Factor XIIIA mobilizes transglutaminase 2 to induce chondrocyte hypertrophic differentiation

Johnson, Kristen; Rose, David M.; Terkeltaub, Robert

doi:10.1242/jcs.011262

Cited by 42 publications

(35 citation statements)

References 47 publications

(82 reference statements)

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“…Several previous studies have indicated an inductive role of ␤1 integrins in hypertrophic differentiation. Signaling via ␣1␤1 and ␣5␤1 integrins was required for hypertrophy of cultured AC chondrocytes induced by transglutaminases (33,34), ␤1 integrin-blocking antibody impaired chondrocyte hypertrophy and collagen X deposition in sternal organ culture (35), and misexpression of ␣5␤1 integrin in embryonic chick legs resulted in joint fusion and initiation of the hypertrophic differentiation program (13). Finally, we have demonstrated that hypertrophic differentiation is delayed in ␤1 fl/fl -Prx1cre ؉ mice.…”

Section: Discussionmentioning

confidence: 67%

β1 Integrin Deficiency Results in Multiple Abnormalities of the Knee Joint

Raducanu

Hunziker

Drosse³

et al. 2009

Journal of Biological Chemistry

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The lack of ␤1 integrins on chondrocytes leads to severe chondrodysplasia associated with high mortality rate around birth. To assess the impact of ␤1 integrin-mediated cell-matrix interactions on the function of adult knee joints, we conditionally deleted the ␤1 integrin gene in early limb mesenchyme using the Prx1-cre transgene. Mutant mice developed short limbed dwarfism and had joint defects due to ␤1 integrin deficiency in articular regions. The articular cartilage (AC) was structurally disorganized, accompanied by accelerated terminal differentiation, altered shape, and disrupted actin cytoskeleton of the chondrocytes. Defects in chondrocyte proliferation, cytokinesis, and survival resulted in hypocellularity. However, no significant differences in cartilage erosion, in the expression of matrix-degrading proteases, or in the exposure of aggrecan and collagen II cleavage neoepitopes were observed between control and mutant AC. We found no evidence for disturbed activation of MAPKs (ERK1/2, p38, and JNK) in vivo. Furthermore, fibronectin fragment-stimulated ERK activation and MMP-13 expression were indistinguishable in control and mutant femoral head explants. The mutant synovium was hyperplastic and frequently underwent chondrogenic differentiation. ␤1-null synoviocytes showed increased proliferation and phospho-focal adhesion kinase expression. Taken together, deletion of ␤1 integrins in the limb bud results in multiple abnormalities of the knee joints; however, it does not accelerate AC destruction, perturb cartilage metabolism, or influence intracellular MAPK signaling pathways. Chondrocytes of the articular cartilage (AC)2 secrete a unique set of extracellular matrix (ECM) molecules that assemble into interactive associates composed of collagens, proteoglycans (PGs), and non-collagenous glycoproteins (1). The fibrillar collagen meshwork supplies cartilage with its tensile strength, whereas the hydrated glycosaminoglycan (GAG) chains of PGs (mainly aggrecan) generate an osmotic swelling pressure that resists compressive forces. In diarthrodial joints, the molecular composition and the physical properties of the cartilage are principal determinants for the shock-absorbing function of articular surfaces upon mechanical loading. During the development of osteoarthritis (OA), an imbalance between anabolic and catabolic processes increases the proteolysis of PGs and collagens (2, 3), which eventually leads to the mechanical weakening of the AC and culminates in its progressive destruction. Physiological and pathological remodeling of the AC ECM is primarily attributed to the activities of matrix metalloproteinases (MMPs) and a disintegrin and metalloproteinase with thrombospondin-like repeat (ADAMTS) proteases (4, 5) and is controlled by the communication between the cells and their environment.An increasing amount of evidence suggests that interactions between chondrocytes and the ECM through the integrin family of heterodimeric (␣␤) transmembrane receptors play a central role in cartilage function (6). Int...

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Section: Discussionmentioning

confidence: 67%

β1 Integrin Deficiency Results in Multiple Abnormalities of the Knee Joint

Raducanu

Hunziker

Drosse³

et al. 2009

Journal of Biological Chemistry

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“…FXIII-A also appears to be required intracellularly as exogenously added FXIII-A did not induce chondrocyte hypertrophy in mixed-strain (129Ola-CBACa) FXIII-A Ϫ/Ϫ chondrocytes (131). Induction of hypertrophy by FXIII-A and TG2 is associated with FAK and p38MAPK phosphorylation (131,279). These studies thus indicate important temporal signaling roles for FXIII-A and TG2.…”

Section: H Tg2 Fxiii-a Bone and Osteoarthritismentioning

confidence: 62%

“…208), all of which are in vitro TG substrates. Inhibition of chondrocyte transamidase activity reduces mineralization in preosteoblasts (18) and in cocultures of chondrocytes and preosteoblasts (209), while addition of either exogenous TG2 (132,209) or FXIII-A increases mineralization/hypertrophy (131). FXIII-A may have a more prominent role than TG2 in early matrix mineralization by intramolecular collagen cross-linking, as well as cross-linking collagen and noncollagenous matrix proteins (201).…”

Section: H Tg2 Fxiii-a Bone and Osteoarthritismentioning

confidence: 99%

Transglutaminases and Disease: Lessons From Genetically Engineered Mouse Models and Inherited Disorders

Iismaa¹,

Mearns²,

Lóránd³

et al. 2009

Physiological Reviews

301

336

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The human transglutaminase (TG) family consists of a structural protein, protein 4.2, that lacks catalytic activity, and eight zymogens/enzymes, designated factor XIII-A (FXIII-A) and TG1-7, that catalyze three types of posttranslational modification reactions: transamidation, esterification, and hydrolysis. These reactions are essential for biological processes such as blood coagulation, skin barrier formation, and extracellular matrix assembly but can also contribute to the pathophysiology of various inflammatory, autoimmune, and degenerative conditions. Some members of the TG family, for example, TG2, can participate in biological processes through actions unrelated to transamidase catalytic activity. We present here a comprehensive review of recent insights into the physiology and pathophysiology of TG family members that have come from studies of genetically engineered mouse models and/or inherited disorders. The review focuses on FXIII-A, TG1, TG2, TG5, and protein 4.2, as mice deficient in TG3, TG4, TG6, or TG7 have not yet been reported, nor have mutations in these proteins been linked to human disease.

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“…TG2 mRNA expression in this model system also coincides with manifestations of the articular chondrocyte hypertrophic differentiation response associated with type X collagen and MMP-13 expression. Because TG2 drives both hypertrophy of cultured chondrocytes (12) and progression of articular cartilage destruction in mouse knee OA (21), TG2 appears to be a prime example of a direct modulator of chondrocyte differentiation that affects the phenotype of tissue repair in OA.…”

Section: Discussionmentioning

confidence: 99%

“…Direct ELISA, using biotin-labeled TG2-specific antibody CUB7402 or FXIIIA specific antibody (Neomarkers, Freemont, CA) (21), was used to quantify synovial fluid levels of TG2 and FXIIIA protein (21) in studies of samples previously analyzed for COMP by ELISA (38). The fluids were concentrated with 100% TCA, and the pellet was then washed, solubilized and dissolved in buffer, and the protein was bound to a Nunc ELISA plate overnight at 4°C.…”

Section: Methodsmentioning

confidence: 99%

Transglutaminase 2 is a marker of chondrocyte hypertrophy and osteoarthritis severity in the Hartley guinea pig model of knee OA

Huebner

Johnson

Kraus

et al. 2009

Osteoarthritis and Cartilage

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Objective The transglutaminase (TG) isoenzyme TG2, which catalyzes protein cross-linking via transamidation, influences healing phenotype in multiple forms of tissue injury. Moreover, TG2 knockout suppresses cartilage destruction but promotes osteophyte formation in instability-induced mouse knee OA. TG2 is marker of growth plate chondrocyte hypertrophy. Moreover, TG2 secreted by chondrocytes acts in part by promoting chondrocyte maturation to hypertrophy, a differentiation state linked with MMP-13 expression and disease progression in OA. Moreover, glucosamine, which is currently under investigation as an OA therapy, binds and inhibits TG2. Here, we examined TG2 as a potential marker of cartilage hypertrophy in the spontaneous guinea pig model of OA. Methods Synovial fluid ELISA and cartilage Immunohistochemistry and quantitative RT-PCR, were used to examine TG2 expression and TG transamidation-catalyzed isopeptide bonds. Results TG isopeptide bonds and TG2 were most abundant in articular cartilage in early knee OA. TG2 expression was robust at sites of early but not established osteophytes. Synovial fluid TG2 correlated with knee OA total histological score (r=0.47, p=0.01), as did medial tibial plateau cartilage TG2 mRNA (r=1.0, p=0.003). At 12 months of age, medial tibial plateau cartilage TG2 mRNA expression rose markedly in association with elevated type X collagen, as well as ADAMTS-5, and MMP-13 expression, changes not shared in age-matched Strain 13 guinea pigs that are less susceptible to knee OA. Conclusion Hartley guinea pig knee TG2 expression associates with enhanced articular chondrocyte hypertrophy and is a biomarker of OA severity.

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Factor XIIIA mobilizes transglutaminase 2 to induce chondrocyte hypertrophic differentiation

Cited by 42 publications

References 47 publications

β1 Integrin Deficiency Results in Multiple Abnormalities of the Knee Joint

β1 Integrin Deficiency Results in Multiple Abnormalities of the Knee Joint

Transglutaminases and Disease: Lessons From Genetically Engineered Mouse Models and Inherited Disorders

Transglutaminase 2 is a marker of chondrocyte hypertrophy and osteoarthritis severity in the Hartley guinea pig model of knee OA

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