N-Cadherin Interacts with Axin and LRP5 To Negatively Regulate Wnt/β-Catenin Signaling, Osteoblast Function, and Bone Formation

Haÿ, Eric; Laplantine, Emmanuel; Geoffroy, Valérie; Frain, Monique; Köhler, Thomas; Müller, Ralph; Marie, Pierre J.

doi:10.1128/mcb.00349-08

Cited by 131 publications

(106 citation statements)

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“…Since both loss of function and over-expression of N-cadherin have been shown to result in osteoporosis, 32,33,44 two distinct mechanisms may account for this. The adhesion may induce relocation of N-cadherin from the intercellular osteoblast junctions to the site of MM contact, resulting in loss of osteoblastosteoblast contact and osteoblast function.…”

Section: Discussionmentioning

confidence: 99%

“…6,7 Besides inhibition by soluble factors, such as Wnt antagonists, activin A, interleukin-3 and interleukin-7, osteoblast function and maturation can also be suppressed through direct contact between MM cells and preosteoblastic cells mediated via a4b1-VCAM-1 and/or N-CAM-N-CAM interactions. 43 The latter findings, in addition to the reported key role of cadherin-based interactions in osteoblast function and differentiation, 9,32,33 prompted us to investigate whether N-cadherin-mediated adhesion of MM cells to osteoblasts (Figure 5B-C and Online Supplementary Figure S3) can contribute to inhibition of osteoblast differentiation. Indeed, silencing of N-cadherin in myeloma cells impaired these cells' capacity to suppress osteoblast differentiation ( Figure 5D-F).…”

Section: Discussionmentioning

confidence: 99%

“…The adhesion may induce relocation of N-cadherin from the intercellular osteoblast junctions to the site of MM contact, resulting in loss of osteoblastosteoblast contact and osteoblast function. Alternatively, adhesion may enhance N-cadherin stability and expression, resulting in inhibition of osteoblast differentiation by interfering with Wnt signaling, 33 a pathway playing a central role in the osteolytic bone disease observed in MM. 11,12,43 Apart from contributing to osteolytic bone disease, the N-cadherin-mediated interaction of MM with osteoblasts may also contribute to another sequela of MM, i.e.…”

Section: Discussionmentioning

confidence: 99%

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N-cadherin-mediated interaction with multiple myeloma cells inhibits osteoblast differentiation

Groen¹,

Rooij²,

Kocemba³

et al. 2011

Haematologica

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The online version of this article has a Supplementary Appendix. BackgroundMultiple myeloma is a hematologic malignancy characterized by a clonal expansion of malignant plasma cells in the bone marrow, which is accompanied by the development of osteolytic lesions and/or diffuse osteopenia. The intricate bi-directional interaction with the bone marrow microenvironment plays a critical role in sustaining the growth and survival of myeloma cells during tumor progression. Identification and functional analysis of the (adhesion) molecules involved in this interaction will provide important insights into the pathogenesis of multiple myeloma. Design and MethodsMultiple myeloma cell lines and patients' samples were analyzed for expression of the adhesion molecule N-cadherin by immunoblotting, flow cytometry, immunofluorescence microscopy, immunohistochemistry and expression microarray. In addition, by means of blocking antibodies and inducible RNA interference we studied the functional consequence of N-cadherin expression for the myeloma cells, by analysis of adhesion, migration and growth, and for the bone marrow microenvironment, by analysis of osteogenic differentiation. ResultsThe malignant plasma cells in approximately half of the multiple myeloma patients, belonging to specific genetic subgroups, aberrantly expressed the homophilic adhesion molecule N-cadherin. N-cadherin-mediated cell-substrate or homotypic cell-cell adhesion did not contribute to myeloma cell growth in vitro. However, N-cadherin directly mediated the bone marrow localization/retention of myeloma cells in vivo, and facilitated a close interaction between myeloma cells and N-cadherin-positive osteoblasts. Furthermore, this N-cadherin-mediated interaction contributed to the ability of myeloma cells to inhibit osteoblastogenesis. ConclusionsTaken together, our data show that myeloma cells frequently display aberrant expression of Ncadherin and that N-cadherin mediates the interaction of myeloma cells with the bone marrow microenvironment, in particular the osteoblasts. This N-cadherin-mediated interaction inhibits osteoblast differentiation and may play an important role in the pathogenesis of myeloma bone disease.Key words: N-cadherin, multiple myeloma, osteoblast differentiation.Citation: Groen RWJ, de Rooij MFM, Kocemba KA, Reijmers RM, de Haan-Kramer A, Overdijk MB, Aalders L, Rozemuller H, Martens ACM, Bergsagel PL, Kersten MJ, Pals ST, and Spaargaren M. N-cadherin-mediated Haematologica 2011;96(11):1653-1661. doi:10.3324/haematol.2010 This is an open-access paper. interaction with multiple myeloma cells inhibits osteoblast differentiation. N-cadherin-mediated interaction with multiple myeloma cells inhibits osteoblast differentiation

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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N-cadherin-mediated interaction with multiple myeloma cells inhibits osteoblast differentiation

Groen¹,

Rooij²,

Kocemba³

et al. 2011

Haematologica

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“…The bones were scanned using a high-resolution micro-computed tomography (microCT) system (SkyScan 1172, MicroPhotonics, Allentown, PA, USA) and analysed using a 3D morphometry evaluation program (NRecon reconstruction program). For histomorphometric analysis, the bones were embedded in methylmethacrylate and 5 mm sections were stained with aniline blue to analyse structural parameters (osteoblast surface, bone volume, trabecular number and thickness), as described previously (Haÿ et al 2009). TRAP staining was carried out to evaluate the number of active osteoclasts (Haÿ et al 2009).…”

Section: Bone Microarchitecture and Histomorphometrymentioning

confidence: 99%

“…For histomorphometric analysis, the bones were embedded in methylmethacrylate and 5 mm sections were stained with aniline blue to analyse structural parameters (osteoblast surface, bone volume, trabecular number and thickness), as described previously (Haÿ et al 2009). TRAP staining was carried out to evaluate the number of active osteoclasts (Haÿ et al 2009). Unstained sections (8 mm thick) were used to assess dynamic parameters (mineral apposition rate (MAR), double labelled surface and bone formation rate (BFR); (Parfitt et al 1987).…”

Section: Bone Microarchitecture and Histomorphometrymentioning

confidence: 99%

Low-dose PTH increases osteoblast activity via decreased Mef2c/Sost in senescent osteopenic mice

Saidak¹,

Hénaff²,

Azzi³

et al. 2014

Journal of Endocrinology

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Intermittent administration of parathyroid hormone (PTH) 1-34 at a standard dose has been shown to induce anabolic effects in bone. However, whether low-dose PTH promotes bone formation during senescence is unknown. To address this issue, we determined the effects of low-dose PTH and analysed the underlying mechanisms in prematurely senescent mice that display osteopenia. Treatment of 9-week-old Samp6 mice for 6 weeks with PTH at a standard dose (100 mg/kg per day) increased vertebral and femoral bone mass and improved bone microarchitecture as a result of increased bone-forming surfaces and mineral apposition rate (MAR). At a tenfold lower dose (10 mg/kg per day), PTH increased axial bone volume and trabecular thickness, as detected by bone histomorphometry but not by micro-computed tomography analysis. This anabolic effect resulted from increased osteoblast activity, as reflected by increased serum N-terminal propeptide of type 1 procollagen (P1NP) levels and MAR, with unchanged bone-forming surface or osteoblast surface. Mechanistically, low-dose PTH increased the expression of osteoblast markers in bone marrow stromal cells and mature osteoblasts, which was associated with increased expression of the Wnt effector Wisp1. Moreover, low-dose PTH decreased the expression of the Mef2c transcription factor, resulting in decreased Sost expression in osteoblasts/osteocytes. These results indicate that PTH at a low dose is effective at promoting bone formation and increased bone volume in senescent osteopenic mice through increased osteoblast activity and modulation of specific Wnt effectors, which raises the potential therapeutic use of intermittent PTH at low dose to increase bone forming activity and bone mass in skeletal senescence.

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CK1ε and p120‐catenin control Ror2 function in noncanonical Wnt signaling

et al. 2018

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Canonical and noncanonical Wnt pathways share some common elements but differ in the responses they evoke. Similar to Wnt ligands acting through the canonical pathway, Wnts that activate the noncanonical signaling, such as Wnt5a, promote Disheveled (Dvl) phosphorylation and its binding to the Frizzled (Fz) Wnt receptor complex. The protein kinase CK1ε is required for Dvl/Fz association in both canonical and noncanonical signaling. Here we show that differently to its binding to canonical Wnt receptor complex, CK1ε does not require p120‐catenin for the association with the Wnt5a co‐receptor Ror2. Wnt5a promotes the formation of the Ror2–Fz complex and enables the activation of Ror2‐bound CK1ε by Fz‐associated protein phosphatase 2A. Moreover, CK1ε also regulates Ror2 protein levels; CK1ε association stabilizes Ror2, which undergoes lysosomal‐dependent degradation in the absence of this kinase. Although p120‐catenin is not required for CK1ε association with Ror2, it also participates in this signaling pathway as p120‐catenin binds and maintains Ror2 at the plasma membrane; in p120‐depleted cells, Ror2 is rapidly internalized through a clathrin‐dependent mechanism. Accordingly, downregulation of p120‐catenin or CK1ε affects late responses to Wnt5a that are also sensitive to Ror2, such as SIAH2 transcription, cell invasion, or cortical actin polarization. Our results explain how CK1ε is activated by noncanonical Wnt and identify p120‐catenin and CK1ε as two critical factors controlling Ror2 function.

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N-Cadherin Interacts with Axin and LRP5 To Negatively Regulate Wnt/β-Catenin Signaling, Osteoblast Function, and Bone Formation

Cited by 131 publications

References 58 publications

N-cadherin-mediated interaction with multiple myeloma cells inhibits osteoblast differentiation

N-cadherin-mediated interaction with multiple myeloma cells inhibits osteoblast differentiation

Low-dose PTH increases osteoblast activity via decreased Mef2c/Sost in senescent osteopenic mice

CK1ε and p120‐catenin control Ror2 function in noncanonical Wnt signaling

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