Abstract
Transglutaminase 2 (TG2) performs multiple reactions, including transamidation, and also plays a role in signal transduction as a GTP-binding protein. In this study, we reveal that TG2 controls osteoclast differentiation and bone homeostasis in mice. Osteoclasts specifically expressed the TG2 isoform among eight TG family members. Suppression in TG2 expression with siRNA led to increased osteoclast formation from primary mouse precursor cells in response to receptor activator of nuclear factor kappaB ligand (RANKL). This osteoclastogenic effect of TG2 knockdown was associated with enhanced induction of c-Fos and NFATc1 by RANKL. Moreover, TG2 knockdown up-regulated B lymphocyte-induced maturation protein 1 (Blimp1), which represses anti-osteoclastogenic genes, in a manner dependent on the NF-κB signaling pathway. To the contrary, TG2 overexpression inhibited osteoclast formation and the expression of osteoclastogenic genes. Consistent with these in vitro results, TG2 knockout mice exhibited lower trabecular bone mass and increased number of osteoclasts compared with wild-type mice. Taken together, our results provide strong evidence that TG2 plays an important role in bone metabolism by suppressing excessive osteoclastogenesis via the regulation of the NF-κB-Blimp1 signaling pathway.
Highlights
Bone is a dynamic tissue that is continuously remodeled through the coupled actions of osteoclasts and osteoblasts[1]
We first examined the expression profile of TG family members in osteoclast precursors (BMMs) and pre-fusion osteoclasts
As Transglutaminase 2 (TG2) was the only TG members expressed at a significant level, we investigated the role of TG2 in osteoclastogenesis by evaluating the effect of TG2 reduction using a siRNA-mediated gene knockdown system
Summary
Bone is a dynamic tissue that is continuously remodeled through the coupled actions of osteoclasts and osteoblasts[1]. M-CSF is critical for the commitment, proliferation, and survival of monocyte/macrophage lineage cells, while RANKL induces the differentiation and fusion of precursor cells into multinucleated cells (MNCs) expressing osteoclast specific genes, such as tartrate-resistant acid phosphatase (TRAP)[4, 5]. RANKL stimulation leads to the activation and induction of the transcription factors NF-κB, c-Fos, and nuclear factor of activated T-cells cytoplasmic 1 (NFATc1)[7,8,9] These transcription factors promote the expression of osteoclast marker genes, including TRAP, v-ATPase subunit d2 (ATP6v0d2), and dendritic cell-specific transmembrane protein (DC-STAMP)[10, 11]. TG family enzymes catalyze posttranslational modifications of various substrates via transamidation, esterification, and hydrolysis reactions in a Ca2+-dependent manner These TG-mediated reactions have an impact on diverse cellular responses, including proliferation[18], differentiation[19], death[20], and migration[21]. Ca2+ and GTP are the most important regulators of TG2 and act as switches between the two distinct functional entities of TG2, transglutaminase and GTP hydrolase, via allosteric modulation[23, 26, 27]
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