Dataset Information

Plastin 3 in X-Linked Osteoporosis: Imbalance of Ca²⁺-Dependent Regulation Is Equivalent to Protein Loss.

ABSTRACT: Osteogenesis imperfecta is a genetic disorder disrupting bone development and remodeling. The primary causes of osteogenesis imperfecta are pathogenic variants of collagen and collagen processing genes. However, recently variants of the actin bundling protein plastin 3 have been identified as another source of osteogenesis imperfecta. Plastin 3 is a highly conserved protein involved in several important cellular structures and processes and is controlled by intracellular Ca²⁺ which potently inhibits its actin-bundling activity. The precise mechanisms by which plastin 3 causes osteogenesis imperfecta remain unclear, but recent advances have contributed to our understanding of bone development and the actin cytoskeleton. Here, we review the link between plastin 3 and osteogenesis imperfecta highlighting in vitro studies and emphasizing the importance of Ca²⁺ regulation in the localization and functionality of plastin 3.

SUBMITTER: Schwebach CL

PROVIDER: S-EPMC7859272 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Plastin 3 in X-Linked Osteoporosis: Imbalance of Ca<sup>2+</sup>-Dependent Regulation Is Equivalent to Protein Loss.

Schwebach Christopher L CL Kudryashova Elena E Kudryashov Dmitri S DS

Frontiers in cell and developmental biology 20210121

Osteogenesis imperfecta is a genetic disorder disrupting bone development and remodeling. The primary causes of osteogenesis imperfecta are pathogenic variants of collagen and collagen processing genes. However, recently variants of the actin bundling protein plastin 3 have been identified as another source of osteogenesis imperfecta. Plastin 3 is a highly conserved protein involved in several important cellular structures and processes and is controlled by intracellular Ca<sup>2+</sup> which po ...[more]

PMID: 33553175

Similar Datasets

Project description:In inflammatory arthritis, the dysregulation of osteoclast activity by proinflammatory cytokines, including TNF, interferes with bone remodeling during inflammation through Ca2+-dependent mechanisms causing pathological bone loss. Ca2+-dependent CREB/c-fos activation via Ca2+-calmodulin kinase IV (CaMKIV) induces transcriptional regulation of osteoclast-specific genes via NFATc1, which facilitate bone resorption. In leukocytes, Ca2+ regulation of NFAT-dependent gene expression oftentimes involves the activity of the Ca2+-activated K+ channel KCa3.1. In this study, we evaluate KCa3.1 as a modulator of Ca2+-induced NFAT-dependent osteoclast differentiation in inflammatory bone loss. Microarray analysis of receptor activator of NF-κB ligand (RANKL)-activated murine bone marrow macrophage (BMM) cultures revealed unique upregulation of KCa3.1 during osteoclastogenesis. The expression of KCa3.1 in vivo was confirmed by immunofluorescence staining on multinucleated cells at the bone surface of inflamed mouse joints. Experiments on in vitro BMM cultures revealed that KCa3.1-/- and TRAM-34 treatment significantly reduced the expression of osteoclast-specific genes (p < 0.05) alongside decreased osteoclast formation (p < 0.0001) in inflammatory (RANKL+TNF) and noninflammatory (RANKL) conditions. In particular, live cell Ca2+ imaging and Western blot analysis showed that TRAM-34 pretreatment decreased transient RANKL-induced Ca2+ amplitudes in BMMs by ∼50% (p < 0.0001) and prevented phosphorylation of CaMKIV. KCa3.1-/- reduced RANKL+/-TNF-stimulated phosphorylation of CREB and expression of c-fos in BMMs (p < 0.01), culminating in decreased NFATc1 protein expression and transcriptional activity (p < 0.01). These data indicate that KCa3.1 regulates Ca2+-dependent NFATc1 expression via CaMKIV/CREB during inflammatory osteoclastogenesis in the presence of TNF, corroborating its role as a target candidate for the treatment of bone erosion in inflammatory arthritis.

Dataset Information

Plastin 3 in X-Linked Osteoporosis: Imbalance of Ca²⁺-Dependent Regulation Is Equivalent to Protein Loss.

Publications

Plastin 3 in X-Linked Osteoporosis: Imbalance of Ca<sup>2+</sup>-Dependent Regulation Is Equivalent to Protein Loss.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

Plastin 3 in X-Linked Osteoporosis: Imbalance of Ca2+-Dependent Regulation Is Equivalent to Protein Loss.

Publications

Plastin 3 in X-Linked Osteoporosis: Imbalance of Ca<sup>2+</sup>-Dependent Regulation Is Equivalent to Protein Loss.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Plastin 3 in X-Linked Osteoporosis: Imbalance of Ca²⁺-Dependent Regulation Is Equivalent to Protein Loss.