FoxO proteins restrain osteoclastogenesis and bone resorption by attenuating H2O2 accumulation

Bartell, Shoshana M.; Kim, Ha‐Neui; Ambrogini, Elena; Han, Li; Iyer, Srividhya; Ucer, Serra; Rabinovitch, Peter S.; Jilka, Robert L.; Weinstein, Robert S.; Zhao, Haibo; O’Brien, Charles A.; Manolagas, Stavros C.; Almeida, Maria

doi:10.1038/ncomms4773

Cited by 213 publications

(231 citation statements)

References 73 publications

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“…40,41 Prx2 gene expression was markedly upregulated in SCD mice compared with healthy controls (supplemental Figure 1C), whereas Catalase expression was similar in both mouse strains (data not shown).…”

Section: Acid As Multimodal Therapy For Sbd 2321mentioning

confidence: 94%

Hypoxia-reperfusion affects osteogenic lineage and promotes sickle cell bone disease

Carbonare

Mattè

Valenti

et al. 2015

Blood

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Key Points• In SCD, recurrent vasoocclusive crisis suppresses osteogenic lineage and activates osteoclasts.• Zoledronic acid acting on both osteoclast and osteoblast compartments is a multimodal therapy to prevent SBD.Sickle cell disease (SCD) is a worldwide distributed hereditary red cell disorder, characterized by severe organ complication. Sickle bone disease (SBD) affects a large part of the SCD patient population, and its pathogenesis has been only partially investigated. Here, we studied bone homeostasis in a humanized mouse model for SCD. Under normoxia, SCD mice display bone loss and bone impairment, with increased osteoclast and reduced osteoblast activity. Hypoxia/reperfusion (H/R) stress, mimicking acute vaso-occlusive crises (VOCs), increased bone turnover, osteoclast activity (RankL), and osteoclast recruitment (Rank) with upregulation of IL-6 as proresorptive cytokine. This was associated with further suppression of osteogenic lineage (Runx2, Sparc). To interfere with the development of SBD, zoledronic acid (Zol), a potent inhibitor of osteoclast activity/ osteoclastogenesis and promoter of osteogenic lineage, was used in H/R-exposed mice. Zol markedly inhibited osteoclast activity and recruitment, promoting osteogenic lineage. The recurrent H/R stress further worsened bone structure, increased bone turnover, depressed osteoblastogenesis (Runx2, Sparc), and increased both osteoclast activity (RankL, Cathepsin k) and osteoclast recruitment (Rank) in SCD mice compared with either normoxic or single-H/R-episode SCD mice. Zol used before recurrent VOCs prevented bone impairment and promoted osteogenic lineage. Our findings support the view that SBD is related to osteoblast impairment, and increased osteoclast activity resulted from local hypoxia, oxidative stress, and the release of proresorptive cytokine such as IL-6. Zol might act on both the osteoclast and osteoblast compartments as multimodal therapy to prevent SBD. (Blood. 2015;126(20):2320-2328 IntroductionSickle cell disease (SCD) is a worldwide distributed hereditary red cell disorder, which affects approximately 75 000 individuals in the United States and almost 20 000 to 25 000 individuals in Europe, this latter mainly related to the immigration fluxes from endemic areas such as Sub-Saharan Africa to European countries.1-3 Studies of the global burden of disease have pointed out the invalidating impact of SCD on patient quality of life.2 This requires the development of new therapeutic options to treat sickle cell-related acute and chronic complications.SCD is caused by a point mutation in the b-globin gene resulting in the synthesis of pathologic hemoglobin S (HbS). HbS displays peculiar biochemical characteristics, polymerizing when deoxygenated with associated reduction in cell ion and water content (cell dehydration), increased red cell density, and further acceleration of HbS polymerization. [4][5][6] Pathophysiologic studies have shown that dense, dehydrated red cells play a central role in acute and chronic clinical manifestations of ...

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Section: Acid As Multimodal Therapy For Sbd 2321mentioning

confidence: 94%

Hypoxia-reperfusion affects osteogenic lineage and promotes sickle cell bone disease

Carbonare

Mattè

Valenti

et al. 2015

Blood

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“…Akt directly phosphorylates FoxOs and results in the abrogation of FoxO-mediated transcription. FoxOs have been shown to play important roles in bone metabolism by influencing both osteoblasts (OB) and OCs via ROS-dependent and ROS-independent mechanisms (1,4,32,44). During osteoclastogenesis, RANKL-induced Akt activation downregulates FoxOs, thereby decreasing their transcription and allowing accumulation of H 2 O 2 in mitochondria.…”

mentioning

confidence: 99%

HDAC2 regulates FoxO1 during RANKL-induced osteoclastogenesis

Dou

Ding

et al. 2016

American Journal of Physiology-Cell Physiology

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The bone-resorbing osteoclast (OC) is essential for bone homeostasis, yet deregulation of OCs contributes to diseases such as osteoporosis, osteopetrosis, and rheumatoid arthritis. Here we show that histone deacetylase 2 (HDAC2) is a key positive regulator during receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclastogenesis and bone resorption. Bone marrow macrophages (BMMs) showed increased HDAC2 expression during osteoclastogenesis. HDAC2 overexpression enhanced, whereas HDAC2 deletion suppressed osteoclastogenesis and bone resorption using lentivirus infection. Mechanistically, upon RANKL activation, HDAC2 activated Akt; Akt directly phosphorylates and abrogates Forkhead box protein O1 (FoxO1), which is a negative regulator during osteoclastogenesis through reducing reactive oxygen species. HDAC2 deletion in BMMs resulted in decreased Akt activation and increased FoxO1 activity during osteoclastogenesis. In conclusion, HDAC2 activates Akt thus suppresses FoxO1 transcription results in enhanced osteoclastogenesis. Our data imply the potential value of HDAC2 as a new target in regulating osteoclast differentiation and function.

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“…9,24 Based on our review of current literature, the studies that used broad ROIs to measure BMD via DXA in mice specified ROIs that contained whole bones (e.g., whole femur). [17][18][19][20] These ROIs were not specific to trabecular bone-rich regions ( Fig. 2A).…”

Section: Discussionmentioning

confidence: 91%

“…In this study, we selected the distal femur, proximal tibia, and lumbar vertebrae for the representative areas because most of the articles analyzed these areas for their micro-CT analysis among the various trabecular bone-rich regions. 19,[26][27][28][29][30][31][32] Moreover, anatomically these areas are relatively larger in marrow cavity and hence have a greater quantity of trabecular bone; this makes quantification easier and more reproducible. For example, in the femur and tibia, distal femur is bigger than the proximal femur and proximal tibia is bigger than the distal tibia.…”

Section: Discussionmentioning

confidence: 99%

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Guidelines for Dual Energy X-Ray Absorptiometry Analysis of Trabecular Bone-Rich Regions in Mice: Improved Precision, Accuracy, and Sensitivity for Assessing Longitudinal Bone Changes

Shi

Lee

Uyeda

et al. 2016

Tissue Engineering Part C: Methods

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Trabecular bone is frequently studied in osteoporosis research because changes in trabecular bone are the most common cause of osteoporotic fractures. Dual energy X-ray absorptiometry (DXA) analysis specific to trabecular bone-rich regions is crucial to longitudinal osteoporosis research. The purpose of this study is to define a novel method for accurately analyzing trabecular bone-rich regions in mice via DXA. This method will be utilized to analyze scans obtained from the International Space Station in an upcoming study of microgravity-induced bone loss. Thirty 12-week-old BALB/c mice were studied. The novel method was developed by preanalyzing trabecular bone-rich sites in the distal femur, proximal tibia, and lumbar vertebrae via high-resolution X-ray imaging followed by DXA and micro-computed tomography (micro-CT) analyses. The key DXA steps described by the novel method were (1) proper mouse positioning, (2) region of interest (ROI) sizing, and (3) ROI positioning. The precision of the new method was assessed by reliability tests and a 14-week longitudinal study. The bone mineral content (BMC) data from DXA was then compared to the BMC data from micro-CT to assess accuracy. Bone mineral density (BMD) intra-class correlation coefficients of the new method ranging from 0.743 to 0.945 and Levene's test showing that there was significantly lower variances of data generated by new method both verified its consistency. By new method, a Bland-Altman plot displayed good agreement between DXA BMC and micro-CT BMC for all sites and they were strongly correlated at the distal femur and proximal tibia (r = 0.846, p < 0.01; r = 0.879, p < 0.01, respectively). The results suggest that the novel method for site-specific analysis of trabecular bone-rich regions in mice via DXA yields more precise, accurate, and repeatable BMD measurements than the conventional method.

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FoxO proteins restrain osteoclastogenesis and bone resorption by attenuating H2O2 accumulation

Cited by 213 publications

References 73 publications

Hypoxia-reperfusion affects osteogenic lineage and promotes sickle cell bone disease

Hypoxia-reperfusion affects osteogenic lineage and promotes sickle cell bone disease

HDAC2 regulates FoxO1 during RANKL-induced osteoclastogenesis

Guidelines for Dual Energy X-Ray Absorptiometry Analysis of Trabecular Bone-Rich Regions in Mice: Improved Precision, Accuracy, and Sensitivity for Assessing Longitudinal Bone Changes

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