Transglutaminases factor XIII-A and TG2 regulate resorption, adipogenesis and plasma fibronectin homeostasis in bone and bone marrow
Open accessAbstract
Appropriate bone mass is maintained by bone-forming osteoblast and bone-resorbing osteoclasts. Mesenchymal stem cell (MSC) lineage cells control osteoclastogenesis via expression of RANKL and OPG (receptor activator of nuclear factor κB ligand and osteoprotegerin), which promote and inhibit bone resorption, respectively. Protein crosslinking enzymes transglutaminase 2 (TG2) and Factor XIII-A (FXIII-A) have been linked to activity of myeloid and MSC lineage cells; however, in vivo evidence has been lacking to support their function. In this study, we show in mice that TG2 and FXIII-A control monocyte-macrophage cell differentiation into osteoclasts as well as RANKL production in MSCs and in adipocytes. Long bones of mice lacking TG2 and FXIII-A transglutaminases, show compromised biomechanical properties and trabecular bone loss in axial and appendicular skeleton. This was caused by increased osteoclastogenesis, a cellular phenotype that persists in vitro. The increased potential of TG2 and FXIII-A deficient monocytes to form osteoclasts was reversed by chemical inhibition of TG activity, which revealed the presence of TG1 in osteoclasts and assigned different roles for the TGs as regulators of osteoclastogenesis. TG2- and FXIII-A-deficient mice had normal osteoblast activity, but increased bone marrow adipogenesis, MSCs lacking TG2 and FXIII-A showed high adipogenic potential and significantly increased RANKL expression as well as upregulated TG1 expression. Chemical inhibition of TG activity in the null cells further increased adipogenic potential and RANKL production. Altered differentiation of TG2 and FXIII-A null MSCs was associated with plasma fibronectin (FN) assembly defect in cultures and FN retention in serum and marrow in vivo instead of assembly into bone. Our findings provide new functions for TG2, FXIII-A and TG1 in bone cells and identify them as novel regulators of bone mass, plasma FN homeostasis, RANKL production and myeloid and MSC cell differentiation.
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Cornification critically relies on CASP14 and multiple transglutaminase isoforms and has long been considered a form of PCD.
“The latter process, which is commonly known as cornification (or keratinization) and critically relies on CASP14 [1026, 1027] and multiple isoforms of transglutaminase [1025, 1028, 1029], has long been considered as a form of PCD [1025, 1030].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [1029]
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Self-citationIs osteoporosis an autoimmune mediated disorder?
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- Authors
- Mousa, A., Cui, C., Song, A., Myneni, V. D., Sun, H., Li, J. J., Murshed, M., Melino, G., & Kaartinen, M. T.
- Affiliations
- McGill University (CA)
- Shriners Hospitals for Children - Canada (CA)
- University of Rome Tor Vergata (IT)
- Corresponding author
- Kaartinen, Mari T
- Venue
- Cell Death & Differentiation
- Published
- 2017-04-07
- Volume
- 24
- Issue
- 5
- Pages
- 844-854
- ISSN
- 1350-9047 (ISSN-L)
- 1476-5403
- PMC
- PMC5423109
- OpenAlex
- W2604145475
- Cited by
- 47
- References
- 61
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 5 · 2023: 4 · 2022: 5 · 2021: 4 · 2020: 7 · 2019: 6 · 2018: 10 · 2017: 2
- FWCI
- 2.79
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Cell Death and Differentiation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Cineca Institutional Research Information System (Tor Vergata University) (submittedVersion)
- Funders
- McGill University
- Réseau de Recherche en Santé Buccodentaire et Osseuse
- China Scholarship Council
- Università degli Studi di Pavia
- Canadian Institutes of Health Research (119403_1)
- Institute of Genetics
- Institute of Musculoskeletal Health and Arthritis
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Health Sciences › Medicine › Orthopedics and Sports Medicine › Bone health and osteoporosis research
- Health Sciences › Medicine › Rheumatology › Osteomyelitis and Bone Disorders Research
- Keywords
- tissue transglutaminase, factor XIII-A, transglutaminase 1, osteoclastogenesis, bone resorption, bone marrow adipogenesis, RANKL, osteoprotegerin, mesenchymal stem cells, monocyte-to-macrophage differentiation, fibronectin assembly, trabecular bone loss, bone mass regulation, osteoblasts
- MeSH terms
- Protein Glutamine gamma Glutamyltransferase 2, Animals, Bone and Bones, Bone Marrow Cells, Bone Resorption, Cell Differentiation, Fibronectins, Gene Expression Regulation, Homeostasis, Mice, Inbred CBA, Mice, Inbred C57BL, Osteoblasts, Osteoclasts, Osteogenesis, Transglutaminases, Signal Transduction, Adipocytes, Mice, Knockout, GTP-Binding Proteins, Factor XIIIa, Adipogenesis, Mice, RANK Ligand, Mesenchymal Stem Cells
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