium, and connective tissue. We hypothesized that a high-resolution RMS/µOCT can characterize healthy and inflamed periodontal tissues for diagnosis and disease activity monitoring. METHODS: A prototype instrument was developed, tested ex vivo on gingival specimens and optimized for in vivo intraoral use. The primary outcome measures were the ratios of oral epithelium to connective tissue thickness (OE:CT) and the amount of DNA to collagen type I (DNA/Col 1), and the thickness of sulcular epithelium (SE). For ex vivo testing, eight subjects with healthy periodontal tissues or with Stage II to IV periodontitis were included in the study and underwent crown-lengthening or periodontal surgical procedures, respectively. Gingival biopsies were scanned by RMS/µOCT and histometric analyses were performed. The proof-of-concept study included OE/CT, DNA/Col 1, and SE assessed in six volunteers with or without signs of gingival inflammation (n = 3/group). RESULTS: The spatially co-registered RMS spectra revealed opposing changes in the collagen and DNA peaks of inflamed compared with healthy tissues (P <0.05). Combined RMS/µOCT analysis showed that OE/CT, DNA/Col, and SE are significantly different between healthy and inflamed sites (P <0.05). Histological assessments confirmed the differences detected by RMS/µOCT. Qualitative analysis of DNA/Col 1 ratios indicated Col I content as the main distinguishing feature for health and DNA content for periodontitis. CONCLUSION: Results suggest that combined RMS/µOCT chairside imaging may distinguish between healthy and diseased sites by evaluating marginal periodontal morphological and biochemical features.

The Relationships Among Periodontitis, Pneumonia and COVID-19.

Periodontitis is a chronic inflammatory disease of the supporting structures of the teeth that affects approximately half of adults 30 years and older. There is increasing interest in the direct and indirect relationships between periodontitis and systemic diseases, including respiratory diseases. The aim of this study was to assess the evidence on links among periodontitis, pneumonia, and COVID-19. Oral and periodontal bacteria may be linked to respiratory disease directly by aspiration of pathogens into the lungs causing pneumonia. As SARS-CoV-2 began to spread worldwide in 2020, questions have arisen of how periodontal disease may also be connected to SARS-CoV-2 infection and severity, including potential replication and dissemination of the virus from periodontal pockets. Some proposed mechanisms include the oral cavity acting as a reservoir or point of entry for SARS-CoV-2, overgrowth of periodontal pathogens, and increased production of proinflammatory cytokines. Due to potential links between periodontal disease and respiratory infections like pneumonia and SARS-CoV-2, oral hygiene and management of periodontitis remain essential to help reduce infection and transmission of SARS-CoV-2.

Impact of Treating Oral Disease on Preventing Vascular Diseases: A Model-Based Cost-effectiveness Analysis of Periodontal Treatment Among Patients With Type 2 Diabetes.

OBJECTIVE: Previous randomized trials found that treating periodontitis improved glycemic control in patients with type 2 diabetes (T2D), thus lowering the risks of developing T2D-related microvascular diseases and cardiovascular disease (CVD). Some payers in the U.S. have started covering nonsurgical periodontal treatment for those with chronic conditions, such as diabetes. We sought to identify the cost-effectiveness of expanding periodontal treatment coverage among patients with T2D. RESEARCH DESIGN AND METHODS: A cost-effectiveness analysis was conducted to estimate lifetime costs and health gains using a stochastic microsimulation model of oral health conditions, T2D, T2D-related microvascular diseases, and CVD of the U.S. POPULATION: Model parameters were obtained from the nationally representative National Health and Nutrition Examination Survey (NHANES) (2009-2014) and randomized trials of periodontal treatment among patients with T2D. RESULTS: Expanding periodontal treatment coverage among patients with T2D and periodontitis would be expected to avert tooth loss by 34.1% (95% CI -39.9, -26.5) and microvascular diseases by 20.5% (95% CI -31.2, -9.1), 17.7% (95% CI -32.7, -4.7), and 18.4% (95% CI -34.5, -3.5) for nephropathy, neuropathy, and retinopathy, respectively. Providing periodontal treatment to the target population would be cost saving from a health care perspective at a total net savings of $5,904 (95% CI -6,039, -5,769) with an estimated gain of 0.6 quality-adjusted life years per capita (95% CI 0.5, 0.6). CONCLUSIONS: Providing nonsurgical periodontal treatment to patients with T2D and periodontitis would be expected to significantly reduce tooth loss and T2D-related microvascular diseases via improved glycemic control. Encouraging patients with T2D and poor oral health conditions to receive periodontal treatment would improve health outcomes and still be cost saving or cost-effective.

Biosensor and Lab-on-a-chip Biomarker-identifying Technologies for Oral and Periodontal Diseases.

Periodontitis is a complex multifactorial disease that can lead to destruction of tooth supporting tissues and subsequent tooth loss. The most recent global burden of disease studies highlight that severe periodontitis is one of the most prevalent chronic inflammatory conditions affecting humans. Periodontitis risk is attributed to genetics, host-microbiome and environmental factors. Empirical diagnostic and prognostic systems have yet to be validated in the field of periodontics. Early diagnosis and intervention prevents periodontitis progression in most patients. Increased susceptibility and suboptimal control of modifiable risk factors can result in poor response to therapy, and relapse. The chronic immune-inflammatory response to microbial biofilms at the tooth or dental implant surface is associated with systemic conditions such as cardiovascular disease, diabetes or gastrointestinal diseases. Oral fluid-based biomarkers have demonstrated easy accessibility and potential as diagnostics for oral and systemic diseases, including the identification of SARS-CoV-2 in saliva. Advances in biotechnology have led to innovations in lab-on-a-chip and biosensors to interface with oral-based biomarker assessment. This review highlights new developments in oral biomarker discovery and their validation for clinical application to advance precision oral medicine through improved diagnosis, prognosis and patient stratification. Their potential to improve clinical outcomes of periodontitis and associated chronic conditions will benefit the dental and overall public health.

Macrophage immunomodulation in chronic osteolytic diseases-the case of periodontitis.

Periodontitis (PD) is a chronic osteolytic disease that shares pathogenic inflammatory features with other conditions associated with nonresolving inflammation. A hallmark of PD is inflammation-mediated alveolar bone loss. Myeloid cells, in particular polymorphonuclear neutrophils (PMN) and macrophages (Mac), are essential players in PD by control of gingival biofilm pathogenicity, activation of adaptive immunity, as well as nonresolving inflammation and collateral tissue damage. Despite mounting evidence of significant innate immune implications to PD progression and healing after therapy, myeloid cell markers and targets for immune modulation have not been validated for clinical use. The remarkable plasticity of monocytes/Mac in response to local activation factors enables these cells to play central roles in inflammation and restoration of tissue homeostasis and provides opportunities for biomarker and therapeutic target discovery for management of chronic inflammatory conditions, including osteolytic diseases such as PD and arthritis. Along a wide spectrum of activation states ranging from proinflammatory to pro-resolving, Macs respond to environmental changes in a site-specific manner in virtually all tissues. This review summarizes the existing evidence on Mac immunomodulation therapies for osteolytic diseases in the broader context of conditions associated with nonresolving inflammation, and discusses osteoimmune implications of Macs in PD.

Therapeutic Targets for Management of Periodontitis and Diabetes.

The increasing incidence of diabetes mellitus (DM) and chronic periodontitis (CP) worldwide imposes a rethinking of individualized therapy for patients with both conditions. Central to bidirectional links between DM and CP is deregulated systemic inflammation and dysfunctional immune responses to altered-self and non-self. Control of blood glucose levels and metabolic imbalances associated with hyperglycemia in DM, and disruption of pathogenic subgingival biofilms in CP are currently the main therapeutic approaches for these conditions. Mounting evidence suggests the need to integrate immune modulatory therapeutics in treatment regimens that address the unresolved inflammation associated with DM and CP. The current review discusses the pathogenesis of DM and CP with emphasis on deregulated inflammation, current therapeutic approaches and the novel pro-resolution lipid mediators derived from Ω-3 polyunsaturated fatty acids.

Salivary Cytoprotective Proteins in Inflammation and Resolution during Experimental Gingivitis--A Pilot Study.

OBJECTIVE: The protective mechanisms that maintain periodontal homeostasis in gingivitis and prevent periodontal tissue destruction are poorly understood. The aim of this study was to identify changes in the salivary proteome during experimental gingivitis. STUDY DESIGN: We used oral neutrophil quantification and whole saliva (WS) proteomics to assess changes that occur in the inflammatory and resolution phases of gingivitis in healthy individuals. Oral neutrophils and WS samples were collected and clinical parameters measured on days 0, 7, 14, 21, 28, and 35. RESULTS: Increased oral neutrophil recruitment and salivary cytoprotective proteins increased progressively during inflammation and decreased in resolution. Oral neutrophil numbers in gingival inflammation and resolution correlated moderately with salivary ß-globin, thioredoxin, and albumin and strongly with collagen alpha-1 and G-protein coupled receptor 98. CONCLUSIONS: Our results indicate that changes in salivary cytoprotective proteins in gingivitis are associated with a similar trend in oral neutrophil recruitment and clinical parameters. CLINICAL RELEVANCE: We found moderate to strong correlations between oral neutrophil numbers and levels of several salivary cytoprotective proteins both in the development of the inflammation and in the resolution of gingivitis. Our proteomics approach identified and relatively quantified specific cytoprotective proteins in this pilot study of experimental gingivitis; however, future and more comprehensive studies are needed to clearly identify and validate those protein biomarkers when gingivitis is active.

Role of PTPα in the destruction of periodontal connective tissues.

IL-1ß contributes to connective tissue destruction in part by up-regulating stromelysin-1 (MMP-3), which in fibroblasts is a focal adhesion-dependent process. Protein tyrosine phosphatase-α (PTPα) is enriched in and regulates the formation of focal adhesions, but the role of PTPα in connective tissue destruction is not defined. We first examined destruction of periodontal connective tissues in adult PTPα(+/+) and PTPα(-/-) mice subjected to ligature-induced periodontitis, which increases the levels of multiple cytokines, including IL-1ß. Three weeks after ligation, maxillae were processed for morphometry, micro-computed tomography and histomorphometry. Compared with unligated controls, there was ∼1.5-3 times greater bone loss as well as 3-fold reduction of the thickness of the gingival lamina propria and 20-fold reduction of the amount of collagen fibers in WT than PTPα(-/-) mice. Immunohistochemical staining of periodontal tissue showed elevated expression of MMP-3 at ligated sites. Second, to examine mechanisms by which PTPα may regulate matrix degradation, human MMP arrays were used to screen conditioned media from human gingival fibroblasts treated with vehicle, IL-1ß or TNFα. Although MMP-3 was upregulated by both cytokines, only IL-1ß stimulated ERK activation in human gingival fibroblasts plated on fibronectin. TIRF microscopy and immunoblotting analyses of cells depleted of PTPα activity with the use of various mutated constructs or with siRNA or PTPα(KO) and matched wild type fibroblasts were plated on fibronectin to enable focal adhesion formation and stimulated with IL-1ß. These data showed that the catalytic and adaptor functions of PTPα were required for IL-1ß-induced focal adhesion formation, ERK activation and MMP-3 release. We conclude that inflammation-induced connective tissue degradation involving fibroblasts requires functionally active PTPα and in part is mediated by IL-1ß signaling through focal adhesions.