Increased Bone Formation in Mice Lacking Apolipoprotein E

Schilling, Arndt F.; Schinke, Thorsten; Münch, Christian; Gebauer, Matthias; Niemeier, Andreas; Priemel, Matthias; Streichert, Thomas; Rueger, Johannes M.; Amling, Michael

doi:10.1359/jbmr.041101

Cited by 84 publications

(70 citation statements)

References 55 publications

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“…This RNA then was subjected to a genome-wide expression analysis using Affymetrix Gene Chip hybridization. (31,32) Here we found that Il33 expression was markedly induced between days 5 and 25 of differentiation, whereas the expression of the other IL-1 family members was either undetectable (Il1a and Il1b) or not regulated (Il18) (Fig. 1A).…”

Section: Il33 Is Expressed By Differentiated Osteoblastsmentioning

confidence: 67%

Interleukin-33 is expressed in differentiated osteoblasts and blocks osteoclast formation from bone marrow precursor cells

Schulze

Bickert

Beil

et al. 2010

Journal of Bone and Mineral Research

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124

127

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Since the hematopoetic system is located within the bone marrow, it is not surprising that recent evidence has demonstrated the existence of molecular interactions between bone and immune cells. While interleukin 1 (IL-1) and IL-18, two cytokines of the IL-1 family, have been shown to regulate differentiation and activity of bone cells, the role of IL-33, another IL-1 family member, has not been addressed yet. Since we observed that the expression of IL-33 increases during osteoblast differentiation, we analyzed its possible influence on bone formation and observed that IL-33 did not affect matrix mineralization but enhanced the expression of Tnfsf11, the gene encoding RANKL. This finding led us to analyze the skeletal phenotype of Il1rl1-deficient mice, which lack the IL-33 receptor ST2. Unexpectedly, these mice displayed normal bone formation but increased bone resorption, thereby resulting in low trabecular bone mass. Since this finding suggested a negative influence of IL-33 on osteoclastogenesis, we next analyzed osteoclast differentiation from bone marrow precursor cells and observed that IL-33 completely abolished the generation of TRACP þ multinucleated osteoclasts, even in the presence of RANKL and macrophage colony-stimulating factor (M-CSF). Although our molecular studies revealed that IL-33 treatment of bone marrow cells caused a shift toward other hematopoetic lineages, we further observed a direct negative influence of IL-33 on the osteoclastogenic differentiation of RAW264.7 macrophages, where IL-33 repressed the expression of Nfatc1, which encodes one of the key transciption factors of osteoclast differentiation. Taken together, these findings have uncovered a previously unknown function of IL-33 as an inhibitor of bone resorption. ß

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Section: Il33 Is Expressed By Differentiated Osteoblastsmentioning

confidence: 67%

Interleukin-33 is expressed in differentiated osteoblasts and blocks osteoclast formation from bone marrow precursor cells

Schulze

Bickert

Beil

et al. 2010

Journal of Bone and Mineral Research

Self Cite

124

127

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“…The presence of the three g carboxyglutamic acid residues is critical for the structure and function of OC in the fully carboxylated state allowing the binding of OC to hydroxyapatite (HA) with a high affinity, regulating the maturation of bone mineral (Hauschka & Wians 1989. However, OC also exists in the general circulation in fully carboxylated, partially carboxylated and completely uncarboxylated forms (Plantalech et al 1991, Cairns & Price 1994, Vergnaud et al 1997, Schilling et al 2005, Ferron et al 2010a. On the basis of results from human and rodent studies, serum OC concentrations have been correlated with bone formation and osteoblast number, thus being used as a serum marker of bone formation (Brown et al 1984;reviewed in Gundberg et al (2012)).…”

Section: Osteocalcinmentioning

confidence: 99%

Endocrine role of bone: recent and emerging perspectives beyond osteocalcin

Oldknow

MacRae

Farquharson

2015

Journal of Endocrinology

102

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Recent developments in endocrinology, made possible by the combination of mouse genetics, integrative physiology and clinical observations have resulted in rapid and unanticipated advances in the field of skeletal biology. Indeed, the skeleton, classically viewed as a structural scaffold necessary for mobility, and regulator of calcium-phosphorus homoeostasis and maintenance of the haematopoietic niche has now been identified as an important regulator of male fertility and whole-body glucose metabolism, in addition to the classical insulin target tissues. These seminal findings confirm bone to be a true endocrine organ. This review is intended to detail the key events commencing from the elucidation of osteocalcin (OC) in bone metabolism to identification of new and emerging candidates that may regulate energy metabolism independently of OC.Key WordsJournal of Endocrinology (2015) 225, R1-R19

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“…Moreover, since a genome-wide expression analysis comparing mouse calvarial osteoblasts at different stages of differentiation revealed that Mdk was expressed at much higher levels than Ptn, we reasoned that the phenotypes observed in transgenic mice overexpressing Ptn might reflect a physiologic function of Mdk. (27)(28)(29) In this regard, it is also important to state that Mdk has been shown to be induced by both glucocoticoids or NF-kB signaling, thereby further underscoring a potential relevance in bone biology. (30,31) Here, we report our skeletal analysis of Mdk-deficient mice.…”

Section: Introductionmentioning

confidence: 99%

Increased trabecular bone formation in mice lacking the growth factor midkine

Neunaber

Catalá-Lehnen

Beil

et al. 2010

Journal of Bone and Mineral Research

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Midkine (Mdk) and pleiotrophin (Ptn) comprise a family of heparin-binding growth factors known primarily for their effects on neuronal cells. Since transgenic mice overexpressing Ptn have been reported to display increased bone density, we have previously analyzed Ptndeficient mice but failed to detect any abnormality of skeletal development and remodeling. Together with the finding that Mdk expression increases in the course of primary osteoblast differentiation, we reasoned that Mdk, rather than Ptn, could play a physiologic role in bone formation. Here, we show that Mdk-deficient mice display an increased trabecular bone volume at 12 and 18 months of age, accompanied by cortical porosity. Histomorphometric quantification demonstrated an increased bone-formation rate compared with wild-type littermates, whereas bone resorption was differentially affected in trabecular and cortical bone of Mdk-deficient mice. To understand the effect of Mdk on bone formation at the molecular level, we performed a genome-wide expression analysis of primary osteoblasts and identified Ank and Enpp1 as Mdk-induced genes whose decreased expression in Mdk-deficient osteoblasts may explain, at least in part, the observed skeletal phenotype. Finally, we performed ovariectomy and observed bone loss only in wild-type but not in Mdk-deficient animals. Taken together, our data demonstrate that Mdk deficiency, at least in mice, results in an increased trabecular bone formation, thereby raising the possibility that Mdk-specific antagonists might prove beneficial in osteoporosis therapy. ß

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Increased Bone Formation in Mice Lacking Apolipoprotein E

Cited by 84 publications

References 55 publications

Interleukin-33 is expressed in differentiated osteoblasts and blocks osteoclast formation from bone marrow precursor cells

Interleukin-33 is expressed in differentiated osteoblasts and blocks osteoclast formation from bone marrow precursor cells

Endocrine role of bone: recent and emerging perspectives beyond osteocalcin

Increased trabecular bone formation in mice lacking the growth factor midkine

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