Sirtuin1 (Sirt1) Promotes Cortical Bone Formation by Preventing β-Catenin Sequestration by FoxO Transcription Factors in Osteoblast Progenitors

Iyer, Srividhya; Han, Li; Bartell, Shoshana M.; Kim, Ha‐Neui; Gubrij, Igor; Cabo, Rafael de; O’Brien, Charles A.; Manolagas, Stavros C.; Almeida, Maria

doi:10.1074/jbc.m114.561803

Cited by 114 publications

(80 citation statements)

References 46 publications

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“…Here, we found that in addition silencing of SIRT1 reduced the proliferation rate of RASF. Similarly, decreased proliferation upon silencing of SIRT1 was reported in human malignant glioma cells, melanoma cells, vascular smooth muscle cells and murine osteoprogenitors [27][28][29][30]. However, SIRT1 was also shown to inhibit proliferation in human colon cancer cells and murine gut epithelial cells [31,32].…”

Section: Discussionmentioning

confidence: 99%

Regulation and function of SIRT1 in rheumatoid arthritis synovial fibroblasts

et al. 2015

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Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by inflammation and destruction of synovial joints. The function of sirtuin (SIRT)1 in RA is inconclusive. In human synovial cells, SIRT1 was shown to promote cytokine production and apoptosis resistance. However, deletion of SIRT1 aggravated inflammatory arthritis in mice and increased production of pro-inflammatory cytokines in murine macrophages. In the current study, we investigated the regulation, expression, and function of SIRT1 in RA, in particular its role in adhesion and proliferation of human RA synovial fibroblasts (RASF). We found that expression of SIRT1 was increased in vivo in synovial tissues of RA smokers and in vitro by stimulation of RASF with TNF, but decreased upon treatment with cigarette smoke extract. Synovial tissues of RA smokers showed higher leukocytic infiltration that positively correlated with enhanced levels of SIRT1. Global transcriptome analysis revealed that SIRT1 modulates expression of genes involved in the regulation of inflammatory response and cell adhesion. In functional studies, silencing of SIRT1 reduced proliferation and leukocytic adhesion to RASF but showed inconsistent results in the regulation of adhesion to plastic. In conclusion, SIRT1 modulates the proliferative and potentially also adhesive properties of RASF and can therefore promote progression of RA. KEY MESSAGES: SIRT1 is upregulated by TNF but decreased upon CSE treatment of RASF. Upregulation of SIRT1 in RA smokers correlates with increased leukocytic infiltration. SIRT1 modulates expression of genes regulating cell adhesion and inflammation. SIRT1 regulates proliferation of RASF. AbstractRheumatoid arthritis (RA) is a chronic autoimmune disease characterized by inflammation and destruction of synovial joints. The function of sirtuin (SIRT)1 in RA is inconclusive. In human synovial cells SIRT1 was shown to promote cytokine production and apoptosis resistance. However, deletion of SIRT1 aggravated inflammatory arthritis in mice and increased production of pro-inflammatory cytokines in murine macrophages. In the current study we investigated the regulation, expression and function of SIRT1 in RA, in particular its role in adhesion and proliferation of human RA synovial fibroblasts (RASF). We found that expression of SIRT1 was increased in vivo in synovial tissues of RA smokers and in vitro by stimulation of RASF with TNFα, but decreased upon treatment with cigarette smoke extract.Synovial tissues of RA smokers showed higher leukocytic infiltration that positively correlated with enhanced levels of SIRT1. Global transcriptome analysis revealed that SIRT1modulates expression of genes involved in the regulation of inflammatory response and cell adhesion. In functional studies, silencing of SIRT1 reduced proliferation and leukocytic adhesion to RASF, but showed inconsistent results in the regulation of adhesion to plastic. In conclusion, SIRT1 modulates the proliferative and potentially also adhesive properties of RASF and can t...

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Section: Discussionmentioning

confidence: 99%

Regulation and function of SIRT1 in rheumatoid arthritis synovial fibroblasts

et al. 2015

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“…2013, Iyer et al. 2014). The deacetylase activity of SirT1 offers many mechanisms through which SirT1 may mediate bone biology, including inhibition of NFkB (Yeung et al.…”

Section: Bonementioning

confidence: 99%

Ageing in the musculoskeletal system

Roberts¹,

Colombier²,

Sowman³

et al. 2016

Acta Orthopaedica

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The extent of ageing in the musculoskeletal system during the life course affects the quality and length of life. Loss of bone, degraded articular cartilage, and degenerate, narrowed intervertebral discs are primary features of an ageing skeleton, and together they contribute to pain and loss of mobility. This review covers the cellular constituents that make up some key components of the musculoskeletal system and summarizes discussion from the 2015 Aarhus Regenerative Orthopaedic Symposium (AROS) (Regeneration in the Ageing Population) about how each particular cell type alters within the ageing skeletal microenvironment.

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“…1 B ). The CKO mice had lower body weight, caused by the expression of the Osx1-Cre transgene, (41,42) which was not altered by diabetes. However, the unkempt appearance and the damp cage bedding of diabetic CKO mice was comparable to that of the diabetic control mice.…”

Section: Resultsmentioning

confidence: 99%

Deletion of FoxO1, 3, and 4 in Osteoblast Progenitors Attenuates the Loss of Cancellous Bone Mass in a Mouse Model of Type 1 Diabetes

Iyer

Han

Ambrogini

et al. 2016

Journal of Bone and Mineral Research

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Type 1 diabetes is associated with osteopenia and increased fragility fractures, attributed to reduced bone formation. However, the molecular mechanisms mediating these effects remain unknown. Insulin promotes osteoblast formation and inhibits the activity of the FoxO transcription factors. FoxOs, on the other hand, inhibit osteoprogenitor proliferation and bone formation. Here, we investigated whether FoxOs play a role in the low bone mass associated with type 1 diabetes, using mice lacking FoxO1, 3, and 4 in osteoprogenitor cells (FoxO1,3,4ΔOsx1-Cre). Streptozotocin-induced diabetes caused a reduction in bone mass and strength in FoxO-intact mice. In contrast, cancellous bone was unaffected in diabetic FoxO1,3,4ΔOsx1-Cre mice. The low bone mass in the FoxO-intact diabetic mice was associated with decreased osteoblast number and bone formation, as well as decreased expression of the anti-osteoclastogenic cytokine osteoprotegerin (OPG) and increased osteoclast number. FoxO deficiency did not alter the effects of diabetes on bone formation; however, it did prevent the decrease in OPG and the increase in osteoclast number. Addition of high glucose to osteoblastic cell cultures decreased OPG mRNA, indicating that hyperglycemia in and of itself contributes to diabetic bone loss. Taken together, these results suggest that FoxOs exacerbate the loss of cancellous bone mass associated with type 1 diabetes and that inactivation of FoxOs might ameliorate the adverse effects of insulin deficiency.

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Sirtuin1 (Sirt1) Promotes Cortical Bone Formation by Preventing β-Catenin Sequestration by FoxO Transcription Factors in Osteoblast Progenitors

Cited by 114 publications

References 46 publications

Regulation and function of SIRT1 in rheumatoid arthritis synovial fibroblasts

Regulation and function of SIRT1 in rheumatoid arthritis synovial fibroblasts

Ageing in the musculoskeletal system

Deletion of FoxO1, 3, and 4 in Osteoblast Progenitors Attenuates the Loss of Cancellous Bone Mass in a Mouse Model of Type 1 Diabetes

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