title: Normal hematopoiesis and lack of β-catenin activation in osteoblasts of patients and mice harboring Lrp5 gain-of-function mutations.
abstract: Osteoblasts are emerging regulators of myeloid malignancies since genetic alterations in them, such as constitutive activation of β-catenin, instigate their appearance. The LDL receptor-related protein 5 (LRP5), initially proposed to be a co-receptor for Wnt proteins, in fact favors bone formation by suppressing gut-serotonin synthesis. This function of Lrp5 occurring in the gut is independent of β-catenin activation in osteoblasts. However, it is unknown whether Lrp5 can act directly in osteoblast to influence other functions that require β-catenin signaling, particularly, the deregulation of hematopoiesis and leukemogenic properties of β-catenin activation in osteoblasts, that lead to development of acute myeloid leukemia (AML). Using mice with gain-of-function (GOF) Lrp5 alleles (Lrp5(A214V)) that recapitulate the human high bone mass (HBM) phenotype, as well as patients with the T253I HBM Lrp5 mutation, we show here that Lrp5 GOF mutations in both humans and mice do not activate β-catenin signaling in osteoblasts. Consistent with a lack of β-catenin activation in their osteoblasts, Lrp5(A214V) mice have normal trilinear hematopoiesis. In contrast to leukemic mice with constitutive activation of β-catenin in osteoblasts (Ctnnb1(CAosb)), accumulation of early myeloid progenitors, a characteristic of AML, myeloid-blasts in blood, and segmented neutrophils or dysplastic megakaryocytes in the bone marrow, are not observed in Lrp5(A214V) mice. Likewise, peripheral blood count analysis in HBM patients showed normal hematopoiesis, normal percentage of myeloid cells, and lack of anemia. We conclude that Lrp5 GOF mutations do not activate β-catenin signaling in osteoblasts. As a result, myeloid lineage differentiation is normal in HBM patients and mice. This article is part of a Special Issue entitled: Tumor Microenvironment Regulation of Cancer Cell Survival, Metastasis, Inflammation, and Immune Surveillance edited by Peter Ruvolo and Gregg L. Semenza.
authors.affiliation: Department of Physiology & Cellular Biophysics, College of Physicians & Surgeons, Columbia University, New York, NY 10032, USA.
authors.forename: Marta
authors.initials: M
authors.lastname: Galán-Díez
authors.affiliation: Molecular Endocrinology Laboratory (KMEB), Department of Endocrinology, Odense University Hospital & University of Southern Denmark, DK-5000 Odense, Denmark.
authors.forename: Adiba
authors.initials: A
authors.lastname: Isa
authors.affiliation: Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Ponzetti
authors.affiliation: Molecular Endocrinology Laboratory (KMEB), Department of Endocrinology, Odense University Hospital & University of Southern Denmark, DK-5000 Odense, Denmark.
authors.forename: Morten Frost
authors.initials: MF
authors.lastname: Nielsen
authors.affiliation: Molecular Endocrinology Laboratory (KMEB), Department of Endocrinology, Odense University Hospital & University of Southern Denmark, DK-5000 Odense, Denmark; The Danish Stem Cell Centre-DanStem, University of Copenhagen, 3B Blegdamsvej, DK-2200 Copenhagen, Denmark.
authors.forename: Moustapha
authors.initials: M
authors.lastname: Kassem
authors.affiliation: Department of Physiology & Cellular Biophysics, College of Physicians & Surgeons, Columbia University, New York, NY 10032, USA. Electronic address: sk2836@cumc.columbia.edu.
authors.forename: Stavroula
authors.initials: S
authors.lastname: Kousteni
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D015519:Bone Density / Q000235:genetics; D002460:Cell Line; D045744:Cell Line, Tumor; D005260:Female; D005434:Flow Cytometry; D006410:Hematopoiesis; D006801:Humans; D060492:Low Density Lipoprotein Receptor-Related Protein-5 / Q000235:genetics*; D008297:Male; D018345:Mice, Knockout; D008875:Middle Aged; D009154:Mutation; D010006:Osteoblasts / Q000378:metabolism*; D010012:Osteogenesis / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D055815:Young Adult; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D060492:Low Density Lipoprotein Receptor-Related Protein-5; D051176:beta Catenin
keywords: Hematopoiesis; High bone mass (HBM); Leukemia; Lrp5; Osteoblasts; β-catenin