TNF-induced osteoclastogenesis and inflammatory bone resorption are inhibited by transcription factor RBP-J

Zhao, Baohong; Grimes, Shannon N.; Li, Susan; Hu, Xiaoyu; Ivashkiv, Lionel B.

doi:10.1083/jcb1962oia2

Cited by 38 publications

(89 citation statements)

References 25 publications

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“…Osteoclast-specific depletion of RBPjκ increases TNF-induced osteoclast formation (12) and local bone erosion in antibody-induced arthritis (41). The NOTCH/RBPjκ pathway promotes LPS-induced M1 inflammatory macrophage polarization (42), while osteoclasts are derived from M2 housekeeping macrophages (43).…”

Section: Figurementioning

confidence: 99%

NOTCH inhibits osteoblast formation in inflammatory arthritis via noncanonical NF-κB

Zhang¹,

Hilton²,

Anolik³

et al. 2014

J. Clin. Invest.

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NOTCH-dependent signaling pathways are critical for normal bone remodeling; however, it is unclear if dysfunctional NOTCH activation contributes to inflammation-mediated bone loss, as observed in rheumatoid arthritis (RA) patients. We performed RNA sequencing and pathway analyses in mesenchymal stem cells (MSCs) isolated from transgenic TNF-expressing mice, a model of RA, to identify pathways responsible for decreased osteoblast differentiation. 53 pathways were dysregulated in MSCs from RA mice, among which expression of genes encoding NOTCH pathway members and members of the noncanonical NF-κB pathway were markedly elevated. Administration of NOTCH inhibitors to RA mice prevented bone loss and osteoblast inhibition, and CFU-fibroblasts from RA mice treated with NOTCH inhibitors formed more new bone in recipient mice with tibial defects. Overexpression of the noncanonical NF-κB subunit p52 and RELB in a murine pluripotent stem cell line increased NOTCH intracellular domain-dependent (NICD-dependent) activation of an RBPjκ reporter and levels of the transcription factor HES1. TNF promoted p52/RELB binding to NICD, which enhanced binding at the RBPjκ site within the Hes1 promoter. Furthermore, MSC-enriched cells from RA patients exhibited elevated levels of HES1, p52, and RELB. Together, these data indicate that persistent NOTCH activation in MSCs contributes to decreased osteoblast differentiation associated with RA and suggest that NOTCH inhibitors could prevent inflammation-mediated bone loss. IntroductionPatients with chronic inflammatory diseases, such as rheumatoid arthritis (RA), often have severe systemic bone loss and increased risk of fracture due to increased bone resorption and decreased bone formation, partially mediated by elevated TNF levels (1). We (1-4) and others (5, 6) have reported that TNF inhibits bone formation by affecting major osteoblast regulatory pathways, including BMP/SMAD/RUNX2 and WNT-β-catenin, but the role of TNF in osteoblast differentiation from MSCs has not been fully defined. The TNF transgenic (TNF-Tg) mouse model we use, line 3647, represents a good model of RA to study the influence of chronically elevated, but relatively low, levels of TNF and TNF-induced inflammation on bone cell function and MSC differentiation into osteoblasts (7). To attempt to identify molecules responsible for reduced differentiation of MSCs into osteoblasts in RA, we performed genome-wide screening and pathway analyses using data from RNA sequencing (RNA-Seq) of MSCs purified from TNF-Tg mice and WT littermates. We found that genes in the NOTCH and noncanonical NF-κB signaling pathways were markedly upregulated in TNF-Tg mouse MSCs, raising the possibility that NOTCH may interact with noncanonical NF-κB proteins in MSCs to inhibit their osteogenic differentiation.NOTCH is a family of evolutionarily conserved receptors that regulate cell fate. NOTCH receptors are activated following direct contact with their ligands expressed on adjacent cells. In mammals, there are 4 NOTCH receptors (NOTCH1-NOTCH4)...

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Section: Figurementioning

confidence: 99%

NOTCH inhibits osteoblast formation in inflammatory arthritis via noncanonical NF-κB

Zhang¹,

Hilton²,

Anolik³

et al. 2014

J. Clin. Invest.

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“…However, TNF-a plays a key role in the pathogenesis of inflammatory bone resorption and associated morbidity in RA. 24 The present study showed that transfection of siCx43 inhibited the expression of TNF-a in RASFs. These observations suggest that Cx43 may play a crucial role in osteoclastogenesis of RA through interaction with TNF-a signaling.…”

Section: Discussionmentioning

confidence: 81%

Expression of Connexin 43 in Synovial Tissue of Patients With Rheumatoid Arthritis

et al. 2016

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“…Since IO was demonstrated to induce the TNF-α expression that further triggers osteoclastic function (13,22,23), the TNF-α level was measured. Consistent with a previous study (13), the TNF-α level in the IO mice was approximately 1.5-fold higher compared to the control group (Fig.…”

Section: Resultsmentioning

confidence: 99%

Excess iron undermined bone load-bearing capacity through tumor necrosis factor-α-dependent osteoclastic activation in mice

Hou²,

Zhang

et al. 2012

Biomedical Reports

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Abstract. Iron overload has been associated with bone mass loss. To elucidate the effects of excess iron on bone metabolism, an iron-overloading mouse model was established by administering iron-dextran at 250 mg/kg to female BALB/c mice. After 4 weeks, the mice were sacrificed and the biomechanical properties of the femurs were examined. The results suggested a notable decrease of the maximal bending stress and the modulus of bending elasticity in the femurs obtained from the excess iron-treated mice compared to the control mice. The levels of the serum osteocalcin, C-telopeptide of type I collagen (CTX-1) and tumor necrosis factor-α (TNF-α) were measured in order to investigate the underlying mechanism responsible for the excess iron-induced bone strength reduction. Overall, the results suggested that iron overload resulted in a marked reduction of bone load-bearing capacity through a TNF-triggered osteoclast differentiation and resorption mechanism.

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TNF-induced osteoclastogenesis and inflammatory bone resorption are inhibited by transcription factor RBP-J

Cited by 38 publications

References 25 publications

NOTCH inhibits osteoblast formation in inflammatory arthritis via noncanonical NF-κB

NOTCH inhibits osteoblast formation in inflammatory arthritis via noncanonical NF-κB

Expression of Connexin 43 in Synovial Tissue of Patients With Rheumatoid Arthritis

Excess iron undermined bone load-bearing capacity through tumor necrosis factor-α-dependent osteoclastic activation in mice

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