Interleukin-11 as a Stimulatory Factor for Bone Formation Prevents Bone Loss with Advancing Age in Mice

Takeuchi, Yasuhiro; Watanabe, Shigekazu; Ishii, Genichiro; Takeda, Satoshi; Nakayama, Konosuke; Fukumoto, Seiji; Kaneta, Yasuyuki; Inoue, Daisuke; Matsumoto, Toshio; Harigaya, Kenichi; Fujita, Toshiro

doi:10.1074/jbc.m207804200

Cited by 134 publications

(92 citation statements)

References 47 publications

(40 reference statements)

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“…It is important to note that IL-11 (and CTGF) can only be considered candidate bone metastasis genes at present. IL-11 is known to stimulate osteoclastic bone resorption in vitro (27)(28)(29), but it has complex effects on bone formation, including positive effects (37). Its role as a mediator of bone metastasis in humans remains to be established.…”

Section: Discussionmentioning

confidence: 99%

Breast cancer bone metastasis mediated by the Smad tumor suppressor pathway

Kang

Tulley

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

492

446

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TGF-␤ can signal by means of Smad transcription factors, which are quintessential tumor suppressors that inhibit cell proliferation, and by means of Smad-independent mechanisms, which have been implicated in tumor progression. Although Smad mutations disable this tumor-suppressive pathway in certain cancers, breast cancer cells frequently evade the cytostatic action of TGF-␤ while retaining Smad function. Through immunohistochemical analysis of human breast cancer bone metastases and functional imaging of the Smad pathway in a mouse xenograft model, we provide evidence for active Smad signaling in human and mouse bonemetastatic lesions. Genetic depletion experiments further demonstrate that Smad4 contributes to the formation of osteolytic bone metastases and is essential for the induction of IL-11, a gene implicated in bone metastasis in this mouse model system. Activator protein-1 is a key participant in Smad-dependent transcriptional activation of IL-11 and its overexpression in bone-metastatic cells. Our findings provide functional evidence for a switch of the Smad pathway, from tumor-suppressor to prometastatic, in the development of breast cancer bone metastasis.IL-11 ͉ Smad4 ͉ TGF-␤ T GF-␤ plays a crucial role as a growth-inhibitory cytokine in many tissues (1, 2). The cytostatic effect of TGF-␤ is mediated by a serine͞threonine kinase receptor complex that phosphorylates Smad2 and Smad3, which then translocate into the nucleus and bind Smad4 to generate transcriptional regulatory complexes (3). SMAD4 (also known as Deleted in Pancreatic Carcinoma locus 4 or DPC4) and, to a lesser extent, SMAD2 suffer mutational inactivation in a proportion of pancreatic and colon cancers (1, 2). However, tumor cells that evade this antiproliferative control by other mechanisms may display an altered sensitivity to TGF-␤ and undergo tumorigenic progression in response to this cytokine (1, 2). Patients whose pancreatic or colon tumors express TGF-␤ receptors fare less well than those with low or absent TGF-␤ receptor expression in the tumor (4). In mouse models of breast cancer, TGF-␤ signaling promotes lung (5, 6) and bone metastasis (7). In the case of osteolytic bone metastasis by breast cancer cells, it has been proposed that TGF-␤ released from the decaying bone matrix stimulates neighboring tumor cells, establishing a vicious cycle that exacerbates the growth of the metastatic lesion (8).The TGF-␤ signaling mechanisms that foster metastasis in human cancer are an important open question and a subject of debate. Because Smad factors are quintessential tumor suppressors, the basis for the protumorigenic effects of TGF-␤ has been sought in the Smad-independent signaling pathways that may be triggered by TGF-␤. Results obtained by means of overexpression of dominant negative mutant components of the Rho pathway (9, 10) or pharmacologic inhibitors of p38 mitogen-activated protein kinase (11, 12) have implicated these pathways in the proinvasive and metastatic effects of TGF-␤ in transformed cells. In contrast, results obta...

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Section: Discussionmentioning

confidence: 99%

Breast cancer bone metastasis mediated by the Smad tumor suppressor pathway

Kang

Tulley

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

492

446

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“…Therefore, we focused on BMP-2, TGF-b1, IL-11, TPO, and estrogen, of which osteosclerotic activity has been proved in vivo [4][5][6][7][8] and examined whether these cytokines or hormones appeared in a culture medium of the megakaryoblasts. By utilizing neutralizing antibodies, we then identified IL-11 as the OPG-inducing factor produced by the megakaryoblasts.…”

Section: Discussionmentioning

confidence: 99%

Interleukin‐11 as an osteoprotegerin‐inducing factor in culture medium of blastic cells from a patient with acute megakaryocytic leukemia complicated with osteosclerosis

et al. 2004

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We came across a rare case of acute megakaryocytic leukemia, the clinical course of which was relatively chronic and nonaggressive. This case was complicated with generalized severe osteosclerosis (OS). The medium in which blastic cells from the patient were cultured showed a strong activity to enhance the expression of an osteosclerotic cytokine, osteoprotegerin (OPG), as revealed by real-time quantitative RT-PCR and Western blot analysis. The OPG-inducing activity of the culture medium was neutralized by the anti-interleukin-11 (IL-11) antibody. These results indicate that IL-11 produced by the blasts was a causative factor of the OS observed in this patient. Am.

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“…Moreover, IL-11 was recently shown to mediate direct antiapoptotic effects on human colonic epithelial cells (Kiessling et al 2004). IL-11 also prevents cartilage matrix degradation in chronically inflamed joints by inducing the expression of tissue inhibitor of metalloproteinases (TIMP) (Maier et al 1993) and is an important regulator of bone remodeling (Elias et al 1995;Takeuchi et al 2002). Other physiological functions of IL-11 include the inhibition of adipogenesis (Keller et al 1993;Takeuchi et al 2002) and the induction of proliferation and differentiation of hippocampal neuronal cells (Du et al 1996;Mehler et al 1993).…”

Section: Introductionmentioning

confidence: 99%

Multiple and highly divergent IL-11 genes in teleost fish

et al. 2005

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Interleukin-11 (IL-11) is a key cytokine in the regulation of proliferation and differentiation of hematopoietic progenitors and is also involved in bone formation, adipogenesis, and protection of mucosal epithelia. Despite this prominent role in diverse physiological processes, IL-11 has been described in only four mammalian species, and recently, in rainbow trout (Oncorhynchus mykiss). Here we report the presence of IL-11 in common carp (Cyprinus carpio), a bony fish species related to zebrafish. IL-11 is expressed in most carp organs and tissues. In vitro expression of IL-11 in cultured macrophages is enhanced by stimulation with lipopolysaccharide and is markedly inhibited by cortisol. A detailed and systematic scan of several fish genome databases confirms that IL-11 is present in all fish, but also reveals the presence of a second, substantially different IL-11 gene in the genomes of phylogenetically distant fish species. We designated both fish paralogues IL-11a and IL-11b. Although sequence identity between fish IL-11a and IL-11b peptides is low, the conservation of their gene structures supplemented by phylogenetic analyses clearly illustrate the orthology of both IL-11a and IL-11b genes of fish with mammalian IL-11. The presence of IL-11 genes in fish demonstrates its importance throughout vertebrate evolution, although the presence of duplicate and divergent IL-11 genes differs from the single IL-11 gene that exists in mammals.

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Interleukin-11 as a Stimulatory Factor for Bone Formation Prevents Bone Loss with Advancing Age in Mice

Cited by 134 publications

References 47 publications

Breast cancer bone metastasis mediated by the Smad tumor suppressor pathway

Breast cancer bone metastasis mediated by the Smad tumor suppressor pathway

Interleukin‐11 as an osteoprotegerin‐inducing factor in culture medium of blastic cells from a patient with acute megakaryocytic leukemia complicated with osteosclerosis

Multiple and highly divergent IL-11 genes in teleost fish

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