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Project description:The role of histone ubiquitination in directing cell lineage specification is only poorly understood. Our previous work indicated a role of the histone 2B ubiquitin ligase RNF40 in controlling osteoblast differentiation in vitro. Here, we demonstrate that RNF40 has a stage-dependent function in controlling osteoblast differentiation in vivo. RNF40 expression is essential for early stages of lineage specification, but is dispensable in mature osteoblasts. Paradoxically, while osteoblast-specific RNF40 deletion led to impaired bone formation, it also resulted in increased bone mass due to impaired bone cell crosstalk. Loss of RNF40 resulted in decreased osteoclast number and function through modulation of RANKL expression in OBs. Mechanistically, we demonstrate that Tnfsf11 (encoding RANKL) is an important target gene of H2B monoubiquitination. These data reveal an important role of RNF40-mediated H2B monoubiquitination in bone formation and remodeling and provide a basis for exploring this pathway for the treatment of conditions such as osteoporosis or cancer-associated osteolysis.
| S-EPMC7862367 | biostudies-literature
Project description:In this study, we focused on elucidating the role of Ring Finger Protein 40 (RNF40) in bone development by using a conditional knockout mouse approach during different stages of osteoblast (OB) differentiation and maturation. RNF40 forms an obligate E3 ubiquitin ligase complex together with RNF20 and mediates the monoubiquitination of lysine 120 of histone H2B (H2BK120ub1). We provide evidence that RNF40 regulates OB differentiation in a stage-dependent manner. Additionally, we show that RNF40 is required for bone cell crosstalk whereby loss of RNF40 leads to a reduction in osteoclast numbers and function through modulation of vitamin D receptor (VDR)-induced Rankl expression in OBs. Taken together, these data imply an important role of RNF40-mediated H2Bub1 in bone formation and remodeling and provide a basis for further investigation of its anti-resorptive potential for the treatment of conditions such as osteoporosis or cancer-associated osteolysis. In this study we show that RNF40 is required in earlier stages of osteoblast differentiation and is involved in bone cell crosstalk by regulating vitamin D induced Rankl expression
2021-02-24 | GSE135628 | GEO
Project description:In this study, we focused on elucidating the role of Ring Finger Protein 40 (RNF40) in bone development by using a conditional knockout mouse approach during different stages of osteoblast (OB) differentiation and maturation. RNF40 forms an obligate E3 ubiquitin ligase complex together with RNF20 and mediates the monoubiquitination of lysine 120 of histone H2B (H2BK120ub1). We provide evidence that RNF40 regulates OB differentiation in a stage-dependent manner. Additionally, we show that RNF40 is required for bone cell crosstalk whereby loss of RNF40 leads to a reduction in osteoclast numbers and function through modulation of vitamin D receptor (VDR)-induced Rankl expression in OBs. Taken together, these data imply an important role of RNF40-mediated H2Bub1 in bone formation and remodeling and provide a basis for further investigation of its anti-resorptive potential for the treatment of conditions such as osteoporosis or cancer-associated osteolysis. In this study we show that RNF40 is required in earlier stages of osteoblast differentiation and is involved in bone cell crosstalk by regulating vitamin D induced Rankl expression
2021-02-24 | GSE135627 | GEO
Project description:RNF40 exerts stage-dependent functions in differentiating osteoblasts and is essential for bone cell crosstalk
| PRJNA559493 | ENA
Project description:RNF40 exerts stage-dependent functions in differentiating osteoblasts and is essential for bone cell crosstalk [ChIP-seq]
| PRJNA559510 | ENA
Project description:RNF40 exerts stage-dependent functions in differentiating osteoblasts and is essential for bone cell crosstalk [RNA-seq]
| PRJNA559511 | ENA
Project description:Recent genome-wide association studies of individuals of Asian and European descent have found that SNPs located within the genomic region (1p31.3) encoding the Wntless (Wls)/Gpr177 protein are associated significantly with reduced bone mineral density. Wls/Gpr177 is a newly identified chaperone protein that specifically escorts Wnt ligands for secretion. Given the strong functional association between the Wnt signaling pathways and bone development and homeostasis, we generated osteoblast-specific Wls-deficient (Ocn-Cre;Wls-flox) mice. Homozygous conditional knockout animals were born at a normal Mendelian frequency. Whole-body dual-energy X-ray absorptiometry scanning revealed that bone-mass accrual was significantly inhibited in homozygotes as early as 20 d of age. These homozygotes had spontaneous fractures and a high frequency of premature lethality at around 2 mo of age. Microcomputed tomography analysis and histomorphometric data revealed a dramatic reduction of both trabecular and cortical bone mass in homozygous mutants. Bone formation in homozygotes was severely impaired, but no obvious phenotypic change was observed in mice heterozygous for the conditional deletion. In vitro studies showed that Wls-deficient osteoblasts had a defect in differentiation and mineralization, with significant reductions in the expression of key osteoblast differentiation regulators. In summary, these results reveal a surprising and crucial role of osteoblast-secreted Wnt ligands in bone-mass accrual.
| S-EPMC3421196 | biostudies-literature
Project description:Background and purposeNaringenin and its derivatives have been assessed in bone health for their oestrogen-'like' effects but low bioavailability impedes clinical potential. This study was aimed at finding a potent form of naringenin with osteogenic action.Experimental approachOsteoblast cultures were harvested from mouse calvaria to study differentiation by naringenin, isosakuranetin, poncirin, phloretin and naringenin-6-C-glucoside (NCG). Balb/cByJ ovariectomized (OVx) mice without or with osteopenia were given naringenin, NCG, 17β-oestradiol (E2) or parathyroid hormone (PTH). Efficacy was evaluated by bone microarchitecture using microcomputed tomography and determination of new bone formation by fluorescent labelling of bone. Plasma levels of NCG and naringenin were determined by HPLC.Key resultsNCG stimulated osteoblast differentiation more potently than naringenin, while isosakuranetin, poncirin or phloretin had no effect. NCG had better oral bioavailability than naringenin. NCG increased the mRNA levels of oestrogen receptors (ERs) and bone morphogenetic protein (an ER responsive gene) in vivo, more than naringenin. In OVx mice, NCG treatment in a preventive protocol increased bone formation rate (BFR) and improved trabecular microarchitecture more than naringenin or E2. In osteopenic mice, NCG but not naringenin, in a therapeutic protocol, increased BFR and improved trabecular microarchitecture, comparable with effects of PTH treatment. Stimulatory effects of NCG on osteoblasts were abolished by an ER antagonist. NCG transactivated ERβ but not ERα. NCG exhibited no uterine oestrogenicity unlike naringenin.Conclusions and implicationsNCG is a potent derivative of naringenin that has bone anabolic action through the activation of osteoblast ERs and exhibited substantial oral bioavailability.
| S-EPMC3372735 | biostudies-literature
Project description:INTRODUCTION:In a cancer-free environment in the adult, the skeleton continuously undergoes remodeling. Bone-resorbing osteoclasts excavate erosion cavities, and bone-depositing osteoblasts synthesize osteoid matrix that forms new bone, with no net bone gain or loss. When metastatic breast cancer cells invade the bone, this balance is disrupted. Patients with bone metastatic breast cancer frequently suffer from osteolytic bone lesions that elicit severe bone pain and fractures. Bisphosphonate treatments are not curative. Under ideal circumstances, osteoblasts would synthesize new matrix to fill in erosion cavities caused by osteoclasts, but this is not what occurs. Our prior evidence demonstrated that osteoblasts are diverted from laying down bone matrix to producing cytokines that facilitate breast cancer cell maintenance in late-stage disease. Here, we have new evidence to suggest that there are subpopulations of osteoblasts in the tumor niche as evidenced by their protein marker expression that have distinct roles in tumor progression in the bone. METHODS:Tumor-bearing tibia of mice was interrogated by immunofluorescent staining for the presence of osteoblasts and alterations in niche protein expression. De-identified tissue from patients with bone metastatic breast cancer was analyzed for osteoblast subpopulations via multi-plex immunofluorescent staining. Effects of breast cancer cells on osteoblasts were recapitulated in vitro by osteoblast exposure to breast cancer-conditioned medium. Triple-negative and estrogen receptor-positive breast cancer proliferation, cell cycle, and p21 expression were assessed upon contact with "educated" osteoblasts. RESULTS:A subpopulation of osteoblasts was identified in the bone tumor microenvironment in vivo of both humans and mice with bone metastatic breast cancer that express RUNX2/OCN/OPN but is negative for IL-6 and alpha-smooth muscle actin. These tumor "educated" osteoblasts (EOs) have altered properties compared to "uneducated" osteoblasts and suppress both triple-negative and estrogen receptor-positive breast cancer cell proliferation and increase cancer cell p21 expression. EO effects on breast cancer proliferation were mediated by NOV and decorin. Importantly, the presence of EO cells in the tibia of mice bearing tumors led to increased amounts of alkaline phosphatase and suppressed the expression of inflammatory cytokines in vivo. CONCLUSIONS:Our work reveals that there is a subpopulation of osteoblasts in the bone tumor microenvironment that demonstrate a functional role in retarding breast cancer cell growth.
| S-EPMC6391840 | biostudies-other
Project description:We previously showed that all-trans-retinoic acid (tRA), an active metabolite of vitamin A, exacerbated pre-existing autoimmunity in lupus; however, its effects before the development of autoimmunity are unknown. Here, using a pristane-induced model, we show that tRA exerts differential effects when given at the initiation vs. continuation phase of lupus. Unlike tRA treatment during active disease, pre-pristane treatment with tRA aggravated glomerulonephritis through increasing renal expression of pro-fibrotic protein laminin β1, activating bone marrow conventional dendritic cells (cDCs), and upregulating the interaction of ICAM-1 and LFA-1 in the spleen, indicating an active process of leukocyte activation and trafficking. Transcriptomic analysis revealed that prior to lupus induction, tRA significantly upregulated the expression of genes associated with cDC activation and migration. Post-pristane tRA treatment, on the other hand, did not significantly alter the severity of glomerulonephritis; rather, it exerted immunosuppressive functions of decreasing circulatory and renal deposition of autoantibodies as well as suppressing the renal expression of proinflammatory cytokines and chemokines. Together, these findings suggest that tRA differentially modulate lupus-associated kidney inflammation depending on the time of administration. Interestingly, both pre- and post-pristane treatments with tRA reversed pristane-induced leaky gut and modulated the gut microbiota in a similar fashion, suggesting a gut microbiota-independent mechanism by which tRA affects the initiation vs. continuation phase of lupus.
| S-EPMC7103630 | biostudies-literature