Decreased Mechanical Strength and Collagen Content in SPARC-Null Periodontal Ligament Is Reversed by Inhibition of Transglutaminase Activity

Trombetta-eSilva, Jessica; Rosset, Emilie A; Hepfer, R. Glenn; Wright, Gregory J.; Baicu, Catalin F.; Yao, Hai; Bradshaw, Amy D.

doi:10.1002/jbmr.2522

Cited by 18 publications

(31 citation statements)

References 40 publications

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“…While an osteopenic skeletal phenotype was apparent in the original description of MT1-MMP −/− mice [6], subsequent work has identified regulatory roles for MT1-MMP in osteoblast differentiation, osteocyte function, and osteogenesis-related signaling pathways [5, 60-65]. A more direct effect on mineralization may result from enzymatic activity of MT1-MMP on ECM-modifying factors such as transglutaminase 2 (TG2), present in bone, teeth, and the PDL [66, 67]. Cleavage of TG2 by MT1-MMP was shown to alter its cross-linking and ATPase activity in osteoblasts, and inhibition of MT1-MMP decreased osteoblast mineralization, in vitro [68], though the function of TG2 in skeletal mineralization remains unclear [69].…”

Section: Discussionmentioning

confidence: 99%

Multiple essential MT1-MMP functions in tooth root formation, dentinogenesis, and tooth eruption

Snider

Wimer

et al. 2016

Matrix Biology

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Membrane-type matrix metalloproteinase 1 (MT1-MMP) is a transmembrane zinc-endopeptidase that breaks down extracellular matrix components, including several collagens, during tissue development and physiological remodeling. MT1-MMP-deficient mice (MT1-MMP−/−) feature severe defects in connective tissues, such as impaired growth, osteopenia, fibrosis, and conspicuous loss of molar tooth eruption and root formation. In order to define the functions of MT1-MMP during root formation and tooth eruption, we analyzed the development of teeth and surrounding tissues in the absence of MT1-MMP. In situ hybridization showed that MT1-MMP was widely expressed in cells associated with teeth and surrounding connective tissues during development. Multiple defects in dentoalveolar tissues were associated with loss of MT1-MMP. Root formation was inhibited by defective structure and function of Hertwig's epithelial root sheath (HERS). However, no defect was found in creation of the eruption pathway, suggesting that tooth eruption was hampered by lack of alveolar bone modeling/remodeling coincident with reduced periodontal ligament (PDL) formation and integration with the alveolar bone. Additionally, we identified a significant defect in dentin formation and mineralization associated with the loss of MT1-MMP. To segregate these multiple defects and trace their cellular origin, conditional ablation of MT1-MMP was performed in epithelia and mesenchyme. Mice featuring selective loss of MT1-MMP activity in the epithelium were indistinguishable from wild type mice, and importantly, featured a normal HERS structure and molar eruption. In contrast, selective knock-out of MT1-MMP in Osterix-expressing mesenchymal cells, including osteoblasts and odontoblasts, recapitulated major defects from the global knock-out including altered HERS structure, short roots, defective dentin formation and mineralization, and reduced alveolar bone formation, although molars were able to erupt. These data indicate that MT1-MMP activity in the dental mesenchyme, and not in epithelial-derived HERS, is essential for proper tooth root formation and eruption. In summary, our studies point to an indispensable role for MT1-MMP-mediated matrix remodeling in tooth eruption through effects on bone formation, soft tissue remodeling and organization of the follicle/PDL region.

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Section: Discussionmentioning

confidence: 99%

Multiple essential MT1-MMP functions in tooth root formation, dentinogenesis, and tooth eruption

Snider

Wimer

et al. 2016

Matrix Biology

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“…Administration of TG inhibitors to SPARC-null PDL resulted in increased collagen content and the generation of larger collagen fibers. The increase in collagen content and the rescued morphology of the collagen fibers was associated with enhanced mechanical strength of the PDL [28]. This study raises the possibility that SPARC bound to collagen reduces accessibility of TGs to certain glutamine and/or lysine residues on collagen.…”

Section: Transglutaminasementioning

confidence: 97%

“…Whether similar SPARC-dependent mechanisms used by fibroblasts control procollagen processing and assembly used by osteoblasts should prove enlightening for future studies. Another extracellular mechanism by which SPARC was recently shown to affect collagen fibril diameter and content, relevant to mineralized tissues, was the regulation of transglutaminase enzyme activity on collagen [28]. …”

Section: Sparc In Procollagen Processing and Fibril Assemblymentioning

confidence: 99%

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SPARC/osteonectin in mineralized tissue

2016

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Secreted protein acidic and rich in cysteine (SPARC/osteonectin/BM40) is one of the most abundant non-collagenous protein expressed in mineralized tissues. This review will focus on elucidating functional roles of SPARC in bone formation building upon results from non-mineralized cells and tissues, the phenotype of SPARC-null bones, and recent discoveries of human diseases with either dysregulated expression of SPARC or mutations in the gene encoding SPARC that give rise to bone pathologies. The capacity of SPARC to influence pathways involved in extracellular matrix assembly such as procollagen processing and collagen fibril formation as well as the capacity to influence osteoblast differentiation and osteoclast activity will be addressed. In addition, the potential for SPARC to regulate cross-linking of extracellular matrix proteins by members of the transglutaminase family of enzymes is explored. Elucidating defined biological functions of SPARC in terms of bone formation and turnover are critical. Further insight into specific cellular mechanisms involved in the formation and homeostasis of mineralized tissues will lead to a better understanding of disease progression.

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“…Previously, utilizing transgenic SPARC‐null mice that show global reductions in collagen content and fiber thickness, we identified TG activity as a key factor in mediating the collagen phenotype in SPARC‐null PDL . Increased TG activity in SPARC‐null PDL resulted in increased immunoreactivity for TG cross‐links and the formation of tighter, thinner collagen fibers.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of transglutaminase activity in periodontitis rescues periodontal ligament collagen content and architecture

Rosset

Trombetta-eSilva

Hepfer

et al. 2019

J of Periodontal Research

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Background and objective Periodontal disease (PD) afflicts approximately 50% of the population in the United States and is characterized by chronic inflammation of the periodontium that can lead to loss of the periodontal ligament through collagen degradation, loss of alveolar bone, and to eventual tooth loss. Previous studies have implicated transglutaminase (TG) activity in promoting thin collagen I fiber morphology and decreased mechanical strength in homeostatic PDL. The aim of this study was to determine whether TG activity influenced collagen assembly in PDL in the setting of periodontal disease. Material and methods A ligature model was used to induce clinically relevant PD in mice. Mice with ligature were assessed at 5 and 14 days to determine PDL collagen morphology, transglutaminase (TG) activity, and bone loss. The effects of inhibition of TG on PDL were assessed by immunohistochemistry and second‐harmonic generation (SHG) to visualize collagen fibers in native tissue. Results Ligature placement around the 2nd molar resulted in significant bone loss and a decrease in total collagen content after 5 days of ligature placement. A significant increase in thin over thick fibers was also demonstrated in mice with ligature at 5 days associated with apparent increases in immunoreactivity for TG2 and for TG‐mediated N‐ε‐γ‐glutamyl cross‐links in PDL. Inhibition of TG activity increased total collagen and thick collagen fiber content over vehicle control in mice with ligature for 5 days. SHG of PDL was used to visualize and quantify the effects of TG inhibition on enhanced collagen fiber organization in unfixed control and diseased PDL. Conclusion These studies support a role of TG in regulating collagen fiber assembly and suggest that strategies to inhibit TG activity in disease might contribute to restoration of PDL tissue integrity.

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Decreased Mechanical Strength and Collagen Content in SPARC-Null Periodontal Ligament Is Reversed by Inhibition of Transglutaminase Activity

Cited by 18 publications

References 40 publications

Multiple essential MT1-MMP functions in tooth root formation, dentinogenesis, and tooth eruption

Multiple essential MT1-MMP functions in tooth root formation, dentinogenesis, and tooth eruption

SPARC/osteonectin in mineralized tissue

Inhibition of transglutaminase activity in periodontitis rescues periodontal ligament collagen content and architecture

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