Differential regulation of matrix metalloproteinase 2 and matrix metalloproteinase 9 by activated protein C: Relevance to inflammation in rheumatoid arthritis

Xue, Meilang; March, Lyn; Sambrook, Philip N.

doi:10.1002/art.22844

Cited by 72 publications

(61 citation statements)

References 49 publications

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“…MMP-9 activation mechanisms are largely unknown (for review, see ref. 39), and in other cell types, APC does not induce activation of MMP-9 (12,40), suggesting that it is likely not a direct effect in our cartilage cultures.…”

Section: Discussionmentioning

confidence: 74%

Activation of cartilage matrix metalloproteinases by activated protein C

Jackson

Smith

et al. 2009

Arthritis & Rheumatism

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Objective. To investigate the role of activated protein C (APC) in cartilage degradation.Methods. Chondrocyte expression of protein C, endothelial protein C receptor (EPCR), and thrombomodulin (TM) were evaluated by reverse transcriptionpolymerase chain reaction (RT-PCR). APC was immunolocalized in developing joints and in osteoarthritic (OA) cartilage from humans. The effect of APC on aggrecan and collagen degradation was examined in explant cultures of ovine cartilage in control cultures and in cultures stimulated with interleukin-1␣ (IL-1␣), tumor necrosis factor ␣ (TNF␣), or retinoic acid (RetA), using colorimetric assays and Western blotting. Chondrocyte expression of matrix metalloproteinases (MMPs), ADAMTS, and tissue inhibitor of metalloproteinases (TIMPs) was measured by RT-PCR. MMP-2 and MMP-9 activity was evaluated by gelatin zymography and MMP-13 by fluorogenic assay.Results. Positive cellular immunostaining for APC was found at sites of MMP activity in developing joints and in OA, but not normal, cartilage. Chondrocytes expressed messenger RNA for protein C, EPCR, and TM, with the latter 2 levels increased by IL-1␣ and TNF␣ stimulation. APC augmented aggrecan release and initiated collagen breakdown in IL-1␣-treated and TNF␣-treated cartilage, but not in normal or in RetAtreated cartilage. APC-stimulated aggrecan and collagen breakdown were due to MMP activity but were not associated with modulation of MMP, ADAMTS, or TIMP expression. APC resulted in MMP-13 activation in cartilage cultures. APC could not directly activate proMMP-13, but it was associated with increased MMP-2 and MMP-9 activity.Conclusion. APC may be a relevant activator of MMPs in cartilage and may play a role in progressive cartilage degradation in arthritis.

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Section: Discussionmentioning

confidence: 74%

Activation of cartilage matrix metalloproteinases by activated protein C

Jackson

Smith

et al. 2009

Arthritis & Rheumatism

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“…APC not only increases collagen 1 expression by osteoblasts, 145 liver myofibroblasts, 146 tenocytes, 147 and collagen IV by endothelial cells, 148 but also regulates MMP expression/activation with a stimulatory effect on MMP-2 by skin keratinocyte, fibroblasts, and endothelial cells 148,149 and an inhibitory effect on MMP-9 by rheumatoid synovial fibroblasts. 150 Moreover, our recent data show that APC has the ability to differentially modify the production of TGF-bs (Fig. 4).…”

Section: Apc a Potential Agent To Prevent/ Treat Abnormal Scarring?mentioning

confidence: 89%

Extracellular Matrix Reorganization During Wound Healing and Its Impact on Abnormal Scarring

Xue

Jackson

2015

Advances in Wound Care

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Significance: When a cutaneous injury occurs, the wound heals via a dynamic series of physiological events, including coagulation, granulation tissue formation, re-epithelialization, and extracellular matrix (ECM) remodeling. The final stage can take many months, yet the new ECM forms a scar that never achieves the flexibility or strength of the original tissue. In certain circumstances, the normal scar is replaced by pathological fibrotic tissue, which results in hypertrophic or keloid scars. These scars cause significant morbidity through physical dysfunction and psychological stress. Recent Advances and Critical Issues: The cutaneous ECM comprises a complex assortment of proteins that was traditionally thought to simply provide structural integrity and scaffolding characteristics. However, recent findings show that the ECM has multiple functions, including, storage and delivery of growth factors and cytokines, tissue repair and various physiological functions. Abnormal ECM reconstruction during wound healing contributes to the formation of hypertrophic and keloid scars. Whereas adult wounds heal with scarring, the developing foetus has the ability to heal wounds in a scarless fashion by regenerating skin and restoring the normal ECM architecture, strength, and function. Recent studies show that the lack of inflammation in fetal wounds contributes to this perfect healing. Future Directions: Better understanding of the exact roles of ECM components in scarring will allow us to produce therapeutic agents to prevent hypertrophic and keloid scars. This review will focus on the components of the ECM and their role in both physiological and pathological (hypertrophic and keloid) cutaneous scar formation. SCOPE AND SIGNIFICANCEThis article reviews the extracellular matrix (ECM) and its remodeling during normal cutaneous wound healing and scar formation, and the differential response of the components of the ECM and their role in pathological (hypertrophic and keloid) cutaneous scar formation. This review focuses on the major players involved in the irregular ECM production as being; fibroblasts and their immature counterparts, myofibroblasts; collagens; transforming growth factor (TGF)-b, which controls the production of collagens; proteoglycans and matrix metalloproteinases (MMPs). We also highlight the complexity of interactions occurring in the ECM of skin during (ab) normal scar formation. TRANSLATIONAL RELEVANCEAbnormal ECM, particularly abnormal collagen remodeling and reorganization, accounts for one of the most important contributing factors to abnormal scarring. Identification of the exact ECM molecules involved in causing abnormal scarring is likely to provide a future treatment target. This may be achieved by promoting the correct balance in collagen ratios or by directly targeting the production of collagen. Overall, a better understanding of the exact roles of ECM components in scarring will help us to produce therapeutic agents to prevent and treat hypertrophic and keloid scars. CLINICAL RELEVANCEThere ...

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“…APC directly activates proMMP-2 (47), and the level of APC is elevated in RA synovial joints, where it colocalizes with MMP-2 (48). In RA fibroblasts and monocytes, APC downregulates proMMP-9 synthesis, reduces tumor necrosis factor ␣ (TNF␣) production, and inhibits NF-B-and p38 mitogen-activated protein kinase activity (49). These observations are dependent on APC binding to its specific receptor, endothelial protein C receptor (EPCR), although this receptor does not signal.…”

Section: Activated Protein C (Apc)mentioning

confidence: 99%