TitleNegative regulation of osteoclast precursor differentiation by CD11b and β2 integrin-B-cell lymphoma 6 signaling.
Publication TypeJournal Article
Year of Publication2013
AuthorsPark-Min, Kyung-Hyun, Lee Eun Young, Moskowitz Neal K., Lim Elisha, Lee Sun-Kyeong, Lorenzo Joseph A., Huang ChuanXin, Melnick Ari M., P Purdue Edward, Goldring Steven R., and Ivashkiv Lionel B.
JournalJ Bone Miner Res
Date Published2013 Jan
KeywordsAnimals, CD11b Antigen, CD18 Antigens, Cell Count, Cell Differentiation, DNA-Binding Proteins, Femur, Fibrinogen, Humans, Integrin beta3, Mice, Mice, Inbred C57BL, NFATC Transcription Factors, Organ Size, Osteoclasts, Osteogenesis, Phenotype, Proto-Oncogene Proteins c-bcl-6, RANK Ligand, Signal Transduction, Stem Cells, Transcription, Genetic, X-Ray Microtomography

<p>Negative regulation of osteoclastogenesis is important for bone homeostasis and prevention of excessive bone resorption in inflammatory and other diseases. Mechanisms that directly suppress osteoclastogenesis are not well understood. In this study we investigated regulation of osteoclast differentiation by the β2 integrin CD11b/CD18 that is expressed on myeloid lineage osteoclast precursors. CD11b-deficient mice exhibited decreased bone mass that was associated with increased osteoclast numbers and decreased bone formation. Accordingly, CD11b and β2 integrin signaling suppressed osteoclast differentiation by preventing receptor activator of NF-κB ligand (RANKL)-induced induction of the master regulator of osteoclastogenesis nuclear factor of activated T cells, cytoplasmic 1 (NFATc1) and of downstream osteoclast-related NFATc1 target genes. CD11b suppressed induction of NFATc1 by the complementary mechanisms of downregulation of RANK expression and induction of recruitment of the transcriptional repressor B-cell lymphoma 6 (BCL6) to the NFATC1 gene. These findings identify CD11b as a negative regulator of the earliest stages of osteoclast differentiation, and provide an inducible mechanism by which environmental cues suppress osteoclastogenesis by activating a transcriptional repressor that makes genes refractory to osteoclastogenic signaling.</p>

Alternate JournalJ Bone Miner Res
PubMed ID22893614
PubMed Central IDPMC3522783
Grant ListK99 AR061430 / AR / NIAMS NIH HHS / United States
R01 AI046712 / AI / NIAID NIH HHS / United States
R01 AR046713 / AR / NIAMS NIH HHS / United States
R01 DE019420 / DE / NIDCR NIH HHS / United States