Soung Do Y, Kalinowski Judith, Baniwal Sanjeev K, Jacome-Galarza Christian E, Frenkel Baruch, Lorenzo Joseph, Drissi Hicham
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.
Mol Endocrinol. 2014 Apr;28(4):546-53. doi: 10.1210/me.2013-1305. Epub 2014 Feb 25.
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.
骨吸收过多是包括骨质疏松症在内的几种代谢性骨病的病因。因此，确定能够抑制破骨细胞形成和/或活性的因素可能会确定新的药物靶点，可用于开发针对这些病症的新疗法。新出现的证据表明，造血的主要调节因子Runx1在破骨细胞前体细胞中表达，可能影响骨骼健康。为了研究Runx1在破骨细胞形成和功能中的潜在作用，我们通过将Runx1条件性敲除小鼠（Runx1(F/F)）与CD11b-Cre转基因小鼠杂交，在骨髓破骨细胞前体细胞中删除其表达。与Cre阴性小鼠相比，破骨细胞前体细胞中缺乏Runx1的小鼠（CD11b-Cre;Runx1(F/F)）股骨小梁和皮质骨量显著减少。此外，与Runx1(F/F)小鼠相比，CD11b-Cre;Runx1(F/F)小鼠血清中1型胶原交联C端肽（一种破骨细胞介导的骨吸收生物标志物）水平显著升高。与Runx1(F/F)小鼠来源的同样培养的细胞相比，CD11b-Cre;Runx1(F/F)小鼠骨髓细胞体外分化形成的抗酒石酸酸性磷酸酶阳性破骨细胞更大、数量更多且骨吸收活性增强。CD11b-Cre;Runx1(F/F)骨髓细胞体外分化为破骨细胞后，破骨细胞相关基因包括液泡型ATP酶D2、组织蛋白酶K、基质金属蛋白酶9、降钙素受体、破骨细胞相关受体、活化T细胞核因子细胞质1和c-Fos的mRNA水平也升高。这些数据表明，破骨细胞前体细胞中Runx1的表达对破骨细胞的形成和活性具有负调节作用，并有助于维持整体骨量。
