Osteoblast-specific Notch2 inactivation causes increased trabecular bone mass at specific sites of the appendicular skeleton

Yorgan, Timur Alexander; Vollersen, Nele; Riedel, Christoph; Jeschke, Anke; Peters, Stephanie; Busse, Björn; Amling, Michael; Schinke, Thorsten

doi:10.1016/j.bone.2016.04.012

Cited by 37 publications

(36 citation statements)

References 40 publications

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“…Notch1 and Notch2 regulate bone remodeling, and their actions are determined by the degree of osteoblast maturity [20]. In contrast to the bone anabolic effects of PTH, induction of Notch1 in mesenchymal precursor cells and mature osteoblasts suppresses cell differentiation and trabecular bone formation, and Notch2 exerts similar inhibitory effects on osteoblast function [21–26]. Conversely, activation of Notch1 in osteocytes induces osteoprotegerin and suppresses sclerostin, leading to an osteopetrotic phenotype [23, 27].…”

Section: Introductionmentioning

confidence: 99%

Parathyroid hormone inhibits Notch signaling in osteoblasts and osteocytes

Zanotti

Canalis

2017

Bone

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Parathyroid hormone (PTH) and Notch receptors regulate bone formation by governing the function of osteoblastic cells. To determine whether PTH interacts with Notch signaling as a way to control osteoblast function, we tested the effects of PTH on Notch activity in osteoblast- and osteocyte-enriched cultures. Notch signaling was activated in osteoblast-enriched cells from wild-type C57BL/6J mice following exposure to the Notch ligand Delta-like (Dll)1 or by the transient transfection of the Notch intracellular domain (NICD), the transcriptionally active fragment of Notch1. To induce Notch signaling in osteocyte-enriched cultures, a murine model of Notch2 gain-of-function was used. PTH opposed the stimulatory effects of Dll1 on Hey1, Hey2 and HeyL mRNA levels in osteoblast-enriched cells and suppressed the expression of selected Notch target genes in osteocyte-enriched cultures, either under basal conditions or in the context of Notch2 gain-of-function. Induction of Notch signaling in osteocytes did not alter the inhibitory effect of PTH on Sost expression, but reduced the stimulation of Tnfsf11 mRNA levels by PTH. In agreement with these in vitro observations, male mice administered with PTH displayed suppressed Hey1 and HeyL expression in parietal bones. Transactivation experiments with a Notch reporter construct and electrophoretic mobility shift assays in osteoblast-enriched cells suggest that PTH acts by decreasing the capacity of Rbpjκ to bind to DNA. In conclusion, downregulation of Notch in osteoblasts and osteocytes may represent a mechanism contributing to the anabolic effects of PTH in bone.

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Section: Introductionmentioning

confidence: 99%

Parathyroid hormone inhibits Notch signaling in osteoblasts and osteocytes

Zanotti

Canalis

2017

Bone

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“…A common explanation for these observations is that Notch signaling influences the maintenance of the mesenchymal stem cell pool and the differentiation of osteoprogenitor cells. Consistently, we have previously observed that Runx2‐Cre –mediated osteoblast‐specific inactivation of Notch2 causes an increase in osteoblastogenesis, triggering excessive bone formation at specific sites of the appendicular skeleton …”

Section: Introductionmentioning

confidence: 99%

High Bone Turnover in Mice Carrying a Pathogenic Notch2 Mutation Causing Hajdu-Cheney Syndrome

Vollersen

Hermans‐Borgmeyer

Cornils

et al. 2017

Journal of Bone and Mineral Research

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Hajdu-Cheney syndrome (HCS) is a rare autosomal-dominant disorder primarily characterized by acro-osteolysis and early-onset osteoporosis. Genetically, HCS is caused by nonsense or deletion mutations within exon 34 of the NOTCH2 gene, resulting in premature translational termination and production of C-terminally truncated NOTCH2 proteins that are predicted to activate NOTCH2-dependent signaling. To understand the role of Notch2 in bone remodeling, we developed a mouse model of HCS by introducing a pathogenic mutation (6272delT) into the murine Notch2 gene. By mCT and undecalcified histology, we observed generalized osteopenia in two independent mouse lines derived by injection of different targeted embryonic stem (ES) cell clones, yet acro-osteolysis did not occur until the age of 52 weeks. Cellular and dynamic histomorphometry revealed a high bone turnover situation in Notch2 þ/HCS mice, since osteoblast and osteoclast indices were significantly increased compared with wild-type littermates. Whereas ex vivo cultures failed to uncover cell-autonomous gain-of-functions within the osteoclast or osteoblast lineage, an unbiased RNA sequencing approach identified Tnfsf11 and Il6 as Notch-signaling target genes in bone marrow cells cultured under osteogenic conditions. Because we further observed that the high-turnover pathology of Notch2 þ/HCS mice was fully normalized by alendronate treatment, our results demonstrate that mutational activation of Notch2 does not directly control osteoblast activity but favors a pro-osteoclastic gene expression pattern, which in turn triggers high bone turnover.

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“…Reports have shown that the Notch signaling pathway plays an important role in modulating the differentiation of osteoblasts and osteoclasts . Yorgan et al .…”

Section: Introductionmentioning

confidence: 99%

“…Yorgan et al . have found that inhibiting osteoblast‐specific Notch2 in mice leads to increased trabecular bone mass at specific sites of the appendicular skeleton. In mammals, there are four notch receptors, Notch1‐4, that span the cell membrane where they participate in cell–cell communication.…”

Section: Introductionmentioning

confidence: 99%

CHI3L1 regulation of inflammation and the effects on osteogenesis in a Staphylococcus aureus‐induced murine model of osteomyelitis

Chen

He²,

Zhang³

et al. 2017

The FEBS Journal

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Osteomyelitis is an inflammation of the bone and bone marrow that occurs as a consequence of infections mainly attributed to Staphylococcus aureus. In a previous study, we found that expression of the chitinase 3-like 1 (CHI3L1) gene affected mineralization of MC3T3-E1 cells infected with S. aureus and there was increased expression of CHI3L1 in the blood of osteomyelitis patients. In the present study, to further investigate the role of CHI3L1 in osteomyelitis, we developed an S. aureus-induced murine model of the disease. We found that the expression of CHI3L1 was significantly up-regulated in femurs of mice infected with S. aureus compared with mice inoculated with a PBS control. To investigate these results further, we performed a CHI3L1 knock-down by lentivirus-mediated RNA interference in mice. Micro-computed tomography of infected femurs revealed that S. aureus triggers profound alterations in bone turnover, and femurs of CHI3L1 short hairpin RNA (shRNA-CHI3L1)-injected mice infected with S. aureus have significantly less cortical bone destruction when compared with control mice infected with S. aureus. Inhibition of CHI3L1 also decreased inflammation by reducing levels of proinflammatory cytokines and promoted the process of osteogenesis. The Notch signaling pathway has been shown to play an important role in modulating the differentiation of osteoblasts and osteoclasts. Our study showed that Notch1, Jagged1 and Hes1 expression significantly decreased in mice infected with S. aureus compared with the control, and shRNA-CHI3L1 could increase their level in S. aureus-infected mice. This research indicates that inhibition of CHI3L1 can reduce the debilitating effects of S. aureus in a murine model of osteomyelitis.

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Osteoblast-specific Notch2 inactivation causes increased trabecular bone mass at specific sites of the appendicular skeleton

Cited by 37 publications

References 40 publications

Parathyroid hormone inhibits Notch signaling in osteoblasts and osteocytes

Parathyroid hormone inhibits Notch signaling in osteoblasts and osteocytes

High Bone Turnover in Mice Carrying a Pathogenic Notch2 Mutation Causing Hajdu-Cheney Syndrome

CHI3L1 regulation of inflammation and the effects on osteogenesis in a Staphylococcus aureus‐induced murine model of osteomyelitis

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