TNF-α inhibits BMP-induced osteoblast differentiation through activating SAPK/JNK signaling

Mukai, Tomoyuki; Otsuka, Fumio; Otani, Hiroyuki; Yamashita, Misuzu; Takasugi, Koji; Inagaki, Kenichi; Yamamura, Masatoshi; Makino, Hírofumi

doi:10.1016/j.bbrc.2007.03.099

Cited by 120 publications

(92 citation statements)

References 20 publications

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“…Besides regulating bone formation and bone differentiation [113,114], considerable recent data have demonstrated that BMPs are multifunctional regulators in a wide array of biological processes in both vertebrates and invertebrates [115]. In addition to bone, there is evidence that expression of BmP genes is high in the kidney (BMP-3, -4 and -7), lung (BMP-3, -4, -5 and -6), small intestine (BMP-3 and -7), heart (BMP-2, -4, -6 and -7), limb bud (BMP-2, -4, -5 and -7) and teeth (BMP-3, -4 and -7) and that they can regulate the cellular homeostasis by paracrine mechanisms [116].…”

Section: Resultsmentioning

confidence: 99%

Multiple Endocrine Regulation by Bone Morphogenetic Protein System

Otsuka

2010

Endocr J

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Abstract. Bone morphogenetic proteins (BMPs) were originally identified with regard to their actions to regulate ectopic formation of bone and cartilage and early embryonic development. Subsequently, our research program has investigated a BMP system that exists in the mammalian ovary and plays roles in regulating numerous granulosa cell functions. BMP ligands including BMP-2, -4, -6, -7 and -15 were found to inhibit gondotropin-dependent progesterone synthesis by granulosa cells, which led to the hypothesis that BMPs are a physiological luteinization inhibitor in growing ovarian follicles during the follicular phase of the ovarian cycle. The physiological importance of the BMP system for normal mammalian reproduction has been further recognized by the discovery of aberrant reproductive phenotypes of female sheep and humans having mutated genes encoding BMP-15. Physiological roles of BMPs in the pituitary, hypothalamus, adrenal and other tissues have also been discovered. Here we discuss recent advances in the understanding of autocrine/paracrine actions of BMPs in the systemic regulation of endocrine function.Key words: Bone morphogenetic protein, Folliculogenesis, Ovary, Reproduction, Steroidogenesis Bone morphogenetic proteins (BmPs) were originally isolated from bone tissues as proteins that induce bone and cartilage formation in ectopic extra-skeletal sites in vivo [1]. The amino acid sequences from the corresponding cDNAs revealed that BmP ligands are structurally classified into transforming growth factor (TGF)-β superfamily member. To date, more than 30 members of the TGF-β superfamily have been identified in various species [2,3]. There is no direct evidence that all molecules designated as BMPs can induce cartilage and/or bone formation, whereas it has been well established that BMPs regulate multiple biological processes including cell proliferation, apoptosis, differentiation and morphogenesis. in this review, the recent advances regarding critical BmP actions in the ovarian folliculogenesis, which has been mostly discovered by Shimasaki's laboratory [4,5], and in many of extra-gonadal endocrine tissues are introduced. i) molecular characteristics and receptor signaling of the Bmp systemLigands of the TGF-β superfamily are initially synthesized as large precursor proteins. The precursor proteins dimerize and then are cleaved by proteolytic processing to produce mature dimeric proteins. The BMPs are distinguished from other members by having seven, rather than nine, conserved cysteine residues in the mature region. Six of the seven common cysteines in the mature protein are linked within the subunit to form a rigid structure called a "cysteine knot." The re-

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Section: Resultsmentioning

confidence: 99%

Multiple Endocrine Regulation by Bone Morphogenetic Protein System

Otsuka

2010

Endocr J

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“…For example, activation of JNK has been shown to contribute to the inhibitory regulation of ALP activity and mineralization by TGF-b in osteoblast cells, (31,42) and also contributes to the inhibitory effect of TNF-a on BMP2-induced osteoblastic differentiation. (43) Moreover, blocking JNK activity has previously been found to upregulate BMP2-induced ALP activity and osteopontin (OPN) expression. (13,39) Taken together, these data support our conclusion that JNK1 functions as a negative regulator in BMP2-induced osteoblastic differentiation.…”

Section: Discussionmentioning

confidence: 99%

c-Jun N-terminal kinase 1 negatively regulates osteoblastic differentiation induced by BMP2 via phosphorylation of Runx2 at Ser104

Huang¹,

Lin²,

Chao³

et al. 2012

Journal of Bone and Mineral Research

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Runx2 plays a crucial role in osteoblastic differentiation, which can be upregulated by bone morphogenetic proteins 2 (BMP2). Mitogenactivated protein kinase (MAPK) cascades, such as extracellular signal-regulated kinase (ERK) and p38, have been reported to be activated by BMP2 to increase Runx2 activity. The role of cjun-N-terminal kinase (JNK), the other kinase of MAPK, in osteoblastic differentiation has not been well elucidated. In this study, we first showed that JNK1 is activated by BMP2 in multipotent C2C12 and preosteoblastic MC3T3-E1 cell lines. We then showed that early and late osteoblastic differentiation, represented by ALP expression and mineralization, respectively, are significantly enhanced by JNK1 loss-of-function, such as treatment of JNK inhibitor, knockdown of JNK1 and ectopic expression of a dominant negative JNK1 (DN-JNK1). Consistently, BMP2-induced osteoblastic differentiation is reduced by JNK1 gain-offunction, such as enforced expression of a constitutively active JNK1 (CA-JNK1). Most importantly, we showed that Runx2 is required for JNK1-mediated inhibition of osteoblastic differentiation, and identified Ser104 of Runx2 is the site phosphorylated by JNK1 upon BMP2 stimulation. Finally, we found that overexpression of the mutant Runx2 (Ser104Ala) stimulates osteoblastic differentiation of C2C12 and MC3T3-E1 cells to the extent similar to that achieved by overexpression of wild-type (WT) Runx2 plus JNK inhibitor treatment. Taken together, these data indicate that JNK1 negatively regulates BMP2-induced osteoblastic differentiation through phosphorylation of Runx2 at Ser104. In addition, unraveling these mechanisms may help to develop new strategies in enhancing osteoblastic differentiation and bone formation. ß

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“…(10) TNF-a stimulates several signaling pathways in osteoblasts, such as p38 MAPK, (37) JNK, (38) NF-kB, (39) and Smurf1, (40) and increases apoptosis.…”

Section: Discussionmentioning

confidence: 99%

LPS-Induced Inhibition of Osteogenesis Is TNF-α Dependent in a Murine Tooth Extraction Model

Tomomatsu

Aoki

Alles

et al. 2009

Journal of Bone and Mineral Research

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TNF-a is a major etiologic factor of inflammatory bone diseases such as periodontitis and rheumatoid arthritis. In addition, patients with metabolic diseases such as chronic heart disease and diabetes have significantly increased plasma levels of TNF-a. Several lines of evidence show inhibition of osteoblastogenesis by TNF-a in vitro. Therefore, bone formation and osteogenesis in these patients might be inhibited because of TNF-a. However, little is known about the inhibitory role of TNF-a in bone formation/ osteogenesis in vivo. The purpose of this study was to investigate the role of TNF-a in osteogenesis using a murine tooth extraction model. Lipopolysaccharide (LPS) was injected subcutaneously into the calvariae of either wildtype (WT) or TNF-a-deficient (KO) mice. The left incisor was extracted 4 days after LPS injection. The measuring area was established as the tooth socket under the mesial root of the first molar. A significant increase in serum TNF-a levels after LPS injection was observed in WT mice. The BMD of the tooth socket was significantly decreased by LPS injection 21 days after extraction in WT but not in KO mice. Histomorphometric analysis showed a significant decrease in the mineral apposition rate after LPS injection, which appeared at an early stage in WT but not in KO mice. Injection of a peptide that blocked the TNF-a signaling pathway by preventing transmission of the NF-kB signal recovered the inhibition of osteogenesis observed after LPS injection. In conclusion, TNF-a might play a major role in LPS-induced inhibition of osteogenesis under inflammatory conditions.

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TNF-α inhibits BMP-induced osteoblast differentiation through activating SAPK/JNK signaling

Cited by 120 publications

References 20 publications

Multiple Endocrine Regulation by Bone Morphogenetic Protein System

Multiple Endocrine Regulation by Bone Morphogenetic Protein System

c-Jun N-terminal kinase 1 negatively regulates osteoblastic differentiation induced by BMP2 via phosphorylation of Runx2 at Ser104

LPS-Induced Inhibition of Osteogenesis Is TNF-α Dependent in a Murine Tooth Extraction Model

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