Negative regulation of osteoclast precursor differentiation by CD11b and β2 integrin-B-cell lymphoma 6 signaling.
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.
Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, New York, NY, USA.
Kyung-Hyun
KH
Park-Min
Eun Young
EY
Lee
Neal K
NK
Moskowitz
Elisha
E
Lim
Sun-Kyeong
SK
Lee
Joseph A
JA
Lorenzo
Chuanxin
C
Huang
Ari M
AM
Melnick
P Edward
PE
Purdue
Steven R
SR
Goldring
Lionel B
LB
Ivashkiv
D000818:Animals; D039481:CD11b Antigen / Q000378:metabolism*; D018821:CD18 Antigens / Q000378:metabolism*; D002452:Cell Count; D002454:Cell Differentiation / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005269:Femur / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism; D005340:Fibrinogen / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D039661:Integrin beta3 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D010010:Osteoclasts / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D010012:Osteogenesis / Q000187:drug effects; D010641:Phenotype; D051560:Proto-Oncogene Proteins c-bcl-6; D053245:RANK Ligand / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013234:Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D055114:X-Ray Microtomography
C084103:BCL6 protein, human; D039481:CD11b Antigen; D018821:CD18 Antigens; D004268:DNA-Binding Proteins; D039661:Integrin beta3; D050778:NFATC Transcription Factors; D051560:Proto-Oncogene Proteins c-bcl-6; D053245:RANK Ligand; D005340:Fibrinogen