title: PTH Signaling in Osteoprogenitors Is Essential for B-Lymphocyte Differentiation and Mobilization.
abstract: Cells of the osteoblast lineage provide critical support for B lymphopoiesis in the bone marrow (BM). Parathyroid hormone (PTH) signaling in osteoblastic cells through its receptor (PPR) is an important regulator of hematopoietic stem cells; however, its role in regulation of B lymphopoiesis is not clear. Here we demonstrate that deletion of PPR in osteoprogenitors results in a significant loss of trabecular and cortical bone. PPR signaling in osteoprogenitors, but not in mature osteoblasts or osteocytes, is critical for B-cell precursor differentiation via IL-7 production. Interestingly, despite a severe reduction in B-cell progenitors in BM, mature B-lymphocytes were increased 3.5-fold in the BM of mice lacking PPR in osteoprogenitors. This retention of mature IgD(+) B cells in the BM was associated with increased expression of vascular cell adhesion molecule 1 (VCAM1) by PPR-deficient osteoprogenitors, and treatment with VCAM1 neutralizing antibody increased mobilization of B lymphocytes from mutant BM. Our results demonstrate that PPR signaling in early osteoblasts is necessary for B-cell differentiation via IL-7 secretion and for B-lymphocyte mobilization via VCAM1.
authors.affiliation: Division of Endocrinology, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Cristina
authors.initials: C
authors.lastname: Panaroni
authors.affiliation: Endocrine Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Keertik
authors.initials: K
authors.lastname: Fulzele
authors.affiliation: Endocrine Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Vaibhav
authors.initials: V
authors.lastname: Saini
authors.affiliation: Endocrine Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Rhiannon
authors.initials: R
authors.lastname: Chubb
authors.affiliation: Endocrine Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Paola Divieti
authors.initials: PD
authors.lastname: Pajevic
authors.affiliation: Division of Endocrinology, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Joy Y
authors.initials: JY
authors.lastname: Wu
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000737:chemistry; D017209:Apoptosis; D001402:B-Lymphocytes / Q000166:cytology*; D001842:Bone and Bones / Q000378:metabolism; D002454:Cell Differentiation; D054377:Chemokine CXCL12 / Q000378:metabolism; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D006412:Hematopoietic Stem Cells / Q000166:cytology; D007150:Immunohistochemistry; D015851:Interleukin-7 / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010006:Osteoblasts / Q000166:cytology; D010011:Osteocytes / Q000166:cytology; D010281:Parathyroid Hormone / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology*; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism; D055114:X-Ray Microtomography
chemical_list: D057134:Antibodies, Neutralizing; D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D015851:Interleukin-7; D010281:Parathyroid Hormone; D011994:Recombinant Proteins; D019010:Vascular Cell Adhesion Molecule-1
keywords: B CELLS; BONE; OSTEOPROGENITORS; PTH RECEPTOR; VCAM1