The Role of Ca2+-NFATc1 Signaling and Its Modulation on Osteoclastogenesis

Kang, Joong Koo; Kang, Namju; Yang, Young-Kyu; Hong, Jeong Hee; Shin, Dong Min

doi:10.3390/ijms21103646

Cited by 61 publications

(35 citation statements)

References 133 publications

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“…Notch2 was reported to exhibit a stimulatory effect on osteoclastogenesis. RANKL induces Notch2 expression during osteoclast differentiation, and overexpression of NICD2 interacting with NF-κB results in activation of NFATc1, a master transcription factor regulating osteoclastogenesis [ 39 , 40 , 41 ]. Furthermore, a mutant receptor Notch2 mouse model was shown to reproduce the Hajdu Cheney syndrome (HCS).…”

Section: The Role Of Notch Signaling In Adult Bone Metabolismmentioning

confidence: 99%

Relevance of Notch Signaling for Bone Metabolism and Regeneration

Ballhause

Jiang

Baranowsky

et al. 2021

IJMS

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Notch1-4 receptors and their signaling pathways are expressed in almost all organ systems and play a pivotal role in cell fate decision by coordinating cell proliferation, differentiation and apoptosis. Differential expression and activation of Notch signaling pathways has been observed in a variety of organs and tissues under physiological and pathological conditions. Bone tissue represents a dynamic system, which is constantly remodeled throughout life. In bone, Notch receptors have been shown to control remodeling and regeneration. Numerous functions have been assigned to Notch receptors and ligands, including osteoblast differentiation and matrix mineralization, osteoclast recruitment and cell fusion and osteoblast/osteoclast progenitor cell proliferation. The expression and function of Notch1-4 in the skeleton are distinct and closely depend on the temporal expression at different differentiation stages. This review addresses the current knowledge on Notch signaling in adult bone with emphasis on metabolism, bone regeneration and degenerative skeletal disorders, as well as congenital disorders associated with mutant Notch genes. Moreover, the crosstalk between Notch signaling and other important pathways involved in bone turnover, including Wnt/β-catenin, BMP and RANKL/OPG, are outlined.

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Section: The Role Of Notch Signaling In Adult Bone Metabolismmentioning

confidence: 99%

Relevance of Notch Signaling for Bone Metabolism and Regeneration

Ballhause

Jiang

Baranowsky

et al. 2021

IJMS

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“…The loss of MEF2C resulted in lack of hyperthophic chondrocytes and absence of endochondral bone formation, whereas MEF2C overexpression led to excessive bone formation [57]. The function of NFATc in bone is most recognized as an essential regulator of osteoclastogenesis from myeloid progenitors [58], but in osteoblasts its role is more controversial, with some opposing outcomes depending on the system used. Overexpression of a nuclear-restricted form of NFATc1 in mice leads to higher bone mass, osteoblast overgrowth and enhanced proliferation [59].…”

Section: Discussionmentioning

confidence: 99%

The Osteogenesis Imperfecta Type V Mutant BRIL/IFITM5 Promotes Transcriptional Activation of MEF2, NFATc, and NR4A in Osteoblasts

Maranda

Gaumond

Moffatt

2022

IJMS

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BRIL (bone restricted ifitm-like; also known as IFITM5) is a transmembrane protein expressed in osteoblasts. Although its role in skeletal development and homeostasis is unknown, mutations in BRIL result in rare dominant forms of osteogenesis imperfecta. The pathogenic mechanism has been proposed to be a gain-of or neomorphic function. To understand the function of BRIL and its OI type V mutant (MALEP BRIL) and whether they could activate signaling pathways in osteoblasts, we performed a luciferase reporter assay screen based on the activity of 26 transcription factors. When overexpressed in MC3T3-E1 and MLO-A5 cells, the MALEP BRIL activated the reporters dependent on MEF2, NFATc, and NR4A significantly more. Additional co-transfection experiments with MEF2C and NFATc1 and a number of their modulators (HDAC4, calcineurin, RCAN, FK506) confirmed the additive or synergistic activation of the pathways by MALEP, and suggested a coordinated regulation involving calcineurin. Endogenous levels of Nr4a members, as well as Ptgs2, were upregulated by MALEP BRIL. Y2H and co-immunoprecipitation indicated that BRIL interacted with CAML, but its contribution as the most upstream stimulator of the Ca2+-calcineurin-MEF2/NFATc cascade was not confirmed convincingly. Altogether the data presented provide the first ever readout to monitor for BRIL activity and suggest a potential gain-of-function causative effect for MALEP BRIL in OI type V, leading to perturbed signaling events and gene expression.

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“…TLRs have been implicated in promoting osteoclast-mediated bone resorption that is associated with inflammatory conditions [ 19 , 20 , 21 ]. LPS completely abrogates the RANKL-induced expression of B lymphocyte-induced maturation protein-1 (Blimp1), a global transcriptional repressor of anti-osteoclastogenic genes encoding Bcl6, IRF8, and MafB [ 22 ].…”

Section: Discussionmentioning

confidence: 99%

Ibudilast Mitigates Delayed Bone Healing Caused by Lipopolysaccharide by Altering Osteoblast and Osteoclast Activity

Chang

et al. 2021

IJMS

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Bacterial infection in orthopedic surgery is challenging because cell wall components released after bactericidal treatment can alter osteoblast and osteoclast activity and impair fracture stability. However, the precise effects and mechanisms whereby cell wall components impair bone healing are unclear. In this study, we characterized the effects of lipopolysaccharide (LPS) on bone healing and osteoclast and osteoblast activity in vitro and in vivo and evaluated the effects of ibudilast, an antagonist of toll-like receptor 4 (TLR4), on LPS-induced changes. In particular, micro-computed tomography was used to reconstruct femoral morphology and analyze callus bone content in a femoral defect mouse model. In the sham-treated group, significant bone bridge and cancellous bone formation were observed after surgery, however, LPS treatment delayed bone bridge and cancellous bone formation. LPS inhibited osteogenic factor-induced MC3T3-E1 cell differentiation, alkaline phosphatase (ALP) levels, calcium deposition, and osteopontin secretion and increased the activity of osteoclast-associated molecules, including cathepsin K and tartrate-resistant acid phosphatase in vitro. Finally, ibudilast blocked the LPS-induced inhibition of osteoblast activation and activation of osteoclast in vitro and attenuated LPS-induced delayed callus bone formation in vivo. Our results provide a basis for the development of a novel strategy for the treatment of bone infection.

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The Role of Ca2+-NFATc1 Signaling and Its Modulation on Osteoclastogenesis

Cited by 61 publications

References 133 publications

Relevance of Notch Signaling for Bone Metabolism and Regeneration

Relevance of Notch Signaling for Bone Metabolism and Regeneration

The Osteogenesis Imperfecta Type V Mutant BRIL/IFITM5 Promotes Transcriptional Activation of MEF2, NFATc, and NR4A in Osteoblasts

Ibudilast Mitigates Delayed Bone Healing Caused by Lipopolysaccharide by Altering Osteoblast and Osteoclast Activity

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