Keratinocyte-specific ablation of protease-activated receptor 2 prevents gingival inflammation and bone loss in a mouse model of periodontal disease

Francis, Nidhish; Ayodele, Babatunde A.; O'Brien-Simpson, Neil M; Birchmeier, Walter; Pike, Robert N.; Pagel, Charles N.; Mackie, Eleanor J.

doi:10.1111/cmi.12891

Cited by 9 publications

(19 citation statements)

References 49 publications

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“…Inflammation-associated periodontal diseases are predominantly induced by the Porphyromonas gingivalis cysteine protease gingipain R, which activates PAR2 [107, 108]. Subsequently, gingipain R activates PAR1 and PAR4, and thereby, human platelets [109–111].…”

Section: Cleavage and Activation Of Pars And Signal Transductionmentioning

confidence: 99%

Protease-activated receptors (PARs): mechanisms of action and potential therapeutic modulators in PAR-driven inflammatory diseases

2019

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Inflammatory diseases have become increasingly prevalent with industrialization. To address this, numerous anti-inflammatory agents and molecular targets have been considered in clinical trials. Among molecular targets, protease-activated receptors (PARs) are abundantly recognized for their roles in the development of chronic inflammatory diseases. In particular, several inflammatory effects are directly mediated by the sensing of proteolytic activity by PARs. PARs belong to the seven transmembrane domain G protein-coupled receptor family, but are unique in their lack of physiologically soluble ligands. In contrast with classical receptors, PARs are activated by N-terminal proteolytic cleavage. Upon removal of specific N-terminal peptides, the resulting N-termini serve as tethered activation ligands that interact with the extracellular loop 2 domain and initiate receptor signaling. In the classical pathway, activated receptors mediate signaling by recruiting G proteins. However, activation of PARs alternatively lead to the transactivation of and signaling through receptors such as co-localized PARs, ion channels, and toll-like receptors. In this review we consider PARs and their modulators as potential therapeutic agents, and summarize the current understanding of PAR functions from clinical and in vitro studies of PAR-related inflammation.

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Section: Cleavage and Activation Of Pars And Signal Transductionmentioning

confidence: 99%

Protease-activated receptors (PARs): mechanisms of action and potential therapeutic modulators in PAR-driven inflammatory diseases

2019

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“…37 Keratinocyte-specific deletion of Par2 prevented periodontal bone loss by suppressing the inflammatory cascade, ultimately inhibiting osteoclast differentiation and activity. 227 Tshr knockout mice only reduced femur length, 37 while P2y13 −/− mice had increased tibia and tail length, 229 and Par2 deletion alleviated mouse arthritis. 230…”

Section: Diseases or Dysfunction Caused By Gpcr Mutation Or Deletion mentioning

confidence: 89%

“…Deletion of 16 δ-group GPCR genes caused bone dysfunctions in mouse models: deficiency of Ebi2 , 86 Gpr55 , 220 Gpr68 , 221 P2y6 , 222 and Ptafr 42 increased mouse bone mass and BMD; while Gpr65 , 223 Gpr103 , 224 Lgr4 , 8,9 P2y1 , 225 Rxfp2 , 211,215 Tshr 37 reduced bone mass and BMD; and P2y12 –/– mice had reduced age-associated bone loss with lower osteoblast activity, 226 while deletion of Par2 227 bone prevented periodontal disease in mice. Defective Ebi2 signaling suppressed osteoclast precursor cell migration to bones, which led to increased male mouse bone mass and protection of female mice from osteoporosis due to age or estrogen deficiency.…”

Section: Diseases or Dysfunction Caused By Gpcr Mutation Or Deletion mentioning

confidence: 99%

The role of GPCRs in bone diseases and dysfunctions

et al. 2019

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The superfamily of G protein-coupled receptors (GPCRs) contains immense structural and functional diversity and mediates a myriad of biological processes upon activation by various extracellular signals. Critical roles of GPCRs have been established in bone development, remodeling, and disease. Multiple human GPCR mutations impair bone development or metabolism, resulting in osteopathologies. Here we summarize the disease phenotypes and dysfunctions caused by GPCR gene mutations in humans as well as by deletion in animals. To date, 92 receptors (5 glutamate family, 67 rhodopsin family, 5 adhesion, 4 frizzled/taste2 family, 5 secretin family, and 6 other 7TM receptors) have been associated with bone diseases and dysfunctions (36 in humans and 72 in animals). By analyzing data from these 92 GPCRs, we found that mutation or deletion of different individual GPCRs could induce similar bone diseases or dysfunctions, and the same individual GPCR mutation or deletion could induce different bone diseases or dysfunctions in different populations or animal models. Data from human diseases or dysfunctions identified 19 genes whose mutation was associated with human BMD: 9 genes each for human height and osteoporosis; 4 genes each for human osteoarthritis (OA) and fracture risk; and 2 genes each for adolescent idiopathic scoliosis (AIS), periodontitis, osteosarcoma growth, and tooth development. Reports from gene knockout animals found 40 GPCRs whose deficiency reduced bone mass, while deficiency of 22 GPCRs increased bone mass and BMD; deficiency of 8 GPCRs reduced body length, while 5 mice had reduced femur size upon GPCR deletion. Furthermore, deficiency in 6 GPCRs induced osteoporosis; 4 induced osteoarthritis; 3 delayed fracture healing; 3 reduced arthritis severity; and reduced bone strength, increased bone strength, and increased cortical thickness were each observed in 2 GPCR-deficiency models. The ever-expanding number of GPCR mutation-associated diseases warrants accelerated molecular analysis, population studies, and investigation of phenotype correlation with SNPs to elucidate GPCR function in human diseases.

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“…The primers for osteopontin and interleukin-6 (IL-6) were as described [6, 23]. Primers for tumour necrosis factor-α (TNFα; forward 5' ACG GCA TGG ATC TCA AAG AC 3', 5"GTG GGT GAG GAG CAC GTA 3'), interleukin-4 (IL-4; forward 5′ TCG ATA AGC TGC ACC ATG AA 3′; reverse 5′ ATG ATG CTC TTT AGG CTT TCC A 3′) and the house-keeping gene cyclophilin A (forward 5′CAC AAA CGG TTC CCA GTT TT 3′; reverse 5′ TC ACC TTC CCA AAG ACC AC 3′) were designed using Primer 3 software (http://primer3.ut.ee/) and blastn; their specificity was confirmed by sequencing of PCR products.…”

Section: Methodsmentioning

confidence: 99%

Normal inflammation and regeneration of muscle following injury require osteopontin from both muscle and non-muscle cells

2019

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Background Osteopontin is secreted by skeletal muscle myoblasts and macrophages, and its expression is upregulated in muscle following injury. Osteopontin is present in many different structural forms, which vary in their expression patterns and effects on cells. Using a whole muscle autograft model of muscle injury in mice, we have previously shown that inflammation and regeneration of muscle following injury are delayed by the absence of osteopontin. The current study was undertaken to determine whether muscle or non-muscle cells provide the source of osteopontin required for its role in muscle regeneration. Methods The extensor digitorum longus muscle of wild-type and osteopontin-null mice was removed and returned to its bed in the same animal (autograft) or placed in the corresponding location in an animal of the opposite genotype (allograft). Grafts were harvested at various times after surgery and analysed by histology, flow cytometry and quantitative polymerase chain reaction. Data were analysed using one- or two-way ANOVA or Kruskal-Wallis test. Results Immunohistochemistry confirmed that osteopontin was expressed by macrophages in osteopontin-null muscle allografts in wild-type hosts and by myoblasts in wild-type allografts in osteopontin-null hosts. The decrease in muscle fibre number observed in wild-type autografts following grafting and the subsequent appearance of regenerating fibres were delayed in both types of allografts to a similar extent as in osteopontin-null autografts. Infiltration of neutrophils, macrophages and M1 and M2 macrophage subtypes were also delayed by lack of osteopontin in the muscle and/or host. While the proportion of macrophages showing the M1 phenotype was not affected, the proportion showing the M2 phenotype was decreased by osteopontin deficiency. Expression of tumour necrosis factor-α and interleukin-4 was lower in osteopontin-null than in wild-type autografts, and there was no difference between the osteopontin-null graft types. Conclusions Osteopontins from muscle and non-muscle sources are equally important in the acute response of muscle to injury, and cannot substitute for each other, suggesting that they play distinct roles in regulation of cell behaviour. Future studies of mechanisms of osteopontin’s roles in acute muscle inflammation and regeneration will need to investigate responses to osteopontins derived from both myoblasts and macrophages.

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Keratinocyte-specific ablation of protease-activated receptor 2 prevents gingival inflammation and bone loss in a mouse model of periodontal disease

Cited by 9 publications

References 49 publications

Protease-activated receptors (PARs): mechanisms of action and potential therapeutic modulators in PAR-driven inflammatory diseases

Protease-activated receptors (PARs): mechanisms of action and potential therapeutic modulators in PAR-driven inflammatory diseases

The role of GPCRs in bone diseases and dysfunctions

Normal inflammation and regeneration of muscle following injury require osteopontin from both muscle and non-muscle cells

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