Protease‐Activated Receptors: A Means of Converting Extracellular Proteolysis into Intracellular Signals

Mackie, Eleanor J.; Pagel, Charles N.; Smith, Rob; Niese, Michael R de; Song, Shujun; Pike, Robert N.

doi:10.1080/15216540213469

Cited by 60 publications

(53 citation statements)

References 36 publications

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“…Trypsin and factor Xa have been shown to activate PAR-1, but at much higher concentrations than thrombin. 2 Like thrombin, factor Xa is likely to be present in bone in conditions involving loss of vascular integrity, but trypsin is unlikely ever to be present in bone.…”

Section: Discussionmentioning

confidence: 99%

“…Three thrombin receptors have been identified, protease-activated receptors (PARs)-1, -3, and -4, which are members of the seven transmembrane domain Gprotein-coupled receptor family. 1,2 Protease-activated receptor-1 is expressed by osteoblasts (bone-forming cells), and mediates thrombin-induced proliferation of these cells. [3][4][5] Thrombin also stimulates osteoclastic bone resorption in vitro.…”

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confidence: 99%

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The Role of Protease-Activated Receptor-1 in Bone Healing

Song

Pagel

Campbell

et al. 2005

The American Journal of Pathology

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Protease-activated receptor (PAR)-1, a G-protein-coupled receptor activated by thrombin, mediates thrombin-induced proliferation of osteoblasts. The current study was undertaken to define the role of PAR-1 in bone repair. Holes were drilled transversely through the diaphysis of both tibiae of PAR-1-null and wildtype mice. Three days later, fewer cells had invaded the drill site from adjacent bone marrow in PAR-1-null mice than in wild-type mice, and a lower percentage of cells were labeled with [ 3 H]thymidine in PAR-1-null drill sites. More osteoclasts were also observed in the drill site of PAR-1-null mice than in wild-type mice 7 days after drilling. New mineralized bone area was less in the drill site and on the adjacent periosteal surface in PAR-1-null mice than in wildtype mice at day 9. From day 14, no obvious differences could be seen between PAR-1-null and wild-type tibiae. In vitro thrombin caused a dose-dependent increase in proliferation of bone marrow stromal cells isolated from wild-type mice but not PAR-1-null mice. Thrombin stimulated survival of bone marrow stromal cells from both wild-type and PAR-1-null mice, but it did not affect bone marrow stromal cell migration in either wild-type or PAR-1-null cells Thrombin is a serine protease, which plays a central role in blood coagulation through its cleavage of fibrinogen, but also exerts specific receptor-mediated effects on cell function. Three thrombin receptors have been identified, protease-activated receptors (PARs)-1, -3, and -4, which are members of the seven transmembrane domain Gprotein-coupled receptor family. 1,2 Protease-activated receptor-1 is expressed by osteoblasts (bone-forming cells), and mediates thrombin-induced proliferation of these cells. [3][4][5] Thrombin also stimulates osteoclastic bone resorption in vitro. 6,7 Thrombin is generated during tissue injury, and PAR-1 activation appears to be involved in pathological processes including inflammation and wound healing. 8 -10 For example, when thrombin or a PAR-1-activating peptide is applied to incisional skin wounds in rats, wound healing is accelerated. 11 Because both osteoblast proliferation and bone resorption are important components of the process of bone repair, we hypothesized that thrombin, through PAR-1, may participate in this process. The current study was undertaken to investigate this hypothesis, using mice with a targeted disruption of the PAR-1 gene. 12 Fifty percent of these mice die at about day 9.5 of gestation, and the remainder survive to become apparently normal adults. Embryonic death of PAR-1-null mice can be prevented by targeted expression of PAR-1 in endothelial cells. 13 Although PAR-1 is expressed by platelets and mediates platelet aggregation in humans, PAR-1 is not expressed by mouse platelets, and therefore is not required for normal blood coagulation in this species. 14 A number of models of bone repair have been established for use in mice, including an unstabilized fracture model, stabilized fracture models involving internal or external fi...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

The Role of Protease-Activated Receptor-1 in Bone Healing

Song

Pagel

Campbell

et al. 2005

The American Journal of Pathology

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“…PARs act as sensors of possible danger, have a role in inflammation, and may also have a central role in the recognition of, and response to, bacteria within the oral cavity (Mackie et al, 2002), including regulation of the inducible β-defensins. Because the three major Gram-negative pathogens associated with periodontal disease, P. gingivalis, Bacteroides forsythus (recently renamed Tannerella forsythensis) and Treponema denticola (Socransky et al, 1998) each have proteases as part of their virulence mechanisms (Curtis et al, 2001;Fenno et al, 2001;Saito et al, 1997); these receptors may aid in differentially stimulating epithelial cell responses to pathogenic vs. commensal oral bacteria.…”

Section: Antimicrobial Peptides In the Oral Environment 123mentioning

confidence: 99%

“…PARs are seven-transmembrane domain G-protein coupled receptors. PAR activation involves proteolytic cleavage of the extracellular domain, resulting in a new amino-terminus that acts as a tethered ligand that binds to one of the extracellular loops of the receptor (Coughlin and Camerer, 2003;Mackie et al, 2002). PAR-1, -3, and -4 are activated by thrombin; PAR-2 is activated by various trypsin-like enzymes, including mast cell tryptase, neutrophil proteinase 3, as well as P. gingivalis proteinases (Lourbakos et al, 1998).…”

Section: Antimicrobial Peptides In the Oral Environment 123mentioning

confidence: 99%

“…HBD-2 regulation in tracheal epithelial cells occurs via CD14, and NF-κB-mediated signaling (Becker et al, 2000;Diamond et al, 2000), and/or via TLR2-mediated signaling (Hertz et al, 2003). However, there is not yet convincing evidence that this pathway is involved in hBD-2 regulation in oral epithelial cells.A second family of recently described receptors is the proteinase-activated receptors or PARs (Coughlin, 2000;Mackie et al, 2002). PARs act as sensors of possible danger, have a role in inflammation, and may also have a central role in the recognition of, and response to, bacteria within the oral cavity (Mackie et al, 2002), including regulation of the inducible β-defensins.…”

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Antimicrobial Peptides in the Oral Environment: Expression and Function in Health and Disease

2005

Current Issues in Molecular Biology

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The oral cavity is a unique environment in which antimicrobial peptides play a key role in maintaining health and may have future therapeutic applications. Present evidence suggests that α-defensins, β-defensins, LL-37, histatin, and other antimicrobial peptides and proteins have distinct but overlapping roles in maintaining oral health and preventing bacterial, fungal, and viral adherence and infection. The expression of the inducible hBD-2 in normal oral epithelium, in contrast to other epithelia, and the apparent differential signaling in response to commensal and pathogenic organisms, provides new insights into innate immunity in this body site. Commensal bacteria are excellent inducers of hBD-2 in oral epithelial cells, suggesting that the commensal bacterial community acts in a manner to benefit the overall innate immune readiness of oral epithelia. This may have major significance for understanding host defense in the complex oral environment. The oral environmentThe oral cavity is a unique environment. Oral mucosa is a critical protective interface between external and internal environments and must serve as a barrier to the myriad microbial species present in this warm, moist environment. The oral cavity is the only area of the body in which hard tissues break through the epithelial surface. The periodontal epithelium surrounding the tooth is specialized to form an attachment and seal around each tooth. This unique function imparts special challenges to the tissue and leads to certain vulnerabilities associated with periodontal disease, especially in view of the continual exposure to the bacterial biofilm (dental plaque) that forms on the tooth surface at the junction of the soft tissue. Thus, this anatomical region is one where there is a significant risk of bacterially induced infection and inflammation.Antimicrobial peptides are important contributors to maintaining the balance between health and disease in this complex environment. These include several salivary antimicrobial peptides, the β-defensins expressed in the epithelium, the α-defensins expressed in neutrophils, and the cathelicidin, LL-37, expressed in both epithelium and neutrophils. These peptides are part of the host innate immune response in this environment. Epithelia, polymorphonuclear leukocytes (neutrophils), and saliva all contribute to the maintaining the health of the oral cavity in overlapping but independent ways. This review will focus on the human oral cavity and include 1) the expression and function of antimicrobial peptides in the oral cavity in the context of innate immune responses, 2) regulation of β-defensins which has led to advances in our understanding of oral epithelial innate immunity, and 3) functional efficacy against oral microbes when it is known. Epithelial antimicrobial peptidesHistorically, the oral epithelium has been considered mainly as a passive covering that becomes damaged and ulcerated in disease. This view has changed dramatically and the epithelial compartment is now seen as providing both...

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