Accentuated Ovariectomy-Induced Bone Loss and Altered Osteogenesis in Heterozygous N-Cadherin Null Mice

Lai, Chung Fang; Cheng, Su‐Li; Mbalaviele, Gabriel; Donsante, Christine; Watkins, Marcus; Radice, Glenn L.; Civitelli, Roberto

doi:10.1359/jbmr.060906

Cited by 37 publications

(27 citation statements)

References 39 publications

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“…We attribute this difference to the presence of a germline null allele, with possible systemic effects as well as mild osteoblastic defects. 16 Moreover, the increased trabecular volume and number we detected in the present study became evident only when male and female mice were analyzed independently. In addition, this phenotype differs from that seen in a previous report using a dominant negative N-cadherin.…”

Section: Discussionmentioning

confidence: 48%

“…We directly targeted the osteoblastic lineage by using Col1-Cre transgenic mice 17 because this specific promoter affects osteoblastic cells that initiated PTH action on the HSC niche, 20,23 and demonstrate lack of osteoblastic N-Cad protein in vivo. We chose not to use N-cadherin ϩ/Ϫ in this mating because global hemizygosity results in osteoblastic defects, 16 which may have affected osteoblastic support of HSCs and/or PTH action.…”

Section: Discussionmentioning

confidence: 99%

“…3,14 Indeed, whereas germline deletion of the gene encoding N-cadherin (Cdh2) is embryonically lethal, 15 hemizygous mice already display osteoblastic defects, having accentuated bone loss with ovariectomy. 16 Moreover, recent data have suggested differential roles of N-cadherin at various stages of osteoblastic differentiation, with actions of N-cadherin both on osteogenic commitment as well as at terminal differentiation. 14 In this work, our goal was to determine whether targeted deletion of Cdh2 in maturing osteoblasts alters the BM microarchitecture, HSC number, and function in homeostasis and disrupts the action of parathyroid hormone (PTH) on the skeleton and/or on hematopoietic stem and progenitor cells (HSPCs).…”

Section: Introductionmentioning

confidence: 99%

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Osteoblastic N-cadherin is not required for microenvironmental support and regulation of hematopoietic stem and progenitor cells

Bromberg¹,

Frisch

Weber³

et al. 2012

Blood

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Hematopoietic stem cell (HSC) regulation is highly dependent on interactions with the marrow microenvironment. Controversy exists on N-cadherin's role in support of HSCs. Specifically, it is unknown whether microenvironmental N-cadherin is required for normal marrow microarchitecture and for hematopoiesis. To determine whether osteoblastic N-cadherin is required for HSC regulation, we used a genetic murine model in which deletion of IntroductionThe molecular signals that mediate regulatory microenvironmental osteoblastic-hematopoietic interactions provide potential therapeutic targets for hematopoietic stem cell (HSC) manipulation 1 but are still largely unknown. Based on the essential role of cadherins in fate specification of germline stem cells 2 and the close proximity of N-cadherin-expressing osteoblastic cells to HSCs, [3][4][5][6] it was initially proposed that N-cadherin may provide HSCs with instructive interactions with their niche. However, much debate was subsequently raised by reports questioning N-cadherin expression by HSCs, 7 whereas others suggested that different N-cadherin levels characterize functionally distinct HSC populations, 5,8,9 which may respond to niche manipulation. 10 Moreover, inducible global genetic N-cadherin deletion lacks hematopoietic defects, 11 but knockdown of N-cadherin in HSCs suppresses their long-term engraftment. 12 Whereas in HSCs N-cadherin, when present, is expressed at very low levels, 13 osteoblastic cells express N-cadherin at several differentiation stages, both in immature and mature cells. 3,14 Indeed, whereas germline deletion of the gene encoding N-cadherin (Cdh2) is embryonically lethal, 15 hemizygous mice already display osteoblastic defects, having accentuated bone loss with ovariectomy. 16 Moreover, recent data have suggested differential roles of N-cadherin at various stages of osteoblastic differentiation, with actions of N-cadherin both on osteogenic commitment as well as at terminal differentiation. 14 In this work, our goal was to determine whether targeted deletion of Cdh2 in maturing osteoblasts alters the BM microarchitecture, HSC number, and function in homeostasis and disrupts the action of parathyroid hormone (PTH) on the skeleton and/or on hematopoietic stem and progenitor cells (HSPCs). Methods MiceCol2.3-Cre mice expressing the Cre-recombinase under the control of the 2.3-kb fragment of the ␣1(I) collagen gene promoter were kindly provided by Dr Gerard Karsenty. 17 Mating of Col2.3-Cre with Cdh2 fl mice (generated in Dr Glenn L. Radice's laboratory, Thomas Jefferson University, Philadelphia, PA) 18 resulted in mice carrying the Col2.3-Cre ϩ Cadh2 fl/fl genotype, which had specific inactivation of N-cadherin in cells of the osteoblastic lineage, designated as OB-NCadh for the rest of the manuscript. 14 This line was maintained in the C57bl/6 background, and expression of the CD45.2 congenic marker was confirmed. Wild-type (WT) mice expressing the CD45.1 congenic marker (B6.SJL-Ptprc a Pep3 b /BoyJ CD45.1) were purchased from The Jackson L...

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Section: Discussionmentioning

confidence: 48%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Osteoblastic N-cadherin is not required for microenvironmental support and regulation of hematopoietic stem and progenitor cells

Bromberg¹,

Frisch

Weber³

et al. 2012

Blood

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“…Either ovariectomy or a sham operation was performed in 4-month-old Mx1;Rgs12 +/+ and Mx1;Rgs12 fl/fl females (n = 5 for each group) as reported previously. 60,61 Three-month-old mice were anesthetized with 1000 cc/min O 2 and 5% isofluorane. Ovaries were approached by two separate flank incisions.…”

Section: Methodsmentioning

confidence: 99%

Regulators of G protein signaling 12 promotes osteoclastogenesis in bone remodeling and pathological bone loss

et al. 2015

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Regulators of G protein signaling (Rgs) have pivotal roles in controlling various cellular processes, such as cell differentiation. How Rgs proteins regulate osteoclast (OC) differentiation, function and bone homeostasis is poorly understood. It was previously demonstrated that Rgs12, the largest protein in the Rgs family, is predominantly expressed in OCs and regulates OC differentiation in vitro. To further understand the role and mechanism of Rgs12 in OC differentiation and bone diseases in vivo, we created OC-targeted Rgs12 knockout mice by using inducible Mx1-Cre and CD11b-Cre. Deletion of Rgs12 in hematopoietic cells or specifically in OC precursors resulted in increased bone mass with decreased OC numbers. Loss of Rgs12 impaired OC differentiation and function with impaired Ca 2+ oscillations and reduced nuclear factor of activated T cells (NFAT) 2 expression. The introduction of wild-type osteoblasts did not rescue the defective osteoclastogenesis. Ectopic expression of NFAT2 rescued defective OC differentiation in CD11b;Rgs12 fl/fl cells and promoted normal OC differentiation. Moreover, deletion of Rgs12 significantly inhibited pathological osteoclastogenesis and bone destruction in Rgs12-deficient mice that were subjected to ovariectomy and lipodysaccharide for bone loss. Thus our findings demonstrate that Rgs12 is an important regulator in OC differentiation and function and identify Rgs12 as a potential therapeutic target for osteoporosis and inflammation-induced bone loss. Bone homeostasis is tightly regulated by the balance between osteoblasts (OBs), the bone-forming cells, and osteoclasts (OCs), the bone-resorbing cells. 1 Pathological conditions such as osteoporosis, inflammation, and cancer break this balance in favor of the augmentation of OC activity, resulting in net bone loss. 2-4 As a result, patients with these diseases suffer from pain and risk of bone fracture. Therefore, understanding OC differentiation and function and uncovering potential therapeutic targets are very important and urgent objectives for treatment of these diseases. 5,6 Mature OCs, derived from the monocyte/macrophage hematopoietic lineage, are multinucleated and tartrateresistant acid phosphatase (TRAP) positive. 7 The breakthrough in understanding osteoclastogenesis came from the discovery that receptor activator of NF-κB ligand (RANKL) and macrophage colony-stimulating factor (M-CSF) have essential roles in stimulating monocyte-macrophage lineage cells to differentiate into mature and functional OCs. [8][9][10] Currently, known crucial RANKL downstream transcription factors and genes include active nuclear factor of activated T cells (NFAT) 2, c-Fos, β 3 -integrin, Cathepsin K, and matrix metallopeptidase 9. 11,12 Among these, NFAT2 acts as a master switch for the terminal differentiation of OCs. 13 Robust induction of NFAT2 is dependent on calcium (Ca 2+ ) oscillations. 14 Ca 2+ oscillations lead to calcineurin-mediated activation of NFAT2 and ensure NFAT2 long-lasting transcriptional activation. 13,14 Despite these...

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“…In bone, N-cadherin is strongly expressed by osteoblasts and is believed to play a significant role in osteogenesis (40,42). Previous loss-offunction studies using overexpression of dominant-negative Ncadherin or heterozygous N-cadherin null mice have indicated that N-cadherin regulates osteoblast differentiation and bone formation (9,10,32). However, the molecular mechanisms by which N-cadherin controls intracellular signals to regulate osteoblastogenesis are not fully understood.…”

mentioning

confidence: 99%

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

Haÿ

Laplantine

Geoffroy

et al. 2009

Molecular and Cellular Biology

133

103

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Wnt signaling plays an important role in the regulation of bone formation and bone mass. The mechanisms that regulate canonical Wnt signaling in osteoblasts are not fully understood. We show here a novel mechanism by which the adhesion molecule N-cadherin interacts with the Wnt coreceptor LRP5 and regulates canonical Wnt/␤-catenin signaling in osteoblasts. We demonstrate that N-cadherin, besides associating with ␤-catenin at the membrane, forms a molecular complex with axin and LRP5 involving the LRP5 cytoplasmic tail domain. N-cadherin overexpression in osteoblasts increases N-cadherin-LRP5 interaction, causing increased ␤-catenin degradation and altered TCF/LEF transcription in response to Wnt3a. This mechanism results in decreased osteoblast gene expression and osteogenesis in basal conditions and in response to Wnt3a. Consistent with a functional mechanism, silencing N-cadherin expression in control cells increases TCF/LEF transcription and enhances the response to Wnt3a. Using N-cadherin transgenic mice, we show that increased N-cadherin-LRP5 interaction resulting from targeted overexpression of N-cadherin in osteoblasts causes increased ␤-catenin ubiquitination and results in cell-autonomous defective osteoblast function, reduced bone formation, and delayed bone mass acquisition. These data indicate that a previously unrecognized N-cadherin-axin-LRP5 interaction negatively regulates Wnt/␤-catenin signaling and is critical in the regulation of osteoblast function, bone formation, and bone mass.

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Accentuated Ovariectomy-Induced Bone Loss and Altered Osteogenesis in Heterozygous N-Cadherin Null Mice

Cited by 37 publications

References 39 publications

Osteoblastic N-cadherin is not required for microenvironmental support and regulation of hematopoietic stem and progenitor cells

Osteoblastic N-cadherin is not required for microenvironmental support and regulation of hematopoietic stem and progenitor cells

Regulators of G protein signaling 12 promotes osteoclastogenesis in bone remodeling and pathological bone loss

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

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