title: Osteocytes, not Osteoblasts or Lining Cells, are the Main Source of the RANKL Required for Osteoclast Formation in Remodeling Bone.
abstract: The cytokine receptor activator of nuclear factor kappa B ligand (RANKL), encoded by the Tnfsf11 gene, is essential for osteoclastogenesis and previous studies have shown that deletion of the Tnfsf11 gene using a Dmp1-Cre transgene reduces osteoclast formation in cancellous bone by more than 70%. However, the Dmp1-Cre transgene used in those studies leads to recombination in osteocytes, osteoblasts, and lining cells making it unclear whether one or more of these cell types produce the RANKL required for osteoclast formation in cancellous bone. Because osteoblasts, osteocytes, and lining cells have distinct locations and functions, distinguishing which of these cell types are sources of RANKL is essential for understanding the orchestration of bone remodeling. To distinguish between these possibilities, we have now created transgenic mice expressing the Cre recombinase under the control of regulatory elements of the Sost gene, which is expressed in osteocytes but not osteoblasts or lining cells in murine bone. Activity of the Sost-Cre transgene in osteocytes, but not osteoblast or lining cells, was confirmed by crossing Sost-Cre transgenic mice with tdTomato and R26R Cre-reporter mice, which express tdTomato fluorescent protein or LacZ, respectively, only in cells expressing the Cre recombinase or their descendants. Deletion of the Tnfsf11 gene in Sost-Cre mice led to a threefold decrease in osteoclast number in cancellous bone and increased cancellous bone mass, mimicking the skeletal phenotype of mice in which the Tnfsf11 gene was deleted using the Dmp1-Cre transgene. These results demonstrate that osteocytes, not osteoblasts or lining cells, are the main source of the RANKL required for osteoclast formation in remodeling cancellous bone.
authors.affiliation: Center for Osteoporosis and Metabolic Bone Diseases, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America; The Central Arkansas Veterans Healthcare System, Little Rock, Arkansas, United States of America.
authors.forename: Jinhu
authors.initials: J
authors.lastname: Xiong
authors.affiliation: Center for Osteoporosis and Metabolic Bone Diseases, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America; The Central Arkansas Veterans Healthcare System, Little Rock, Arkansas, United States of America.
authors.forename: Marilina
authors.initials: M
authors.lastname: Piemontese
authors.affiliation: Center for Osteoporosis and Metabolic Bone Diseases, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America; The Central Arkansas Veterans Healthcare System, Little Rock, Arkansas, United States of America.
authors.forename: Melda
authors.initials: M
authors.lastname: Onal
authors.affiliation: Center for Osteoporosis and Metabolic Bone Diseases, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America; The Central Arkansas Veterans Healthcare System, Little Rock, Arkansas, United States of America.
authors.forename: Josh
authors.initials: J
authors.lastname: Campbell
authors.affiliation: Center for Osteoporosis and Metabolic Bone Diseases, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America; The Central Arkansas Veterans Healthcare System, Little Rock, Arkansas, United States of America.
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Goellner
authors.affiliation: Department of Oral Biology, University of Missouri-Kansas City School of Dentistry, Kansas City, Missouri, United States of America.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Dusevich
authors.affiliation: Department of Oral Biology, University of Missouri-Kansas City School of Dentistry, Kansas City, Missouri, United States of America.
authors.forename: Lynda
authors.initials: L
authors.lastname: Bonewald
authors.affiliation: Center for Osteoporosis and Metabolic Bone Diseases, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America; The Central Arkansas Veterans Healthcare System, Little Rock, Arkansas, United States of America.
authors.forename: Stavros C
authors.initials: SC
authors.lastname: Manolagas
authors.affiliation: Center for Osteoporosis and Metabolic Bone Diseases, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America; The Central Arkansas Veterans Healthcare System, Little Rock, Arkansas, United States of America.
authors.forename: Charles A
authors.initials: CA
authors.lastname: O'Brien
mesh_terms: D000818:Animals; D015519:Bone Density; D016723:Bone Remodeling; D002455:Cell Division; D051379:Mice; D008822:Mice, Transgenic; D010006:Osteoblasts / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology*; D010011:Osteocytes / Q000378:metabolism*; D053245:RANK Ligand / Q000235:genetics / Q000378:metabolism*; D011995:Recombination, Genetic
chemical_list: D053245:RANK Ligand; C505689:Tnfsf11 protein, mouse