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Mol Endocrinol. 2014 Apr;28(4):546-53. doi: 10.1210/me.2013-1305. Epub 2014 Feb 25.

Runx1-mediated regulation of osteoclast differentiation and function.

Author information

1
New England Musculoskeletal Institute (D.Y.S., J.K., C.E.J.-G., J.L., H.D.), Department of Orthopaedic Surgery (H.D.), and Department of Medicine (C.E.J.-G.), University of Connecticut Health Center, Farmington, Connecticut 06030; and Department of Orthopaedic Surgery and Biochemistry and Molecular Biology (S.K.B., B.F.), University of Southern California, Los Angeles, California 90089.

Abstract

Excessive bone resorption is the cause of several metabolic bone diseases including osteoporosis. Thus, identifying factors that can inhibit osteoclast formation and/or activity may define new drug targets that can be used to develop novel therapies for these conditions. Emerging evidence demonstrates that the master regulator of hematopoiesis, Runx1, is expressed in preosteoclasts and may influence skeletal health. To examine the potential role of Runx1 in osteoclast formation and function, we deleted its expression in myeloid osteoclast precursors by crossing Runx1 floxed mice (Runx1(F/F)) with CD11b-Cre transgenic mice. Mice lacking Runx1 in preosteoclasts (CD11b-Cre;Runx1(F/F)) exhibited significant loss of femoral trabecular and cortical bone mass compared with that in Cre-negative mice. In addition, serum levels of collagen type 1 cross-linked C-telopeptide, a biomarker of osteoclast-mediated bone resorption, were significantly elevated in CD11b-Cre;Runx1(F/F) mice compared with those in Runx1(F/F) mice. Tartrate-resistant acid phosphatase-positive osteoclasts that differentiated from bone marrow cells of CD11b-Cre;Runx1(F/F) mice in vitro were larger, were found in greater numbers, and had increased bone resorbing activity than similarly cultured cells from Runx1(F/F) mice. CD11b-Cre;Runx1(F/F) bone marrow cells that were differentiated into osteoclasts in vitro also had elevated mRNA levels of osteoclast-related genes including vacuolar ATPase D2, cathepsin K, matrix metalloproteinase 9, calcitonin receptor, osteoclast-associated receptor, nuclear factor of activated T cells cytoplasmic 1, and cFos. These data indicate that Runx1 expression in preosteoclasts negatively regulates osteoclast formation and activity and contributes to overall bone mass.

PMID:
24606124
PMCID:
PMC3968404
DOI:
10.1210/me.2013-1305
[Indexed for MEDLINE]
Free PMC Article

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