The LIM-only protein FHL2 controls mesenchymal cell osteogenic differentiation and bone formation through Wnt5a and Wnt10b

Brun, Julia; Fromigué, Olivia; Dieudonné, François-Xavier; Marty, Caroline; Chen, J.; Dahan, Jennifer; Wei, Y.; Marie, Pierre J.

doi:10.1016/j.bone.2012.08.040

Cited by 7 publications

(7 citation statements)

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“…Fhl2 can interact with β‐catenin, potentiating β‐catenin nuclear translocation and TCF/LEF transcription [Hamidouche et al, ]. Fhl2 can also be activated by Wnt3a at a transcriptional level [Brun et al, ], resulting in osteogenesis of bone marrow mesenchymal stem cells. Since Fhl2 acts similarly to Fhl1 during osteogenesis, they may functionally compensate each other because of evolutionary conservation.…”

Section: Discussionmentioning

confidence: 99%

Estrogen Enhances Activity of Wnt Signaling During Osteogenesis by Inducing Fhl1 Expression

Shih

Lee

et al. 2015

J of Cellular Biochemistry

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Estrogen is a crucial hormone for osteoclast inhibition and for preventing osteoporosis. However, the hormone's role in osteoblast growth and differentiation remains unclear. The complexity of estrogen's role in guiding osteoblast behavior arises partly from crosstalk with other signaling pathways, including Wnt signaling. In this study, we show that the Wnt agonist, LiCl, induced Fhl1 gene expression, which substantially enhanced osteoblast differentiation. Staining with alizarin red revealed that MC3T3-E1 mineralization was enhanced by overexpression of Fhl1. In addition, Fhl1 promoted the expression of the osteogenic markers, Runt-related transcription factor 2 (Runx2), osteocalcin (OCN), and osteopontin (OPN), whereas MC3T3-E1 cells with gene knockdown of Fhl1 exhibited limited mineralization and expression of Runx2, OCN, and OPN. We further demonstrate evidences from quantitative reverse transcription real-time polymerase chain reaction and reporter assay that Fhl1 expression was synergistically stimulated by estrogen (E2) and LiCl, but reduced by the estrogen-receptor inhibitor fulvestrant (ICI 182,780). However, estrogen could not enhance osteogenesis while Fhl1 expression was knocked down. Because estrogen and Wnt signaling frequently interact in developmental processes, we propose that Fhl1 can be an acting molecule mediating both signaling pathways during osteogenesis.

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Section: Discussionmentioning

confidence: 99%

Estrogen Enhances Activity of Wnt Signaling During Osteogenesis by Inducing Fhl1 Expression

Shih

Lee

et al. 2015

J of Cellular Biochemistry

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“…Because both effects were blocked by conditional disruption of Igf1 in osteocytes, it would suggest that osteocyte-derived IGF-I is important for the endosteal lamellar bone formation as well as for the periosteal woven bone formation. There is strong evidence that the periosteal woven bone formation in response to mechanical loading is mediated through the commitment of mesenchymal stem cells into osteoblast lineage cells primarily by the Wnt signaling (4,5). The mechanism by which loading enhances endosteal lamellar bone formation has not been determined, but it is likely mediated through stimulation of cell proliferation and activity of existing osteoblasts by yet-to-beidentified signaling pathways.…”

Section: E277mentioning

confidence: 99%

Osteocyte-derived insulin-like growth factor I is essential for determining bone mechanosensitivity

Lau

Baylink

Rodriguez

et al. 2013

American Journal of Physiology-Endocrinology and Metabolism

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This study sought to determine whether deficient Igf1 expression in osteocytes would affect loading-induced osteogenic response. Tibias of osteocyte Igf1 conditional knockout (KO) mice (generated by cross-breeding Igf1 floxed mice with Dmp1-Cre transgenic mice) and wild-type (WT) littermates were subjected to four-point bending for 2 wk. Microcomputed tomography confirmed that the size of tibias of conditional mutants was smaller. Loading with an equivalent loading strain increased periosteal woven bone and endosteal lamellar bone formation in WT mice but not in conditional KO mice. Consistent with the lack of an osteogenic response, the loading failed to upregulate expression of early mechanoresponsive genes (Igf1, Cox-2, c-fos) or osteogenic genes (Cbfa-1, and osteocalcin) in conditional KO bones. The lack of osteogenic response was not due to reduced osteocyte density or insufficient loading strain. Deficient osteocyte Igf1 expression reduced the loading-induced upregulation of expression of canonical Wnt signaling genes (Wnt10b, Lrp5, Dkk1, sFrp2). The loading also reduced (by 40%) Sost expression in WT mice, but the loading not only did not reduce but upregulated (~1.5-fold) Sost expression in conditional KO mice. Conditional disruption of Igf1 in osteocytes also abolished the loading-induced increase in the bone β-catenin protein level. These findings suggest an impaired response in the loading-induced upregulation of the Wnt signaling in conditional KO mice. In summary, conditional disruption of Igf1 in osteocytes abolished the loading-induced activation of the Wnt signaling and the corresponding osteogenic response. In conclusion, osteocyte-derived IGF-I plays a key determining role in bone mechanosensitivity.

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“…FHL2 is a serum-inducible coactivator of the transcription factor AP1 (7), the downstream effector of receptor tyrosine kinase-initiated signaling cascades. In Wnt/␤-catenin signaling, FHL2 exerts both transcription corepressor and coactivator functions of ␤-catenin, depending on the cellular context (8)(9)(10)(11). The main receptor of Sonic hedgehog Patched recruits a proapoptotic complex containing FHL2 and caspase 9 and triggers cell death through a caspase 9-dependent mechanism (12).…”

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confidence: 99%

LIM-Only Protein FHL2 Activates NF-κB Signaling in the Control of Liver Regeneration and Hepatocarcinogenesis

Dahan

Nouët

Jouvion

et al. 2013

Molecular and Cellular Biology

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The LIM-only protein FHL2 controls mesenchymal cell osteogenic differentiation and bone formation through Wnt5a and Wnt10b

Cited by 7 publications

References 0 publications

Estrogen Enhances Activity of Wnt Signaling During Osteogenesis by Inducing Fhl1 Expression

Estrogen Enhances Activity of Wnt Signaling During Osteogenesis by Inducing Fhl1 Expression

Osteocyte-derived insulin-like growth factor I is essential for determining bone mechanosensitivity

LIM-Only Protein FHL2 Activates NF-κB Signaling in the Control of Liver Regeneration and Hepatocarcinogenesis

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