A histone lysine methyltransferase activated by non-canonical Wnt signalling suppresses PPAR-γ transactivation

Takada, Ichiro; Mihara, Makoto; Suzawa, Miyuki; Ohtake, Fumiaki; Kobayashi, Shinji; Igarashi, Mamoru; Youn, M.; Takeyama, Ken Ichi; Nakamura, Takashi; Mezaki, Yoshihiro; Takezawa, Shinichiro; Yogiashi, Yoshiko; Kitagawa, Hirochika; Yamada, Gen; Takada, Shinji; Minami, Yasuhiro; Shibuya, H.; Matsumoto, Kunihiro; Kato, Shigeaki

doi:10.1038/ncb1647

Cited by 405 publications

(335 citation statements)

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“…We also report that Wnt5a stimulated TNAP activity in hu- man osteoblasts [28,40,41]. We hypothesize that Wnt5a stimulates TNAP and mineralization through inhibition of PPAR activity in osteoblasts [25,30]. More importantly, we also report that Wnt5a blockade decreased basal TNAP activity indicating that Wnt5a is a constitutive autocrine activator of mineralization [34,41].…”

Section: Discussionsupporting

confidence: 66%

“…In particular, Wnt5a seems to be the predominant Wnt expressed during osteoblastic differentiation of human MSCs [24]. Moreover, Wnt5a +/À mice present a reduced bone mass phenotype with decreased osteoblast number [25]. Finally and importantly, Wnt5a levels are increased in inflamed joints from patients with RA [26], and also in the early inflammation phase that takes place during fracture healing [27].…”

Section: Introductionmentioning

confidence: 99%

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Autocrine stimulation of osteoblast activity by Wnt5a in response to TNF-α in human mesenchymal stem cells

Briolay

Lencel²,

Bessueille

et al. 2013

Biochemical and Biophysical Research Communications

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a b s t r a c tAlthough anti-tumor necrosis factor (TNF)-a treatments efficiently block inflammation in ankylosing spondylitis (AS), they are inefficient to prevent excessive bone formation. In AS, ossification seems more prone to develop in sites where inflammation has resolved following anti-TNF therapy, suggesting that TNF-a indirectly stimulates ossification. In this context, our objectives were to determine and compare the involvement of Wnt proteins, which are potent growth factors of bone formation, in the effects of TNF-a on osteoblast function. In human mesenchymal stem cells (MSCs), TNF-a significantly increased the levels of Wnt10b and Wnt5a. Associated with this effect, TNF-a stimulated tissue-non specific alkaline phosphatase (TNAP) and mineralization. This effect was mimicked by activation of the canonical bcatenin pathway with either anti-Dkk1 antibodies, lithium chloride (LiCl) or SB216763. TNF-a reduced, and activation of b-catenin had little effect on expression of osteocalcin, a late marker of osteoblast differentiation. Surprisingly, TNF-a failed to stabilize b-catenin and Dkk1 did not inhibit TNF-a effects. In fact, Dkk1 expression was also enhanced in response to TNF-a, perhaps explaining why canonical signaling by Wnt10b was not activated by TNF-a. However, we found that Wnt5a also stimulated TNAP in MSCs cultured in osteogenic conditions, and increased the levels of inflammatory markers such as COX-2. Interestingly, treatment with anti-Wnt5a antibodies reduced endogenous TNAP expression and activity. Collectively, these data suggest that increased levels of Dkk1 may blunt the autocrine effects of Wnt10b, but not that of Wnt5a, acting through non-canonical signaling. Thus, Wnt5a may be potentially involved in the effects of inflammation on bone formation.

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Section: Discussionsupporting

confidence: 66%

Section: Introductionmentioning

confidence: 99%

Autocrine stimulation of osteoblast activity by Wnt5a in response to TNF-α in human mesenchymal stem cells

Briolay

Lencel²,

Bessueille

et al. 2013

Biochemical and Biophysical Research Communications

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“…WNT3a promotes OB differentiation and function, conversely dickkopf (DKK)1, soluble frizzled receptor-like proteins (sFRP)3 and sclerostin inhibit osteo-genesis [27][28][29]. BM serum of MM patients is often characterized by high levels of WNT inhibitors, which are considered promising therapeutic targets.…”

Section: Pathogenesis Of Osteoblast Inhibition In MMmentioning

confidence: 99%

Bone Anabolic Agents for the Treatment of Multiple Myeloma

Vallet

2011

Cancer Microenvironment

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The majority of patients with multiple myeloma develop bone osteolytic lesions, which may lead to severe complications, including pain and fractures. The pathogenesis of bone disease depends on uncoupled bone remodeling, characterized by increased bone resorption due to upregulation of osteoclast activity and decreased bone formation due to osteoblast inhibition. In myeloma, impaired osteoblast differentiation and increased apoptosis have been described. Responsible for these effects are integrin-mediated adhesion to tumor cells and soluble factors, including WNT antagonists, BMP2 inhibitors and numerous cytokines. Based on the evidence of osteoblast suppression in myeloma, bone anabolic agents have been developed and are currently undergoing clinical evaluation. Due to bidirectional inhibitory effects characterizing tumor cells and osteoblasts interactions, agents targeting osteoblasts are expected to reduce tumor burden along with improvement of bone health. This review summarizes the current knowledge on osteoblast inhibition in myeloma and provides an overview on the clinical grade agents with bone anabolic properties, which represent new promising therapeutic strategies in myeloma.

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“…Six hours after transfection, the culture medium was changed to BM. For experiments testing added compounds, the medium was supplemented with KN93 (6.6 nM; Sigma Chemical Co., St. Louis, MO, USA), KCl (50 mM; Merck, Darmstadt, Germany), (50) secreted Fizzled-related protein 2 (sFRP2); 4 nM, RD System, Minneapolis, MN, USA), (51) or sFRP3 (10 nM, RD System) (52) and used to pretreat the C2C12 cells for 1 hour before the mechanical stretching application.…”

Section: Cell Culture and Stretching Experimentsmentioning

confidence: 99%

Mechanical stretching induces osteoprotegerin in differentiating C2C12 precursor cells through noncanonical Wnt Pathways

Chen

et al. 2010

Journal of Bone and Mineral Research

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Mechanical loading is known to be important for maintaining the formation and resorption rates of bone. To study the mechanisms by which mechanical loading regulates osteogenesis, we investigated the role of the Wnt pathway in C2C12 cells committed to osteogenic differentiation in response to cyclic mechanical stretching. Osteoprotegerin (OPG) acts as a decoy receptor for RANKL to inhibit osteoclastogenesis and resorption of bone. Our results demonstrate that stretching leads to a sustained increase in OPG expression in C2C12 cells. The expression of osteogenic marker genes, such as osteocalcin and alkaline phosphatase, was transiently decreased by stretching at 24 hours and returned to control levels at 48 hours. The addition of inhibitors of the canonical Wnt/b-catenin pathways, such as the secreted FZD-related peptide sRFP2, as well as siRNA-mediated knockdown, did not inhibit the effect of stretching on OPG expression. In contrast, treatment with inhibitors of noncanonical Wnt signaling, including KN93, and siRNA for Nemo-like kinase (NLK) blocked most of the mechanical inductive effect on OPG. Furthermore, stretching-induced OPG production in the culture medium was able to inhibit the osteoclast formation of bone marrow macrophages. These results suggest that mechanical stretching may play an important role in bone remodeling through the upregulation of OPG and that the mechanical signaling leading to OPG induction involves the noncanonical Wnt pathway. ß

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A histone lysine methyltransferase activated by non-canonical Wnt signalling suppresses PPAR-γ transactivation

Cited by 405 publications

References 50 publications

Autocrine stimulation of osteoblast activity by Wnt5a in response to TNF-α in human mesenchymal stem cells

Autocrine stimulation of osteoblast activity by Wnt5a in response to TNF-α in human mesenchymal stem cells

Bone Anabolic Agents for the Treatment of Multiple Myeloma

Mechanical stretching induces osteoprotegerin in differentiating C2C12 precursor cells through noncanonical Wnt Pathways

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