Host metalloproteinases in Lyme arthritis

Hu, Linden T.; Eskildsen, Manuel; Masgala, Catherine; Steere, Allen C.; Arner, Elizabeth C.; Pratta, Michael A.; Grodzinsky, Alan J.; Loening, Andreas M.; Perides, George

doi:10.1002/1529-0131(200106)44:6<1401::aid-art234>3.0.co;2-s

Cited by 64 publications

(62 citation statements)

References 53 publications

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“…It has been previously shown that B. burgdorferi, unlike most other bacteria that cause septic arthritis, does not produce collagenases or other enzymes capable of destroying joint extracellular matrix (5,18). Instead, we have shown that cartilage degradation in Lyme arthritis is due to induction of a class of host enzymes called matrix metalloproteinases (MMPs) (13,20). All MMPs share a common function of extracellular matrix degradation (8).…”

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confidence: 99%

“…Two MMPs in particular, collagenase-1 (MMP-1) and stromelysin-1 (MMP-3), were found to be elevated in the synovial fluid of patients with Lyme arthritis (20). In vitro models of Lyme arthritis confirmed the ability of B. burgdorferi to induce these MMPs from human chondrocytes (HCs) and the ability of MMP inhibitors to block B. burgdorferi-induced cartilage degradation (13).…”

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confidence: 99%

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Borrelia burgdorferi-Induced Expression of Matrix Metalloproteinases from Human Chondrocytes Requires Mitogen-Activated Protein Kinase and Janus Kinase/Signal Transducer and Activator of Transcription Signaling Pathways

et al. 2004

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Borrelia burgdorferi-Induced Expression of Matrix Metalloproteinases from Human Chondrocytes Requires Mitogen-Activated Protein Kinase and Janus Kinase/Signal Transducer and Activator of Transcription Signaling Pathways

et al. 2004

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“…Hu and co-workers [11] studied the involvement of MMPs in cartilage and bone erosions in LA. They examined synovial fluid from patients with LA for MMP-2, MMP-3 and MMP-9.…”

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confidence: 98%

“…MMP-1, MMP-3, MMP-8 and -9 have been found in synovial fluid of Lyme arthritis (LA) patients [7]. Different MMPs (MMP-1, 2, -3,-10, -13, and -19) have been shown to be induced in different ways in human and murine LA [3,11]. Lin and colleagues [7] found that the levels of synovial MMPs, also MMP-8, were significantly higher in antibiotic treatment resistant patients.…”

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confidence: 99%

Serum Matrix Metalloproteinase-8 and -9 Levels in Disseminated Lyme Borreliosis with Special Reference to Arthritis

Lauhio¹,

Oksi²,

Tervahartiala³

et al. 2012

BIO

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Recent evidence suggests that matrix metalloproteinases (MMPs) are involved in pathogenesis of Lyme borreliosis (LB). We studied serum levels of MMP-8 and MMP-9 in disseminated LB patients with special reference to arthritis. Serum MMP-8 and-9 levels were analyzed by enzyme-linked immunoabsorbent assay from 110 patients from our previous multicenter, prospective study. Serum samples were taken before betalactam antibiotic treatment at study entry and after antibiotic treatment, at 1 year follow-up.Among disseminated LB patients (n = 110) mean (± SEM) serum MMP-8 and -9 levels (ng/ml) at study entry were statistically significantly higher than at 1 year follow-up (28.0 ± 1.9 versus 23.1 ± 1.6, P = 0.0313 and 398.0 ± 22.7 vs. 334.3 ± 23.6, P = 0.0219, respectively). Among Lyme arthritis (LA) patients (n = 34) at study entry serum MMP-8, but not MMP-9, levels decreased significantly when compared to serum levels of those at 1 year follow-up (35.7 ± 4.4 vs. 22.4 ± 2.3, P = 0.0093 and 398.6 ± 44.1 vs. 297.8 ± 40.3, P = 0.0505, respectively). The mean (± SEM) serum levels (ng/ml) of MMP-8 were significantly higher after betalactam antibiotic treatment at 1 year follow-up among antibiotic resistant LA patients with poor response than among those LA patients who were totally recovered (32.8 ± 6.4 vs. 20.1 ± 2.3, P = 0.0376). In contrast, the mean (± SEM) serum levels (ng/ml) of MMP-9 of antibiotic resistant LA patients showed no statistical significant difference when compared to those LA patients who were totally recovered at 1 year follow-up (297.8 ± 40.3 vs. 396.8 ± 93.9, P = 0.80).In conclusion, our results suggest that serum MMP-8 levels are excessively upregulated in disseminated LB contributing to inflammatory response, and related to persistent joint symptoms. This novel finding may offer in the future new laboratory possibilities to diagnose patients with persistent symptoms after betalactam antibiotic treatment. In addition the present findings suggest that to improve the outcome of disseminated borreliosis, the therapy of disseminated LB should include MMP-8 inhibitor such as doxycycline, possibly in combination therapy such as a combination of ceftriaxone and doxycycline. BIO © [2012], Copyright CCAAS Anneli Lauhio, et. al., BIO 2012, 2, 68-74 69 http://ccaasmag.org/BIO

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“…18 Particularly relevant to the present study, elevated levels of MMP-9 have been observed in the erythema migrans lesions and cerebrospinal and synovial fluid of patients with Lyme disease. [21][22][23][24] Once secreted, MMP-9 cleaves the ECM, thus facilitating cell migration through a normally dense fibrillar environment. In addition to fostering general leukocyte movement, degradation of collagen also liberates small tripeptide fragments such as proline-glycine-proline (PGP), which exhibit an affinity for the chemokine receptors CXCR1/2 as do the neutrophil chemoattractants CXCL8/KC and MIP-2.…”

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CD14 Signaling Reciprocally Controls Collagen Deposition and Turnover to Regulate the Development of Lyme Arthritis

Sahay

Singh

Gnanamani

et al. 2011

The American Journal of Pathology

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CD14 is a glycosylphosphatidylinositol-anchored protein expressed primarily on myeloid cells (eg, neutrophils, macrophages, and dendritic cells). CD14 ؊/؊ mice infected with Borrelia burgdorferi, the causative agent of Lyme disease, produce more proinflammatory cytokines and present with greater disease and bacterial burden in infected tissues. Recently, we uncovered a novel mechanism whereby CD14 ؊/؊ macrophages mount a hyperinflammatory response, resulting from their inability to be tolerized by B. burgdorferi. Paradoxically, CD14 deficiency is associated with greater bacterial burden despite the presence of highly activated neutrophils and macrophages and elevated levels of cytokines with potent antimicrobial activities. Killing and clearance of Borrelia, especially in the joints, depend on the recruitment of neutrophils. Neutrophils can migrate in response to chemotactic gradients established through the action of gelatinases (eg, matrix metalloproteinase 9), which degrade collagen components of the extracellular matrix to generate tripeptide fragments of proline-glycine-proline. Using a mouse model of Lyme arthritis, we demonstrate that CD14 deficiency leads to decreased activation of matrix metalloproteinase 9, reduced degradation of collagen, and diminished recruitment of neutrophils. This reduction in neutrophil numbers is associated with greater numbers of Borrelia in infected tissues. Variation in the efficiency of neutrophil-mediated clearance of B. burgdorferi may underlie differences in the severity of Lyme arthritis observed in the patient population and suggests avenues for development of adjunctive therapy designed to augment host immunity.

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Host metalloproteinases in Lyme arthritis

Cited by 64 publications

References 53 publications

Borrelia burgdorferi-Induced Expression of Matrix Metalloproteinases from Human Chondrocytes Requires Mitogen-Activated Protein Kinase and Janus Kinase/Signal Transducer and Activator of Transcription Signaling Pathways

Borrelia burgdorferi-Induced Expression of Matrix Metalloproteinases from Human Chondrocytes Requires Mitogen-Activated Protein Kinase and Janus Kinase/Signal Transducer and Activator of Transcription Signaling Pathways

Serum Matrix Metalloproteinase-8 and -9 Levels in Disseminated Lyme Borreliosis with Special Reference to Arthritis

CD14 Signaling Reciprocally Controls Collagen Deposition and Turnover to Regulate the Development of Lyme Arthritis

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