齐墩果酸抑制破骨细胞的分化及机制研究

目的研究齐墩果酸对破骨细胞分化的影响。方法体外获取小鼠骨髓源性单核巨噬细胞,诱导并分化成破骨细胞,分化过程中用不同浓度的齐墩果酸进行干预。结果①与对照组相比,2.5μM和5μM的齐墩果酸可明显减少抗酒石酸酸性磷酸酶(TartrateResistant Acid Phosphatase,TRAP)阳性的破骨细胞数量(P0.01)。②与对照组相比,2.5μM和5μM的齐墩果酸可显著减少破骨分化过程中的特异性基因如组织蛋白酶K(Cathepsin K,CTSK)、活性T细胞核因子c1(Nuclear Factor of Activated T Cell C1,NFATC1)和TRAP等基因的表达(P0.01)。③与对照组相比,5μM的齐墩果酸可显著抑制破骨分化通路上NFATC1蛋白的表达,而对磷酸化的p38、细胞外调节蛋白激酶(Extracellular Regulated Protein Kinase,ERK)、应激活化蛋白激酶(c-Jun N-terminal Kinase,JNK)和蛋白激酶B(Protein Kinase B,即AKT)的表达则无抑制作用。结论齐墩果酸可通过调控破骨分化通路上NFATC1的表达,抑制NFATC1、TRAP和CTSK等基因的表达,来抑制破骨细胞的分化。     

体外研究橙皮苷抑制钛颗粒介导的破骨细胞分化

目的研究橙皮苷对钛颗粒介导前破骨细胞分化及成熟的影响。 方法骨髓巨噬细胞在巨噬细胞集落刺激因子(M-CSF)30 ng/ml及核因子κB受体活化因子配体(Rankl)50 ng/ml刺激下,诱导分化为破骨细胞。扫描电镜观察钛磨损颗粒形貌结构。对不同浓度下橙皮苷对巨噬细胞增殖的影响进行t检验分析得出最低有效浓度;对抗酒石酸酸性磷酸酶(TRAP)阳性细胞数及骨吸收陷窝面积判断橙皮苷对破骨细胞分化及成熟的影响。最后通过实时定量PCR(RT-PCR)验证橙皮苷对钛颗粒介导的破骨基因,包括活化T细胞核因子(NFATc1)、组织蛋白酶K (CTSK)、TRAP的影响。TRAP阳性细胞数及骨吸收陷窝面积、RT-PCR结果数据均采用t检验分析。 结果扫描电镜显示钛磨损颗粒大小在1～3 μm。CCK-8实验结果显示橙皮苷对巨噬细胞增殖有促进作用,浓度超过40 μmol/L后,会对巨噬细胞产生抑制作用(F＝40.1, P<0.01),所以选择40 μmol/L作为对巨噬细胞分化的影响。在抗酒石酸酸性磷酸酶染色中发现40 μmol/L的橙皮苷会明显抑制前破骨细胞的分化,TRAP阳性细胞数目及破骨细胞的面积明显减少(t＝5.5,P<0.05)。与对照组相比,扫描电镜观察钛颗粒介导骨吸收陷窝面积明显增多,但加入40 μmol/L的橙皮苷后,这种吸收效果或明显减少(t＝6.1,P<0.05)。最后,通过RT-PCR实验得出,40 μmol/L的橙皮苷会明显抑制破骨细胞分化相关NFATc1, CTSK,TRAP基因(t＝7.1、4.8、9.1,均为P<0.05)。 结论橙皮苷抑制钛颗粒介导的破骨细胞分化及成熟。     

模拟微重力条件下重组骨保护素融合蛋白(rhOPG-HSA)对破骨前体细胞Raw264.7抑制效应的研究

目的探讨在模拟微重力(Simulated microgravity,SMG)条件下重组骨保护素融合蛋白(rhOPG-HSA)对破骨前体细胞Raw264.7的抑制效应。方法在SMG条件下,分别培养破骨前体细胞Raw264.7与成骨细胞MC3T3-E1,利用ELISA法检测MC3T3-E1细胞培养液中骨保护素活性,用巨噬细胞集落刺激因子(M-CSF)以及可溶性破骨细胞分化因子(sRANKL)诱导Raw264.7分化为破骨细胞,通过抗酒石酸酸性磷酸酶(TRAP)染色法鉴定rhOPG-HSA抑制破骨细胞能力,利用半定量RT-PCR测定破骨细胞中TRAP的表达。结果 SMG条件下,骨保护素活性在72 h后显著降低(P<0.01);Raw264.7细胞经M-CSF及sRANKL诱导3、4、5 d后,与阴性对照组相比,TRAP阳性染色的破骨细胞用rhOPG-HSA处理后明显减少(P<0.05),RT-PCR测定结果表明破骨细胞TRAP的表达降低(P<0.05)。结论 SMG条件下,rhOPG-HSA能够抑制破骨前体细胞Raw264.7的分化。     

健骨方对破骨细胞形成和成骨细胞增殖分化的影响

目的　探讨健骨方水提物对破骨细胞分化及成骨细胞增殖分化的影响。方法　制备健骨方水提物,通过MTT法测定药物对骨髓单核巨噬细胞（BMMs）细胞的毒性,采用核因子κB受体活化因子配体（RANKL）诱导BMMs分化形成破骨细胞,加入不同浓度药物进行干预,采用抗酒石酸酸性磷酸酶( TRACP) 染色法测定破骨细胞分化抑制作用,采用Western Blot 法测定RANKL诱导的NF-κB破骨细胞分化信号通路,运用RT-qPCR法测定信号通路下游破骨细胞分化关键基因NFATc1、C-FOS等的mRNA表达水平。以MC3T3-E1细胞作为前体成骨细胞,加入不同浓度药物进行干预,通过CCK8法测定细胞增殖能力、PNPP法检测碱性磷酸酶（ALP）活性、茜素红S染色法测定细胞矿化能力。结果　MTT法结果显示,健骨方细胞有毒性浓度大于500 μg/mL（P＜0.05）,破骨细胞分化抑制IC50为1.25 μg/mL。机制研究显示健骨方显著下调了RANKL-NF-κB信号通路中的p-P65、P53的蛋白表达（P＜0.05）,显著抑制了通路下游C-FOS、NFATc1等的mRNA表达水平（P＜0.01,P＜0.05）。此外,成骨细胞活性检测显示,健骨方能明显促进MC3T3-E1细胞增殖、提高ALP活性及增加成骨细胞钙化的能力。结论 健骨方具有抑制破骨细胞分化和促进成骨前体细胞增殖、分化、矿化的药效作用。其作用与抑制破骨细胞分化RANKL-NF-κB信号通路及其下游C-FOS、NFATc1等基因,上调成骨细胞分化促进因子CAL1A2、SPARC和FOSL1基因的表达有关。     

降钙素基因相关肽对大鼠骨髓单核巨噬细胞破骨分化作用的实验研究

目的 通过体外实验研究外源性降钙素基因相关肽（calcitonin gene-related peptide,CGRP)对大鼠骨髓单核巨噬细胞 (BMMs)破骨分化能力的影响,为CGRP在抗骨质疏松治疗方面的应用提供理论依据。方法 采用差速贴壁的方法分离出SD大鼠髓腔内单核巨噬细胞,原代培养并传代,在培养体系中添加含不同浓度CGRP (实验组：10–7 mol/L、10–8 mol/L、10–9 mol/ L;对照组：无CGRP)的破骨诱导液,对前体细胞进行破骨诱导7天后进行相关实验检测,分别采用抗酒石酸酸性磷酸酶染色(TRAP染色）观察破骨细胞的生成能力;用RT-PCR方法检测破骨细胞系特征性基因（RANK、TRAP、NFATc1); Western-blot检测破骨特征性TRAP和RANK蛋白的表达;骨磨片甲苯胺蓝染色检测诱导的破骨细胞的骨吸收功能。结果TRAP染色显示 CGRP各浓度组镜下成熟破骨细胞的个数显著低于对照组,有统计学差异(P <0.05)并随CGRP浓度的增高成熟破骨细胞数减少,CGRP组间亦差异明显(P <0. 05);RT-PCR检测破骨特征性RANK、TRAP、NFATc1 mRNA和Westem-blot测破骨特征性TRAP、RANK蛋白的表达各CGRP组均低于对照组(P < 0. 05);骨磨片破骨细胞甲苯胺蓝染色后单倍视野下CGRP组破骨陷窝数量也明显少于对照组(P < 0. 05),且与药物组浓度与陷窝数量呈负相关性。结论 CGRP能够抑制BMMs向破骨方向的分化,为CGRP抗骨质疏松的治疗提供理论支持。     

不同浓度白藜芦醇对破骨细胞分化的影响及自噬的作用

目的研究不同浓度白藜芦醇(RSV)对破骨细胞分化的影响及自噬在其中的作用。方法RANKL诱导RAW264.7细胞分化过程中,加入不同浓度(0、0.1、0.5、1、5及10μmol/L)RSV,CCK-8检测干预后12、24、48、72 h时的细胞活力;TRAP染色观察破骨细胞分化程度。加或不加入3-甲基嘌呤(3-MA)抑制自噬,RT-PCR检测破骨分化相关标志物TRAP、MMP-9、CTSK和自噬相关标志物LC3、Beclin-1、P62的mRNA表达情况;Western blot检测自噬相关蛋白LC3II/I、Beclin-1、P62的表达情况。结果RANKL诱导分化过程中,细胞增殖活力提高,加入0.1~10μmol/L的RSV,细胞活力先上升后下降,在0.5μmol/L时达到最大;0.1μmol/L和0.5μmol/L的RSV能提高TRAP染色阳性的破骨细胞数和TRAP、MMP-9、CTSK、LC3、Beclin-1、P62的mRNA表达,自噬相关蛋白LC3II/I和Beclin-1也增加,P62的蛋白表达则减少;而1~10μmol/L RSV随浓度升高相关mRNA及蛋白LC3II/I和Beclin-1的表达减少,P62的蛋白表达增加;加入3-MA后,相关mRNA及蛋白LC3II/I和Beclin-1的表达减少,P62的蛋白表达增加。结论RSV浓度在0.1~10μmol/L范围内,破骨细胞分化和自噬水平先升高后降低,抑制自噬可以抑制破骨细胞的分化。白藜芦醇影响破骨细胞分化可能部分是通过调节自噬发挥作用。     

艾拉莫德对类风湿关节炎外周血破骨细胞分化及破骨细胞相关基因表达的影响

目的观察艾拉莫德对类风湿关节炎(rheumatoid arthritis,RA)外周血破骨细胞分化形成及破骨细胞相关基因表达的影响。方法使用人核因子kB受体活化因子配体(receptor activator of nuclear factor-κB ligand,RANKL)及人巨噬细胞集落刺激因子(macrophage colony-stimulating factor,M-CSF)诱导RA患者外周血淋巴细胞(Peripheral blood mononuclear cell,PBMCs)分化为成熟破骨细胞,抗酒石酸酸性磷酸酶(tartrate-resistant acid phosphatase,TRAP)染色进行鉴定。CCK-8法筛选艾拉莫德抑制破骨细胞形成的浓度。观察艾拉莫德25μg/mL、12.5μg/mL、6.25μg/mL对RA患者PBMCs生成破骨细胞的影响,RT-PCR法检测不同浓度艾拉莫德对破骨细胞分化过程中TRAP、组织蛋白酶K(Cathepsin K,CTSK)、细胞核因子κB受体活化因子(receptor activator of nuclear factor-κB,RANK)、激活蛋白-1(Activator protein-1,AP-1)mRNA表达的影响。结果 100 ng/mL RANKL和50 ng/mL M-CSF在第14天将RA患者PBMCs诱导为破骨细胞。CCK-8检测结果显示艾拉莫德25μg/mL、12.5μg/mL、6.25μg/mL三个浓度对PBMCs细胞活力无明显影响,且均能抑制破骨细胞的生成,以25μg/mL组最为显著。艾拉莫德能抑制TRAP、CTSK、RANK、AP-1 mRNA的表达水平,且随艾拉莫德浓度的升高抑制作用越明显。结论艾拉莫德通过抑制破骨细胞特异性基因表达来抑制破骨细胞分化、增殖。     

巴斯德毕赤酵母菌株分泌表达的重组骨保护素融合蛋白生物学活性的研究

目的探讨巴斯德毕赤酵母菌株分泌表达的重组骨保护素融合蛋白(recombiant humanosteoprogerin-human serum album,rhOPG-HSA)对破骨细胞的抑制效应。方法利用巨噬细胞集落刺激因子(macrophage colony stimulating factor,M-CSF)以及破骨细胞分化因子(receptor activator ofnuclear factor-kβligand,RANKL)诱导骨髓单核细胞Raw264.7分化为破骨细胞,通过抗酒石酸酸性磷酸酶(tartrate-resistant acid phosphatase,TRAP)染色和甲苯胺蓝染色法鉴定rhOPG-HSA抑制破骨细胞及其骨吸收能力。结果 rhOPG-HSA组与阴性对照组相比,Raw264.7细胞诱导3d,4d,5d后,TRAP阳性染色的破骨细胞明显减少;Raw264.7细胞与骨薄片共培养诱导10d后,骨吸收陷窝明显减少。结论 rhOPG-HSA能够抑制破骨细胞的分化及骨吸收。     

由“从瘀论治”理论探讨三七中槲皮素对破骨细胞分化自噬调控机制

目的 探究槲皮素对破骨细胞分化自噬调控机制的影响。方法 本实验分为对照组、RANKL组、RANKL+槲皮素组。通过CCK8检测摸索槲皮素的处理浓度，按照上述分组诱导7 d后进行TRAP染色验证模型成功后，加槲皮素干预48 h进行TRAP染色，通过qPCR检测TRAP、CTSK、NFATC-1、ATG5、p62、mTOR、Beclin-1基因表达。结果 根据CCK8结果选择槲皮素1 mg/L浓度；TRAP染色结果显示RANKL组破骨细胞显著增多，槲皮素干预后破骨细胞减少；qPCR 结果显示模型组TRAP、P62、CTSK、NFATC-1基因表达上升，ATG5、Beclin-1、mTOR基因表达下降，槲皮素干预组TRAP、CTSK、NFATC-1、ATG5、p62、mTOR、Beclin-1基因均下降。电镜观察显示槲皮素干预后破骨细胞自噬小体数量减少。结论 槲皮素可以通过降低自噬基因表达水平抑制破骨细胞的分化。     

温阳补肾方含药血清对破骨细胞凋亡率及RANK蛋白的影响

目的:探讨温阳补肾方含药血清对破骨细胞凋亡率及RANK蛋白的影响。方法:体外诱导破骨前体细胞系RAW264.7向破骨细胞分化,分别用温阳补肾方低、中、高剂量含药血清和生理盐水血清干预,通过流式细胞术检测各组凋亡率,Western Blot检测各组RANK蛋白水平。结果:与空白对照组比较,温阳补肾方含药血清可诱导破骨细胞凋亡(P=0.000),降低破骨细胞RANK蛋白的表达(P=0.000)。结论:温阳补肾方含药血清可诱导破骨细胞凋亡,温阳补肾方高剂量效果最佳。     

The small molecule harmine regulates NFATc1 and Id2 expression in osteoclast progenitor cells

Small molecule compounds that potently affect osteoclastogenesis could be useful as chemical probes for elucidating the mechanisms of various biological phenomena and as effective therapeutic strategies against bone resorption. An osteoclast progenitor cell-based high-throughput screening system was designed to target activation of NFAT, which is a key event for osteoclastogenesis. Orphan ligand library screening using this system identified the β-carboline derivative harmine, which is a highly potent inhibitor of dual-specificity tyrosine-phosphorylation regulated kinase 1A (DYRK1A), to be an NFAT regulator in osteoclasts. RAW264.7 cells highly expressed DYRK1A protein, and in vitro phosphorylation assay demonstrated that harmine directly inhibited the DYRK1A-mediated phosphorylation (in-activation) of NFATc1. Harmine promoted the dephosphorylation (activation) of NFATc1 in RAW264.7 cells within 24h, and it significantly increased the expression of NFATc1 in RAW264.7 cells and mouse primary bone marrow macrophages (BMMs) both in the presence and absence of RANKL stimulation. Although harmine promoted NFATc1 expression and stimulated target genes for osteoclastogenesis, cell-cell fusion and the formation of TRAP-positive multinucleated osteoclasts from RAW264.7 cells and BMMs was significantly inhibited by harmine treatment. Meanwhile, harmine remarkably promoted the expression of inhibitor of DNA binding/differentiation-2 (Id2), which is a negative regulator for osteoclastogenesis, in RAW264.7 cells and BMMs. An Id2-null-mutant showed slightly increased osteoclast formation from BMMs, and the harmine-mediated inhibition of osteoclast formation was abolished in the BMMs of Id2-null-mutant mice. These results suggest that harmine is a potent activator of NFATc1 that interferes with the function of DYRK1A in osteoclast precursors and also up-regulates Id2 protein, which may dominantly inhibit expression pathways associated with cell-cell fusion, thereby leading to the disruption of the fusion events mediating osteoclastogenesis. The small molecule harmine is therefore expected to provide an experimental tool for investigating signaling cascades in osteoclastogenesis, especially those centered on DYRK1A-mediated NFATc1 and Id2 regulation.     

Specific RANK Cytoplasmic Motifs Drive Osteoclastogenesis

Upon receptor activator of NF-κB ligand (RANKL) binding, RANK promotes osteoclast formation through the recruitment of tumor necrosis factor (TNF) receptor-associated factors (TRAFs). In vitro assays identified two RANK intracellular motifs that bind TRAFs: PVQEET^560–565 (Motif 2) and PVQEQG^604–609 (Motif 3), which potently mediate osteoclast formation in vitro. To validate the in vitro findings, we have generated knock-in (KI) mice harboring inactivating mutations in RANK Motifs 2 and 3. Homozygous KI (RANK^KI/KI) mice are born at the predicted Mendelian frequency and normal in tooth eruption. However, RANK^KI/KI mice exhibit significantly more trabecular bone mass than age- and sex-matched heterozygous KI (RANK^+/KI) and wild-type (RANK^+/+) counterparts. Bone marrow macrophages (BMMs) from RANK^KI/KI mice do not form osteoclasts when they are stimulated with macrophage colony-stimulating factor (M-CSF) and RANKL in vitro. RANKL is able to activate the NF-κB, ERK, p38, and JNK pathways in RANK^KI/KI BMMs, but it cannot stimulate c-Fos or NFATc1 in the RANK^KI/KI cells. Previously, we showed that RANK signaling plays an important role in Porphyromonas gingivalis (Pg)-mediated osteoclast formation by committing BMMs into the osteoclast lineage. Here, we show that RANKL-primed RANK^KI/KI BMMs are unable to differentiate into osteoclasts in response to Pg stimulation, indicating that the two RANK motifs are required for Pg-induced osteoclastogenesis. Mechanistically, RANK Motifs 2 and 3 facilitate Pg-induced osteoclastogenesis by stimulating c-Fos and NFATc1 expression during the RANKL pretreatment phase as well as rendering c-Fos and NFATc1 genes responsive to subsequent Pg stimulation. Cell-penetrating peptides (CPPs) conjugated with RANK segments containing Motif 2 or 3 block RANKL- and Pg-mediated osteoclastogenesis. The CPP conjugates abrogate RANKL-stimulated c-Fos and NFATc1 expression but do not affect RANKL-induced activation of NF-κB, ERK, p38, JNK, or Akt signaling pathway. Taken together, our current findings demonstrate that RANK Motifs 2 and 3 play pivotal roles in osteoclast formation in vivo and mediate Pg-induced osteoclastogenesis in vitro.     

钛颗粒诱导破骨细胞分化过程中活化T细胞核因子c1的表达

目的探讨钙调磷酸酶（CN）／活化T细胞核因子（NFAT）途经在磨损颗粒诱导破骨细胞分化调节中的作用。方法MTT法检测11R—VIVIT肽和钛（Ti）颗粒对小鼠骨髓单核／巨噬细胞系细胞（BMMs）活力的影响;RT—PCR法分析Ti颗粒诱导破骨细胞分化过程中NFATcl mRNA表达,并观察1R—VIVIT肽对Ti颗粒诱导NFATcl表达的影响;TRAP染色进行破骨细胞分化鉴定。结果11R—VIVIT肽和Ti颗粒均不影响体外培养中的BMMs活力;Ti颗粒显著刺激破骨细胞分化（P〈0.01）和NFATcl mRNA表达;应用11R—VIVIT肽阻断CN／NFAT途径可显著抑制Ti颗粒诱导的NFATcl表达。结论Ti颗粒刺激BMMs向破骨细胞分化;其作用机制可能与激活CN／NFAT途径有关。     

Decreased SH3BP2 inhibits osteoclast differentiation and function

Germline mutations in SH3BP2 gene have been identified in patients with cherubism, a skeletal disorder characterized by excessive osteoclastic bone resorption that is limited to the mandible and maxilla. We previously demonstrated that SH3BP2 overexpression in Raw264.7 cells increased RANKL‐induced osteoclastogenesis. Here, we examine the effect of decreased SH3BP2 on osteoclastogenesis. shRNA knockdown of SH3BP2 decreased PLCγ2 phosphorylation and NFATc1 expression, and reduced the expression of osteoclast‐specific genes. In BMMs knockdown of SH3BP2 led to reductions in both the number and the surface area of TRAP positive and multinucleated osteoclasts. Bone resorptive activity was also dramatically blocked by shRNA knockdown of SH3BP2. Similarly Sh3bp2(?/?) deficient mice BMMs formed smaller osteoclasts that stained less with TRAP than wild‐type mice. Taken together, this study demonstrates that SH3BP2 knockdown significantly decreases osteoclast differentiation and function. These results suggest that SH3BP2 plays a critical role in osteoclastogenesis and is a potential target for suppression of pathologic bone resorption. © 2011 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 29: 1521–1527, 2011     

CTLA4-Ig Directly Inhibits Osteoclastogenesis by Interfering With Intracellular Calcium Oscillations in Bone Marrow Macrophages

CTLA4-Ig (cytotoxic T-lymphocyte antigen 4-immunoglobulin; Abatacept) is a biologic drug for rheumatoid arthritis. CTLA4 binds to the CD80/86 complex of antigen-presenting cells and blocks the activation of T cells. Although previous reports showed that CTLA4-Ig directly inhibited osteoclast differentiation, the whole inhibitory mechanism of CTLA4-Ig for osteoclast differentiation is unclear. Bone marrow macrophages (BMMs) from WT mice were cultured with M-CSF and RANKL with or without the recombinant mouse chimera CTLA4-Ig. Intracellular calcium oscillations of BMMs with RANKL were detected by staining with calcium indicator fura-2 immediately after administration of CTLA4-Ig or after one day of treatment. Calcium oscillations were analyzed using Fc receptor gamma- (FcRγ-) deficient BMMs. CTLA4-Ig inhibited osteoclast differentiation and reduced the expression of the nuclear factor of activated T cells NFATc1 in BMMs in vitro. Calcium oscillations in BMMs were suppressed by CTLA4-Ig both immediately after administration and after one day of treatment. CTLA4-Ig did not affect osteoclastogenesis and did not cause remarkable changes in calcium oscillations in FcRγ-deficient BMMs. Finally, to analyze the effect of CTLA4-Ig in vivo, we used an LPS-induced osteolysis model. CTLA4-Ig suppressed LPS-induced bone resorption in WT mice, not in FcRγ-deficient mice. In conclusion, CTLA4-Ig inhibits intracellular calcium oscillations depending on FcRγ and downregulates NFATc1 expression in BMMs. © 2019 American Society for Bone and Mineral Research.     

Novel extraneural role of neurite outgrowth inhibitor A: modulation of osteoclastogenesis via positive feedback regulation of nuclear factor of activated T cell cytoplasmic 1

Osteoclasts are bone-resorbing cells differentiated from macrophage/monocyte lineage precursors upon receptor activator of NF-κB ligand (RANKL) stimulation. In a proteomic approach to identify proteins involved in osteoclastogenesis, we observed a dramatic increase in the expression of neurite outgrowth inhibitor A (Nogo-A) upon RANKL stimulation of mouse bone marrow macrophages (BMMs) in a nuclear factor of activated T cell cytoplasmic 1 (NFATc1)-dependent manner. The knockdown of Nogo-A in BMMs significantly reduced RANKL-dependent osteoclast differentiation accompanied by diminished NFATc1 induction, suggesting that a positive feedback mechanism is involved. Conversely, Nogo-A overexpression in BMMs as well as in RAW264.7 macrophages greatly augmented osteoclastogenesis, with concomitant increase in the NFATc1 induction. Both the mitogen-activated protein kinase (MAPK) pathway and calcium oscillation, which are central to RANKL-dependent NFATc1 activation and induction, were enhanced by Nogo-A. Finally, Nogo-A knockdown in mouse calvariae prevented interleukin 1 (IL-1)-induced bone loss. These findings not only reveal an unprecedented extraneural role of Nogo-A in osteoclastogenesis but also suggest a novel drug target against bone-lytic diseases.