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      Zinc finger protein ZFP36L1 promotes osteoblastic differentiation but represses adipogenic differentiation of mouse multipotent cells

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          Abstract

          Zinc finger protein 36, C3H type-like 1 (ZFP36L1) is a member of the tristetraprolin (TTP) family and its role in the aging-related bone loss is currently unknown. We present evidence that ZFP36L1 expression in rat femurs and bone marrow mesenchymal stem cells (bmMSCs) was down-regulated with aging. ZFP36L1 knockdown decreased osteoblastic differentiation of MC3T3-E1 and C3H10T1/2 cells, and increased adipogenic differentiation of 3T3-L1 and C3H10T1/2 cells, whereas ZFP36L1 overexpression did the opposite. The finding that ZFP36L1 overexpression enhanced osteoblastic and repressed adipogenic differentiation was also corroborated by ex vivo experiments. Troglitazone prevented ZFP36L1 from inhibiting adipogenic differentiation, suggesting the significance of PPAR?2 repression in ZFP36L1s inhibitory effect on adipogenic differentiation. ZFP36L1 overexpression repressed the expression of Ppar?2 mRNA, but not the PPAR? promoter activity. Biotin pull-down and electrophoretic mobility-shift assays suggested that ZFP36L1 might interact with endogenous Ppar?2 mRNA by binding to its 3UTR. The ZFP36L1-containing ribonucleoprotein complexes of ZFP36L1-overexpressing cells contained less Ppar?2 mRNA than those of control cells. In a luciferase reporter construct, replacement of the SV40 poly(A) fragment by the 3UTR of Ppar?2 mRNA reduced the expression of luciferase transcripts in ZFP36L1-overexpressing cells. Examination of the kinetic expression of Ppar?2 mRNA after transcriptional blockage showed that ZFP36L1 might enhance the degradation of the transcripts. Together, these data imply that ZFP36L1 overexpression might repress adipogenesis at least by down-regulating PPAR?2 expression through post-transcriptional mechanisms. Thus, our findings support the notion that decrease of ZFP36L1 expression in bmMSCs with aging might contribute to the aging-related bone loss.

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          Most cited references20

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          mTOR regulates MAPKAPK2 translation to control the senescence-associated secretory phenotype

          Senescent cells secrete a combination of factors collectively known as the senescence-associated secretory phenotype (SASP). The SASP reinforces senescence and activates an immune surveillance response but it can also display pro-tumorigenic properties and contribute to age-related pathologies. In a drug screen to find novel SASP regulators, we uncovered the mTOR inhibitor rapamycin as a potent SASP suppressor. Here we report a mechanism by which mTOR controls the SASP by differentially regulating the translation of the MK2/MAPKAPK2 kinase through 4EBP1. In turn, MAPKAPK2 phosphorylates the RNA binding protein ZFP36L1 during senescence, inhibiting its ability to degrade the transcripts of numerous SASP components. Consequently, mTOR inhibition or constitutive activation of ZFP36L1 impairs the non-cell-autonomous effects of senescent cells both in tumour-suppressive and promoting-promoting contexts. Altogether, our results place regulation of the SASP as a key mechanism by which mTOR could influence cancer, age-related diseases and immune responses.
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            Mechanisms of disease: is osteoporosis the obesity of bone?

            Osteoporosis and obesity, two disorders of body composition, are growing in prevalence. Interestingly, these diseases share several features including a genetic predisposition and a common progenitor cell. With aging, the composition of bone marrow shifts to favor the presence of adipocytes, osteoclast activity increases, and osteoblast function declines, resulting in osteoporosis. Secondary causes of osteoporosis, including diabetes mellitus, glucocorticoids and immobility, are associated with bone-marrow adiposity. In this review, we ask a provocative question: does fat infiltration in the bone marrow cause low bone mass or is it a result of bone loss? Unraveling the interface between bone and fat at a molecular and cellular level is likely to lead to a better understanding of several diseases, and to the development of drugs for both osteoporosis and obesity.
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              PPARgamma insufficiency enhances osteogenesis through osteoblast formation from bone marrow progenitors.

              Based on the fact that aging is associated with a reciprocal decrease of osteogenesis and an increase of adipogenesis in bone marrow and that osteoblasts and adipocytes share a common progenitor, this study investigated the role of PPARgamma, a key regulator of adipocyte differentiation, in bone metabolism. Homozygous PPARgamma-deficient ES cells failed to differentiate into adipocytes, but spontaneously differentiated into osteoblasts, and these were restored by reintroduction of the PPARgamma gene. Heterozygous PPARgamma-deficient mice exhibited high bone mass with increased osteoblastogenesis, but normal osteoblast and osteoclast functions, and this effect was not mediated by insulin or leptin. The osteogenic effect of PPARgamma haploinsufficiency became prominent with aging but was not changed upon ovariectomy. The PPARgamma haploinsufficiency was confirmed to enhance osteoblastogenesis in the bone marrow cell culture but did not affect the cultures of differentiated osteoblasts or osteoclast-lineage cells. This study demonstrates a PPARgamma-dependent regulation of bone metabolism in vivo, in that PPARgamma insufficiency increases bone mass by stimulating osteoblastogenesis from bone marrow progenitors.
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                Author and article information

                Journal
                Oncotarget
                Oncotarget
                Oncotarget
                ImpactJ
                Oncotarget
                Impact Journals LLC
                1949-2553
                28 March 2017
                9 February 2017
                : 8
                : 13
                : 20588-20601
                Affiliations
                1 Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan Town, Miaoli, Taiwan, Republic of China
                2 Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan, Republic of China
                Author notes
                Correspondence to: Shankung Lin, shankung@ 123456nhri.org.tw
                Article
                15246
                10.18632/oncotarget.15246
                5400528
                28206953
                43c6f138-d16a-4f8c-be69-62f25283a682
                Copyright: © 2017 Tseng et al.

                This article is distributed under the terms of the Creative Commons Attribution License (CC-BY), which permits unrestricted use and redistribution provided that the original author and source are credited.

                History
                : 30 June 2016
                : 9 November 2016
                Categories
                Research Paper: Gerotarget (Focus on Aging)

                Oncology & Radiotherapy
                zfp36l1,osteoporosis,aging-related bone loss,osteoblastogenesis,adipogenesis,gerotarget

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