Evidence for osteocyte regulation of bone homeostasis through RANKL expression

Osteocytes embedded in bone have been postulated to orchestrate bone homeostasis by regulating both bone-forming osteoblasts and bone-resorbing osteoclasts. We find here that purified osteocytes express a much higher amount of receptor activator of nuclear factor-κB ligand (RANKL) and have a greater capacity to support osteoclastogenesis in vitro than osteoblasts and bone marrow stromal cells. Furthermore, the severe osteopetrotic phenotype that we observe in mice lacking RANKL specifically in osteocytes indicates that osteocytes are the major source of RANKL in bone remodeling in vivo.

[1]  M. Noble,et al.  Generation of osteoclast-inductive and osteoclastogenic cell lines from the H-2KbtsA58 transgenic mouse. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[2]  Martin Tj.  Paracrine regulation of osteoclast formation and activity: milestones in discovery. , 2004 .

[3]  L. Bonewald,et al.  The Amazing Osteocyte , 2010, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[4]  Peter Pivonka,et al.  Model structure and control of bone remodeling: a theoretical study. , 2008, Bone.

[5]  Yongwon Choi,et al.  Diverse roles of the tumor necrosis factor family member TRANCE in skeletal physiology revealed by TRANCE deficiency and partial rescue by a lymphocyte-expressed TRANCE transgene. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[6]  M. Bouxsein,et al.  Control of Bone Mass and Remodeling by PTH Receptor Signaling in Osteocytes , 2008, PloS one.

[7]  L. Bonewald,et al.  DMP1-targeted Cre Expression in Odontoblasts and Osteocytes , 2007, Journal of dental research.

[8]  B. Hall,et al.  Buried alive: How osteoblasts become osteocytes , 2006, Developmental dynamics : an official publication of the American Association of Anatomists.

[9]  P. Delmas,et al.  Bone quality--the material and structural basis of bone strength and fragility. , 2006, The New England journal of medicine.

[10]  J. Miyazaki,et al.  A novel reporter mouse strain that expresses enhanced green fluorescent protein upon Cre‐mediated recombination , 2000, FEBS letters.

[11]  N. Bishop,et al.  Osteoclast-poor human osteopetrosis due to mutations in the gene encoding RANKL , 2007, Nature Genetics.

[12]  T. Martin,et al.  Modulation of osteoclast differentiation and function by the new members of the tumor necrosis factor receptor and ligand families. , 1999, Endocrine reviews.

[13]  J. Penninger,et al.  RANKL/RANK—beyond bones , 2011, Journal of Molecular Medicine.

[14]  S. Morony,et al.  OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis , 1999, Nature.

[15]  G. Rodan,et al.  Role of osteoblasts in hormonal control of bone resorption—A hypothesis , 2006, Calcified Tissue International.

[16]  H. Takayanagi.  Osteoimmunology: shared mechanisms and crosstalk between the immune and bone systems , 2007, Nature Reviews Immunology.

[17]  Lynda F. Bonewald,et al.  Osteocyte Wnt/β-Catenin Signaling Is Required for Normal Bone Homeostasis , 2010, Molecular and Cellular Biology.

[18]  T. Martin,et al.  Osteoblastic cells are involved in osteoclast formation. , 1988, Endocrinology.

[19]  D. Rowe,et al.  Identification of differentially expressed genes between osteoblasts and osteocytes. , 2009, Bone.

[20]  K. Metsikkö,et al.  Isolated primary osteocytes express functional gap junctions in vitro , 2006, Cell and Tissue Research.