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.

The novel G-protein, G_h/tissue transglutaminase (TGase II), has both guanosine triphosphatase and Ca²⁺-activated transglutaminase activity and has been implicated in a number of processes including signal transduction, apoptosis, bone ossification, wound healing, and cell adhesion and spreading. To determine the role of G_h in vivo, the Cre/loxPsite-specific recombinase system was used to develop a mouse line in which its expression was ubiquitously inactivated. Despite the absence of G_h expression and a lack of intracellular TGase activity that was not compensated by other TGases, theTgm2 ^−/− mice were viable, phenotypically normal, and were born with the expected Mendelian frequency. Absence of G_h coupling to α₁-adrenergic receptor signaling in Tgm2 ^−/− mice was demonstrated by the lack of agonist-stimulated [α-³²P]GTP photolabeling of a 74-kDa protein in liver membranes. Annexin-V positivity observed with dexamethasone-induced apoptosis was not different inTgm2 ^−/− thymocytes compared withTgm2 ^+/+ thymocytes. However, with this treatment there was a highly significant decrease in the viability (propidium iodide negativity) of Tgm2 ^−/−thymocytes. Primary fibroblasts isolated fromTgm2 ^−/− mice also showed decreased adherence with culture. These results indicate that G_h may be importantly involved in stabilizing apoptotic cells before clearance, and in responses such as wound healing that require fibroblast adhesion mediated by extracellular matrix cross-linking.

Stimulating regeneration of complex tissues and organs after injury to effect complete structural and functional repair, is an attractive therapeutic option that would revolutionize clinical medicine. Compared to many metazoan phyla that show extraordinary regenerative capacity, which in some instances persists throughout life, regeneration in mammalians, particularly humans, is limited or absent. Here we consider recent insights in the elucidation of molecular mechanisms of regeneration that have come from studies of tissue homeostasis and injury repair in mammalian tissues that span the spectrum from little or no self-renewal, to those showing active cell turnover throughout life. These studies highlight the diversity of factors that constrain regeneration, including immune responses, extracellular matrix composition, age, injury type, physiological adaptation, and angiogenic and neurogenic capacity. Despite these constraints, much progress has been made in elucidating key molecular mechanisms that may provide therapeutic targets for the development of future regenerative therapies, as well as previously unidentified developmental paradigms and windows-of-opportunity for improved regenerative repair.

Rationale: Idiopathic pulmonary fibrosis (IPF) is a deadly progressive disease with few treatment options. Transglutaminase 2 (TG2) is a multifunctional protein, but its function in pulmonary fibrosis is unknown. Objectives: To determine the role of TG2 in pulmonary fibrosis. Methods: The fibrotic response to bleomycin was compared between wild-type and TG2 knockout mice. Transglutaminase and transglutaminase-catalyzed isopeptide bond expression was examined in formalin-fixed human lung biopsy sections by immunohistochemistry from patients with IPF. In addition, primary human lung fibroblasts were used to study TG2 function in vitro. Measurements and Main Results: TG2 knockout mice developed significantly reduced fibrosis compared with wild-type mice as determined by hydroxyproline content and histologic fibrosis score (P < 0.05). TG2 expression and activity are increased in lung biopsy sections in humans with IPF compared with normal control subjects. In vitro overexpression of TG2 led to increased fibronectin deposition, whereas transglutaminase knockdown led to defects in contraction and adhesion. The profibrotic cytokine transforming growth factor-β causes an increase in membrane-localized TG2, increasing its enzymatic activity. Conclusions: TG2 is involved in pulmonary fibrosis in a mouse model and in human disease and is important in normal fibroblast function. With continued research on TG2, it may offer a new therapeutic target.