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Journal of Central South University Medical Sciences logoLink to Journal of Central South University Medical Sciences
. 2023 Sep 28;48(9):1403–1410. [Article in Chinese] doi: 10.11817/j.issn.1672-7347.2023.220534

多发性骨髓瘤骨病发病机制的研究进展

Advances in the pathogenesis of multiple myeloma bone disease

HU Cong 1,2, KUANG Chunmei 1, ZHOU Wen 1,✉
Editor: 彭 敏宁
PMCID: PMC10929876  PMID: 38044652

Abstract

Multiple myeloma (MM) is a clonal proliferative malignant tumor of plasma cells in bone marrow. With the aging of population in China, the incidence of MM is on the rise. Multiple myeloma bone disease (MBD) is one of the common clinical manifestations of MM, and 80%-90% of MM patients are accompanied by osteolytic lesions at the time of their first visit to the clinic. MBD not only increases the disability rate of patients, but also severely reduces the physical function of patients due to skeletal lesions and bone-related events. Currently available drugs for treating of MBD are ineffective and associated with side effects. Therefore, it is important to find new therapeutic approaches for the treatment of MBD. It is generally believed that the increased osteoclast activity and suppressed osteoblast function are the main pathologic mechanisms for MBD. However, more and more studies have suggested that soluble molecules in the bone marrow microenvironment, including cytokines, extracellular bodies, and metabolites, play an important role in the development of MBD. Therefore, exploring the occurrence and potential molecular mechanisms for MBD from multiple perspectives, and identifying the predictive biomarkers and potential therapeutic targets are of significance for the clinical treatment of MBD.

Keywords: multiple myeloma bone disease, bone marrow microenvironment, cytokines, exosome, metabolites

多发性骨髓瘤(multiple myeloma，MM)是一种好发于中老年人的恶性浆细胞疾病。多发性骨髓瘤骨病(multiple myeloma bone disease，MBD)是MM最常见的临床表现之一，随着病程的进展，80%~90%的患者在首次就诊时即伴有溶骨性病变和剧烈骨痛，超过50%的患者出现压缩性骨折，严重降低MM患者的生活质量[1]。因此，深入探索MBD发病机制为其治疗提供新的思路具有重要意义。

MBD的病理学机制主要涉及骨髓微环境各类细胞或其分泌型产物与破骨前体细胞、成骨前体细胞的相互作用，以及刺激破骨细胞活化和抑制成骨细胞功能。骨髓微环境由成骨细胞、破骨细胞、骨细胞、内皮细胞、间充质干细胞、造血细胞和细胞因子等可溶性因子组成。其中，MM细胞作为MM骨髓微环境中最重要的细胞成分，可通过直接或间接作用促进MBD的发生。MM细胞通过整合素α4β7(very late antigen-4，VLA-4)和表达血管细胞黏附分子-1(vascular cellular adhesion molecule-1，VCAM-1即VLA-4配体)的骨髓基质细胞(bone marrow stromal cells，BMSCs)介导黏附作用，这是诱导溶骨性病变的关键[2-5]。除直接作用外，MM细胞还通过分泌细胞因子等间接作用在MBD中发挥重要作用。骨髓微环境中其他细胞如淋巴细胞、骨细胞、血管内皮细胞和脂肪细胞等同样通过直接或间接作用诱导破骨细胞活化和成骨细胞失活。骨髓微环境细胞分泌的可溶性因子主要包括细胞因子、胞外体和代谢产物。本文就细胞因子、胞外体及代谢产物介导MM破骨细胞和成骨细胞失衡的调控机制予以综述。

1. 细胞因子介导MBD的机制

细胞因子是指由免疫细胞和某些非免疫细胞(内皮细胞、表皮细胞等)经刺激而合成、分泌的一类具有广泛生物学活性的小分子蛋白质，可分为肿瘤坏死因子超家族、趋化因子、白细胞介素、生长因子、集落刺激因子、干扰素等，其与相应受体结合调节细胞生长、分化等。在MM骨髓微环境中，恶性浆细胞、骨细胞和骨髓间充质细胞相互作用产生大量细胞因子，这些因子通过促进破骨细胞分化和抑制新骨生成，打破骨骼重建平衡，导致溶骨性损伤。

1.1. 细胞因子介导破骨细胞活化

在MM骨髓微环境中，恶性浆细胞和其他细胞通过直接作用产生诸多因子诱导破骨细胞活化。其中，肿瘤坏死因子家族成员之一核因子-κB受体激活因子配体(receptor activator of nuclear factor-kappa B ligand，RANKL)是诱导破骨细胞分化最重要的细胞因子，其诱导破骨细胞分化的主要机制是与破骨前体细胞表面受体核因子-κB受体激活因子(receptor activator of nuclear factor-kappa B，RANK)结合活化核因子-κB(nuclear factor-kappa B，NF-κB)信号通路。MM细胞与BMSCs直接接触上调RANKL的表达，诱导破骨细胞活化，导致MM溶骨性病变[6]。护骨素(osteoprotegerin，OPG)是由骨细胞分泌的RANKL的拮抗剂，通过阻断RANKL与RANK的结合，抑制NF-κB信号通路活化，从而抑制破骨细胞生成。研究[7]发现高比率RANKL/OPG的MM患者生存期较短。由此可见，RANKL与OPG的比例失调是MBD的重要诱因[8]。肿瘤坏死因子-α(tumor necrosis factor alpha，TNF-α)作为肿瘤坏死因子家族的另一重要成员，在MBD的发生中发挥重要作用。一方面，TNF-α通过上调BMSCs中的转录因子X盒结合蛋白1(X-box binding protein-1，XBP1)的表达促进RANKL和IL-6的产生，从而促进破骨细胞形成[9-10]；另一方面，TNF-α本身可直接通过激活NF-κB信号通路诱导破骨细胞形成，增强RANKL的作用[11-12]。然而，目前尚不清楚MM患者体内TNF-α的来源。

趋化因子配体3[human chemokine (C-C motif) ligand 3，CCL3]是一种由MM细胞产生的趋化因子，可作用于BMSCs、破骨细胞、成骨细胞[13-15]。CCL3通过激活PI3K/Akt和ERK/MAPK通路及c-Myc表达，促进破骨细胞活化[16]，同时增强RANKL和IL-6对破骨细胞的活化，从而诱导MBD的发生。CCL3单抗可以有效抑制抗酒石酸酸性磷酸酶(tartrated resistant acid phosphatse，TRAP)阳性破骨细胞的形成，同时减缓小鼠胶原诱导的关节炎进一步侵蚀[17-21]。

此外，白细胞介素家族IL-3和IL-6等细胞因子同样通过刺激破骨细胞形成和成熟的方式诱导MBD[22-24]。IL-3是由嗜碱性粒细胞和活化的T细胞分泌产生的一种细胞因子，可以增强MM细胞中RANKL的分泌，促进破骨细胞的增殖与活化。在MM骨髓微环境中浆细胞样树突状细胞(plasmacytoid dendritic cells，pDCs)数量增加，pDCs刺激MM细胞分泌IL-3，IL-3与激活素A共同介导核因子κB抑制因子α(nuclear factor-κB inhibitor，IκBα)/NF-κB信号通路的激活，进而促进破骨细胞的形成。同时IL-3可以促进pDCs存活和MM细胞生长，导致pDCs中IL-3受体(IL-3 receptor，IL-3R)表达上调。IL-3抑制剂SL-401可通过降低pDCs的活力来抑制MM细胞生长，也可作用于破骨前体细胞表面的IL-3R，从而抑制破骨细胞的形成[25]。IL-6主要由MM细胞分泌，通过增强破骨前体细胞细胞骨架相关蛋白4(cytoskeleton-associated protein 4，CKAP4)受体表达激活NF-κB信号通路[26]，诱导破骨细胞生成。

1.2. 细胞因子抑制成骨细胞分化

骨髓微环境细胞释放成骨失活因子导致成骨细胞分化受抑是MBD发展的另一种机制。成骨细胞分化受Wnt，转化生长因子β(transforming growth factor-β，TGF-β)及骨形态发生蛋白(bone morphogenetic protein，BMP)通路调控。当骨髓微环境中负调控这些通路的细胞因子增加时，成骨细胞发育受阻，加重MBD。Dickkopf相关蛋白1(Dickkopf-1，DKK1)是MBD患者体内上升最显著的因子，主要由MM细胞和骨细胞分泌。DKK1通过竞争性地结合BMSCs表面的Wnt蛋白受体来抑制Wnt/β-catein通路，从而抑制成骨细胞分化[27]。此外，MM细胞通过分泌分泌型frizzled相关蛋白(secreted frizzled-related proteins，sFRPs)、骨硬化蛋白和Sostdc1蛋白[28]等抑制Wnt/β- catein信号通路，导致成骨细胞失活[26, 29-31]。TGF-β由骨基质中的骨细胞和成骨细胞以非活性形式产生，在骨吸收过程中可被破骨细胞激活。抑制TGF-β信号通路可恢复成骨细胞分化并抑制MM细胞生长[32-33]。BMP信号失活抑制成骨细胞分化是诱导MBD的另一种机制。肝细胞生长因子(hepatocyte growth factor，HGF)是BMP信号的负调节因子，主要由内皮细胞分泌[34-35]。研究[36]表明：与HGF水平正常的患者相比，HGF水平升高的MM患者骨特异性碱性磷酸酶(alkaline phosphatase，ALP)活性显著降低。这提示HGF通过抑制成骨细胞生成促进MBD的发生。BMP抑制剂LDN193189及BMPR1a-Fc在抑制破骨细胞生成和活化的同时，增加成骨细胞数量并抑制硬化素水平，有效改善MBD[37]。此外，前述调控破骨细胞产生的细胞因子CCL3和IL-3对成骨细胞分化具有抑制作用，其主要机制是下调成骨细胞分化重要调控分子Runt相关转录因子2(Runt-related transcription factor 2，RUNX2)、Osterix、ALP和骨钙素(osteocalcin，OCN)的表达[38-39](表1)。

表1.

细胞因子在多发性骨髓瘤骨病中的主要作用

Table 1 Main role of cytokines in multiple myeloma bone disease

细胞因子 水平 功能 参考文献
RANKL ↑ 激活NF-κB信号通路，促进破骨细胞活化 [6]
TNF-α ↑ 上调XBP1的表达，促进RANKL、IL-6产生；激活NF-κB信号，促进破骨细胞形成 [9-12]
CCL3 ↑

激活PI3K/Akt、ERK/MAPK通路促进破骨细胞活化，下调RUNX2、Osterix表达，

抑制成骨细胞分化

 [16, 38-39]
IL-3 ↑ 抑制ALP、OCN表达及成骨细胞分化，增强RANKL分泌，促进破骨细胞活化 [22-25]
IL-6 ↑ 增强破骨前体细胞CKAP4受体表达、激活NF-κB信号通路，促进破骨细胞形成 [26]
OPG ↓ 与RANKL拮抗，抑制NF-κB信号通路活化，抑制破骨细胞活化 [7-8]
DKK1 ↑ 结合Wnt蛋白受体抑制Wnt/β-catenin通路，抑制成骨细胞分化 [27]
sFRPs ↑ 抑制Wnt/β-catenin通路，抑制成骨细胞活性 [28-31]
TGF-β ↑ 破骨细胞激活TGF-β信号通路，抑制成骨细胞分化 [32-33]
HGF ↑ 抑制ALP活性，抑制成骨细胞分化 [34-36]
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RANKL：核因子-κB受体激活因子配体；TNF-α：肿瘤坏死因子-α；NF-κB：核因子-κB；XBP1：转录因子X盒结合蛋白1；RUNX2：Runt相关转录因子2；CCL3：趋化因子配体3；IL-3：白细胞介素3；ALP：碱性磷酸酶；OCN：骨钙素；IL-6：白细胞介素6；CKAP4：细胞骨架相关蛋白4；OPG：护骨素；DKK1：Dickkopf相关蛋白1；sFRPs：分泌型frizzled相关蛋白；TGF-β：转化生长因子β；HGF：肝细胞生长因子。

2. 胞外体介导MBD的机制

胞外体是指含有蛋白质、细胞因子、脂质、miRNA、长非编码RNA和环状RNA的盘状囊泡(40~100 nm)，其主要来源于细胞内溶酶体微粒内陷形成的多囊泡体，经多囊泡体外膜与细胞膜融合后释放到胞外基质中。近年来，胞外体在MBD发生中的作用逐渐被阐明，其中MM细胞衍生的胞外体在MBD中的研究较多。MM细胞来源的胞外体主要通过向微环境传递蛋白、细胞因子和长非编码RNA促进MBD发生。

2.1. 胞外体介导破骨细胞活化

MM细胞来源的胞外体通过促进破骨细胞分化诱导MBD。MM细胞来源的胞外体不仅促进破骨细胞分化，而且抑制破骨前体细胞的凋亡并促进其存活。然而有研究[40]报道结直肠癌细胞的胞外体不具备诱导破骨细胞分化的功能，提示MM细胞分泌的胞外体含有特异性诱导破骨细胞分化的成分。随后Faict等[41]分析5TGM1细胞来源的胞外体成分，发现胞外体内体蛋白TSG101和Syntenin可增强破骨细胞的活性，抑制成骨细胞的分化和功能，诱导骨溶解。胞外体阻断剂GW4869可有效逆转骨溶解。此外，MM细胞能够通过向外界传递含IL-32胞外体的方式诱导骨溶解。MM细胞通过缺氧诱导因子1α(hypoxia-inducible factor-1α，HIF-1α)上调IL-32的表达，高表达IL-32的JJN3细胞胞外体通过激活NF-κB信号通路促进破骨细胞分化，而敲除IL-32的JJN3细胞胞外体对破骨细胞形成无显著作用。与IL-32表达较低的患者相比，高表达IL-32的MM患者的预后较差[42]。含HGF的MM细胞胞外体通过介导间充质上皮转化因子(c-mesenchymal-epithelial transition factor，c-Met)酸化激活HGF/c-Met信号通路，从而上调成骨细胞内IL-11的表达，促进破骨细胞的活化[43]。总之，MM细胞来源的胞外体通过分泌型蛋白质促进破骨细胞分化来诱导MBD。

2.2. 胞外体抑制成骨细胞分化

MM细胞来源的胞外体抑制BMSCs向成骨细胞分化是胞外体诱导MBD的另一重要机制。Zhang等[44]发现MM细胞胞外体上调BMSCs中miR-103a-3p的表达，抑制其向成骨细胞分化，从而加剧MBD的发生。Liu等[45]研究发现MM细胞的胞外体通过促进BMSCs分泌IL-6，上调脱嘌呤/脱嘧啶核酸内切酶1(apurinic/apyrimidinic endonuclease 1，APE1)和NF-κB的表达，导致RUNX2、Osterix和OCN的表达减少，从而抑制BMSCs的成骨分化。与MM细胞胞外体促进破骨细胞分化类似的是，胞外体同样通过传递蛋白质或非编码RNA导致骨形成损伤。譬如，MM来源的胞外体通过传递双调蛋白(amphiregulin，AREG)使表皮生长因子受体配体(epidermal growth factor receptor，EGFR)磷酸化增加，激活EGFR通路，促进MM细胞与BMSCs的黏附作用以及促进BMSCs释放IL-8来抑制成骨细胞的形成[46]。LncRNA RUNX2-AS1通过lncRUNX2-AS1/RUNX2途径特异性地抑制BMSCs的RUNX2表达从而抑制成骨细胞分化的能力[47]。Wu等[48]发现含有LINC00461的MM细胞胞外体通过下调BMSCs中miR-324-3p的表达，降低Wnt/β-catenin通路的活性，从而抑制骨髓间充质干细胞向成骨细胞分化。有趣的是，MM细胞胞外体的分泌依赖于特定的蛋白质。研究[49-52]表明：MM细胞胞外体分泌旺盛与肝素酶高表达相关，肝素酶抑制剂显著抑制MM的增殖、血管生成和骨转移。综上所述，MM细胞来源的胞外体通过增强破骨细胞活性和抑制成骨细胞分化在MBD中扮演重要角色(表2)，靶向MM细胞胞外体的分泌与转移可能为MBD治疗提供新策略。

表2.

胞外体在多发性骨髓瘤骨病的主要作用

Table 2 Main role of exosomes in multiple myeloma bone disease

胞外体 水平 功能 参考文献
AREG ↑ 抑制BMSCs中RUNX2表达，抑制成骨细胞分化 [46]
TSG101 ↑ 促进破骨细胞活化、抑制成骨细胞分化 [41]
Syntenin ↑ 促进破骨细胞活化、抑制成骨细胞分化 [41]
IL-6 ↑ 上调APE1、NF-κB的表达，下调RUNX2、Osterix、OCN的表达，抑制成骨细胞分化 [45]
IL-32 ↑ 激活NF-κB信号通路，促进破骨细胞分化 [42]
HGF ↑ 激活HGF/c-Met信号通路，促进破骨细胞分化 [43]
LINC00461 ↑ 下调BMSCs中miR-324-3p的表达，抑制成骨细胞分化 [48]
RUNX2-AS1 ↑ 抑制BMSCs中RUNX2表达，抑制成骨细胞分化 [47]
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AREG：双调蛋白；BMSCs：骨髓基质细胞；RUNX2：Runt相关转录因子2；TSG101：胞外体内体蛋白；Syntenin：胞外体内体蛋白；IL-6：白细胞介素6；APE1：脱嘌呤/脱嘧啶核酸内切酶1；OCN：骨钙素；IL-32：白细胞介素32；HGF：肝细胞生长因子；c-Met：间充质上皮转化因子。

3. 代谢产物介导MBD的机制

代谢产物包括糖、脂肪酸和氨基酸等。代谢产物在破骨细胞和成骨细胞的分化过程中同样发挥重要作用。脂肪酸代谢和氨基酸代谢失衡通过促进或抑制破骨细胞和成骨细胞分化从而诱导MBD。

3.1. 代谢产物介导破骨细胞活化

目前，代谢产物在MBD发生中的报道甚少。最新研究[53]发现：MBD患者MM细胞中基质金属蛋白酶13(matrix metallopeptidase-13，MMP13)呈高表达。高表达MMP13的MM细胞通过分泌MMP13促进患者骨髓I型骨胶原降解。而骨胶原最重要的成分是甘氨酸，骨胶原降解势必增加体内甘氨酸含量。反之，微环境中甘氨酸被MM细胞吸收利用进一步增强其恶性增殖和耐药的表型。在体内，限制外源性甘氨酸摄入能有效抑制MM骨溶解[53]。这一研究揭示了肿瘤细胞与骨胶原之间的恶性循环式相互作用，为后期MBD的治疗提供了新思路。

3.2. 代谢产物抑制成骨细胞分化

MM患者谷氨酰胺和脂肪酸代谢失衡抑制成骨细胞形成是诱导MBD的另一种机制。Chiu等[54]研究发现由于恶性浆细胞不表达谷氨酰胺合成酶，而MM细胞对谷氨酰胺高度上瘾，需通过谷氨酰胺酶消耗大量氨基酸以维持其活性状态，因此MM细胞通过吸收微环境中谷氨酰胺从而导致患者体内谷氨酰胺含量显著降低。BMSCs吸收谷氨酰胺后向成骨细胞分化的能力增强。骨髓微环境中低浓度谷氨酰胺不利于成骨细胞分化，从而抑制成骨细胞形成，诱导MBD。抑制MM细胞利用谷氨酰胺可能是预防MM溶骨性病变的新方法。Liu等[55]研究发现：MBD的发生与骨髓脂肪细胞密切相关，骨髓瘤细胞通过整合素6(integrin α 6，ITGa6)介导的ERK1/2和NF-κB信号通路诱导脂肪细胞重编程，增加脂肪细胞中多梳蛋白抑制复合物2(polycomb repressive complex 2，PRC2)的表达，从而上调过氧化物酶体增殖激活受体γ(peroxisome proliferator-activated receptor γ，PPARγ)基因组蛋白甲基化，PPARγ活性降低导致脂肪因子Adiponectin、Visfatin、Adipsin表达下调，而TNF-α表达上调，从而激活破骨细胞生成并抑制成骨细胞生成，最终诱导MBD的发生。

4. 结 语

骨髓微环境中可溶性分子(包括细胞因子、胞外体和代谢产物)通过介导破骨细胞活化和成骨细胞失活诱导MBD，为MBD的治疗提供理论依据和新靶点。骨髓微环境中细胞因子、胞外体和代谢产物既能单独诱导MBD，又能协同促进疾病进程。骨髓微环境中的细胞因子一方面通过直接与破骨前体细胞或成骨前体细胞表面受体相互作用，促进破骨细胞成熟，抑制成骨细胞，诱导MBD；另一方面，细胞因子被囊泡吸收后以胞外体的形式促进破骨细胞分化或抑制成骨细胞形成诱导MBD。氨基酸和脂肪酸代谢失衡是MBD的另一诱因，代谢产物直接作用于破骨前体细胞和成骨细胞诱导MBD。但是，尚未有文献报道代谢产物以胞外体的形式发挥作用。此外，细胞因子异常是否通过诱导骨髓微环境代谢失衡促进MBD，以及代谢失衡是否通过促进细胞因子异常表达发挥促MBD作用仍有待后续研究。目前，针对MBD患者RANKL异常增加而开发的临床药物地舒单抗临床疗效欠佳。未来，细胞因子、胞外体及代谢产物三者的调控机制的逐渐阐明，有望为MBD患者提供新的治疗靶点或联合用药方案。

基金资助

国家自然科学基金(82130006)；湖南省研究生科研创新项目(CX20220348)；中南大学研究生科研创新项目(2022ZZTS0266)。

This work was supported by the National Natural Science Foundation (82130006), the Postgraduate Research Innovation Project of Hunan Province (CX20220348), and the Fundamental Research Fund for Graduate of Central South University (2022ZZTS0266), China.

利益冲突声明

作者声称无任何利益冲突。

作者贡献

胡聪 文献查询，论文撰写及修改；匡春梅 论文修改；周文 论文指导。所有作者阅读并同意最终的文本。

原文网址

http://xbyxb.csu.edu.cn/xbwk/fileup/PDF/2023091403.pdf

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