Canonical Wnts and BMPs cooperatively induce osteoblastic differentiation through a GSK3β-dependent and β-catenin-independent mechanism

Fukuda, Tsuyoshi; Kokabu, Shoichiro; Ohte, Satoshi; Sasanuma, Hiroyuki; Kanomata, Kazuhiro; Yoneyama, Katsumi; Kato, Hitoshi; Akita, Masumi; Oda, Hiromi; Katagiri, Takenobu

doi:10.1016/j.diff.2010.05.002

Cited by 49 publications

(43 citation statements)

References 46 publications

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“…Both Wnt and Bmp signaling have been reported to act synergistically in regulating cell-specific programs during differentiation and regeneration. 30,31 It was shown that Wnts and BMPs can cooperatively induce early osteoblast differentiation in C2C12 cells in a GSK3b-dependent manner, 32 and that constitutive activation of RhoA in human mesenchymal stem cells can induce osteogenesis in vitro. 33 However, it has not been determined whether upregulation of both Wnt and Bmp signaling produces an additive induction of RhoGTP expression.…”

Section: Discussionmentioning

confidence: 99%

Foxc2 induces Wnt4 and Bmp4 expression during muscle regeneration and osteogenesis

et al. 2013

Cell Death Differ

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Proliferation and fusion of myoblasts is a well-orchestrated process occurring during muscle development and regeneration. Although myoblasts are known to originate from muscle satellite cells, the molecular mechanisms that coordinate their commitment toward differentiation are poorly understood. Here, we present a novel role for the transcription factor Forkhead box protein C2 (Foxc2) in regulating proliferation and preventing premature differentiation of activated muscle satellite cells. We demonstrate that Foxc2 expression is upregulated early in activated mouse muscle satellite cells and then diminishes during myogenesis. In undifferentiated C2C12 myoblasts, downregulation of endogenous Foxc2 expression leads to a decrease in proliferation, whereas forced expression of FOXC2 sustains proliferation and prevents differentiation into myotubes. We also show that FOXC2 induces Wnt signaling by direct interaction with the Wnt4 (wingless-type MMTV integration site family member-4) promoter region. The resulting elevated expression of bone morphogenetic protein-4 (Bmp4) and RhoA-GTP proteins inhibits the proper myoblast alignment and fusion required for myotube formation. Interestingly, continuous forced expression of FOXC2 alters the commitment of C2C12 myoblasts toward osteogenic differentiation, which is consistent with FOXC2 expression observed in patients with myositis ossificans, an abnormal bone growth within muscle tissue. In summary, our results suggest that ( Muscle satellite cells are resident stem cells localized between the basal lamina and the sarcolemma of myofibers. During postnatal development, these satellite cells provide myonuclei for growth of skeletal muscle. In adult skeletal muscles, satellite cells comprise 1-4% of myofibers and remain quiescent 1,2 unless involved in homeostasis, hypertrophy or muscle repair at which time they become activated, proliferate and produce the myoblasts needed to replace or repair myofibers.2,3 Deregulation of factors involved in the maintenance of muscle homeostasis and in the differentiation of muscle precursors can lead to a variety of pathologic conditions, including muscular dystrophies and myositis ossificans or heterotopic ossification. 4,5 The role of muscle satellite cells in the pathology of these disorders is not well understood. Identification of key regulators and elucidation of the processes involved in satellite cell activation and differentiation could provide important insights into the etiology, treatment and/or prevention of muscle disorders.Recent studies have shown that bone morphogenetic proteins (BMPs) are important in the activation and proliferation of muscle satellite cells, and in the prevention of premature myogenic differentiation. 6,7 BMPs are members of the transforming growth factor-b (TGF-b) family that initiate signaling by binding to transmembrane type-1 and type-2 BMP receptors (BMPRs). Upon ligand binding, transphosphorylation of type-1 by type-2 receptors activates the receptor-regulated Smad (Sma and Mad-related protein) tr...

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Section: Discussionmentioning

confidence: 99%

Foxc2 induces Wnt4 and Bmp4 expression during muscle regeneration and osteogenesis

et al. 2013

Cell Death Differ

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“…Plasmids encoding constitutively active b-catenin has been described previously [31]. Mouse C/EBPa (plasmid ID; MmCD00314721), mouse C/EBPb (plasmid ID; MmCD00297423) were provided by DF/HCC DNA Resource Core (BCMP Department 240 Longwood Ave. Boston, MA 02115).…”

Section: Plasmidsmentioning

confidence: 99%

“…TLE3 (3.0), TLE3 (2.0), TLE3 (1.0), and TLE3 (0.5)-luciferase reporter vector were respectively constructed by subcloning from 3.0, 2.0, 1.0, and 0.5 kbp fragment of the 5 0 flanking region of the mouse TLE3 gene into the pGL4,14 basic luciferase reporter vector. Super TOP flash-luciferase reporter vector [31] was kindly provided by Dr. Randall Moon. All of the final constructs were confirmed by sequencing.…”

Section: Plasmidsmentioning

confidence: 99%

Expression of TLE3 by bone marrow stromal cells is regulated by canonical Wnt signaling

Kokabu¹,

Sato²,

Ohte³

et al. 2014

FEBS Letters

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Edited by Zhijie ChangKeywords: Osteoblastogenesis Osteoporosis Wnt Groucho Transducing-like enhancer of split Co-repressor a b s t r a c t Transducing-like enhancer of split 3 (TLE3), one of the Groucho/TLE family members, targets Runx2 transcription and suppresses osteoblast differentiation in bone marrow stromal cells (BMSCs). Here, we identify Wnt responsive elements of the TLE3 promoter region through comparative genomic and functional analyses and show that expression of TLE3 is increased by Wnt signaling, which is important for osteoblast differentiation. We also demonstrated that TLE3 is able to suppress canonical Wnt signaling in BMSCs. Taken together, our data suggest that induction of TLE3 by Wnt signaling is part of a negative feedback loop active during osteoblast differentiation.

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“…Involvemennt of GSK3 in the synergestic effects of Wnt and BMP-4 on osteoblastic differentiation has recently been reported (Fukuda et al 2010). Wnt3a, a canonical Wnt, synergistically stimulated ColI expression and ALP activity in the presence of BMP-4.…”

Section: Glycogen Synthase Kinase 3 (Gsk3) In Wnt Signalsmentioning

confidence: 97%

Roles of Kinases in Osteoblast Function

Matsuguchi¹

2012

Advances in Protein Kinases

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Canonical Wnts and BMPs cooperatively induce osteoblastic differentiation through a GSK3β-dependent and β-catenin-independent mechanism

Cited by 49 publications

References 46 publications

Foxc2 induces Wnt4 and Bmp4 expression during muscle regeneration and osteogenesis

Foxc2 induces Wnt4 and Bmp4 expression during muscle regeneration and osteogenesis

Expression of TLE3 by bone marrow stromal cells is regulated by canonical Wnt signaling

Roles of Kinases in Osteoblast Function

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