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中华乳腺病杂志(电子版)

中华乳腺病杂志(电子版) ›› 2023, Vol. 17 ›› Issue (06) : 329 -339. doi: 10.3877/cma.j.issn.1674-0807.2023.06.002

论著

骨织素抑制破骨细胞分化改善肿瘤骨转移中骨溶解的机制研究
康夏, 田浩, 钱进, 高源, 缪洪明†(), 齐晓伟†()   
  1. 400038　重庆，陆军军医大学第一附属医院乳腺甲状腺外科；400038　重庆，陆军军医大学高原军事医学系病理生理学教研室；610000　成都，解放军西部战区总医院胰腺损伤与修复四川省重点实验室
    400038　重庆，陆军军医大学第一附属医院乳腺甲状腺外科
    400038　重庆，陆军军医大学高原军事医学系病理生理学教研室
  • 收稿日期:2023-09-28 出版日期:2023-12-01
  • 通信作者: 缪洪明, 齐晓伟
  • 基金资助:
    重庆市杰出青年自然科学基金资助项目(CSTB2023NSCQ-JQX0012)

Osteorin attenuates osteolysis during bone metastasis of cancers through inhibiting osteoclastogenesis

Xia Kang, Hao Tian, Jin Qian, Yuan Gao, Hongming Miao†(), Xiaowei Qi†()   

  1. Department of Breast Surgery, First Affiliated Hospital of Army Medical University, Chongqing 400038, China; Department of Pathophysiology, College of High Altitude Military Medicine, Army Medical University, Chongqing 400038, China; Pancreatic Injury and Repair Key Laboratory of Sichuan Province, General Hospital of Western Theater Command, Chengdu 610000, China
    Department of Breast Surgery, First Affiliated Hospital of Army Medical University, Chongqing 400038, China
    Department of Pathophysiology, College of High Altitude Military Medicine, Army Medical University, Chongqing 400038, China
  • Received:2023-09-28 Published:2023-12-01
  • Corresponding author: Hongming Miao, Xiaowei Qi
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引用本文：

康夏, 田浩, 钱进, 高源, 缪洪明, 齐晓伟. 骨织素抑制破骨细胞分化改善肿瘤骨转移中骨溶解的机制研究[J]. 中华乳腺病杂志(电子版), 2023, 17(06): 329-339.

Xia Kang, Hao Tian, Jin Qian, Yuan Gao, Hongming Miao, Xiaowei Qi. Osteorin attenuates osteolysis during bone metastasis of cancers through inhibiting osteoclastogenesis[J]. Chinese Journal of Breast Disease(Electronic Edition), 2023, 17(06): 329-339.

目的

探讨骨织素对乳腺癌等肿瘤骨转移后破骨细胞分化以及骨溶解的调控作用及可能的分子机制。

方法

体内实验：分别在Balb/c雌性小鼠胫骨骨髓腔注射4T1乳腺癌细胞或在C57BL/6雄性小鼠的胫骨骨髓腔中注射MC-38结直肠癌细胞构建肿瘤骨转移模型，实验组局部注射骨织素进行干预，对照组注射等量溶剂。收集第14或21天胫骨样本切片，用番红固绿染色检测骨小梁情况，TRAP染色检测破骨细胞分化情况，显微CT检测胫骨骨丢失情况。体外实验：在4T1乳腺癌细胞或MC-38结直肠癌细胞条件培养基刺激下，用核因子κB受体活化因子配体(RANKL)和巨噬细胞集落刺激因子(M-CSF)诱导破骨细胞分化，同时使用骨织素进行干预，TRAP染色和TRAP ELISA法检测破骨细胞形成和TRAP蛋白浓度，实时荧光定量PCR法检测破骨分化标志物表达情况。蛋白印迹检测骨织素对AKT蛋白磷酸化的影响。破骨细胞计数、骨密度、骨量标志物等两组比较采用t检验，多组间比较采用单因素方差分析。

结果

体外实验结果显示：4T1和MC-38细胞条件培养基培养环境下，骨织素组的破骨细胞数均低于对照组[4T1：(4.60±1.14)个比(10.60±1.67)个，t＝6.626, P<0.001; MC-38: (4.00±1.00)个比(10.20±1.92)个，t＝6.395，P<0.001)。体内实验显示：小鼠乳腺癌骨转移模型中，骨织素组的破骨细胞面积与骨小梁面积百分比低于对照组[14 d: (5.55±1.56)%比(12.79±1.08)%，t＝7.640，P<0.001；21 d：(7.21±1.41)%比16.96±2.00)%，t＝7.966，P＝0.001)；小鼠结直肠癌骨转移模型中，骨织素组的破骨细胞面积与骨小梁面积百分比低于对照组[14 d: (5.57±0.87)%比(10.69±0.64)%，t＝9.500，P<0.001；21 d：(8.47±0.86)%比(15.53±2.81)%，t＝4.805，P＝0.003)。实时荧光定量PCR检测显示在骨织素组中2个破骨分化标志物OCSTAMP和NFATC1的mRNA表达水平较对照组降低(OCSTAMP：4T1，t＝10.018，P＝0.001；MC-38，t＝24.537，P<0.001; NFATC1: 4T1，t＝3.356，P＝0.028；MC-38，t＝3.377，P＝0.028)。在4T1及MC-38细胞条件培养基中，与对照组相比，骨织素组AKT蛋白的磷酸化水平降低(t＝3.289，P＝0.030；t＝5.363，P＝0.006)。AKT通路激活剂SC79处理后会逆转骨织素抑制破骨细胞形成的能力(4T1：F＝8.598，P＝0.005；MC-38：F＝9.125，P＝0.007)。显微CT显示：乳腺癌骨转移或结直肠癌骨转移模型中骨织素组的骨密度显著改善。

结论

骨织素能通过抑制AKT通路激活，减少破骨细胞形成数量，进而抑制乳腺癌和结直肠癌骨转移的骨溶解。

关键词: 乳腺肿瘤, 结直肠肿瘤, 转移, 破骨细胞
Objective

To investigate the effect of osteocrin on osteoclastogenesis and osteolysis during bone metastasis of breast cancer (BC) or colorectal cancer (CRC).

Methods

In vivo experiments: 4T1 BC cells or MC-38 CRC cells were injected into medullary space of tibial of Balb/c female mice or C57BL/6 male mice with treatment of osteocrin (osteocrin group) or vehicle (control group), respectively. The samples were harvested at 14 or 21 days after injection. Safranin O-Fast green staining was used to detect the trabecular area and TRAP staining was utilized to detect the number of osteoclasts. Furthermore, the severity of bone loss was detected by micro-CT. In vitro experiments: osteoclastogenesis was induced under the stimulation of conditional medium collected from 4T1 cells or MC-38 cells in the presence of receptor activator of nuclear factor-kappa B ligand (RANKL)and macrophage colony-stimulating factor (M-CSF) and treated by osteocrin or vehicle. The TRAP staining and ELISA were used to detect the number of osteoclasts and TRAP protein level. The real-time PCR were performed to detect the level of osteoclastogenic biomarkers. Western blot was performed to analyze the effect of osteocrin on the phosphorylation of AKT. The number of osteoclasts, bone mineral density or bone volume markers were compared between two groups using t test, among multiple groups using one-way analysis of variance.

Results

The results of in vitro experiments showed that the number of osteoclasts in the culture environment of 4T1 and MC-38 cell conditioning medium was significantly lower in the osteocrin group than that in the control group [4T1: 4.60±1.14 vs 10.60±1.67, t=6.626, P<0.001; MC-38: 4.00±1.00 vs 10.20±1.92, t=6.395, P<0.001). The results of in vivo experiments showed that in the breast cancer bone metastasis model of mice, the proportion of osteoclasts area to trabecular bone area was significantly lower in the osteocrin group than in the control group [14 d: (5.55±1.56)% vs (12.79±1.08)%, t=7.640, P<0.001; 21 d: (7.21±1.41)% vs 16.96±2.00)%, t=7.966, P=0.001); in the colorectal cancer bone metastasis model of mice, the proportion of osteoclasts area to trabecular bone area was significantly lower in the osteocrin group than in the control group [14 d: (5.57±0.87)% vs (10.69±0.64)%, t=9.500, P<0.001; 21 d: (8.47±0.86)% vs (15.53±2.81)%, t=4.805, P=0.003). Real-time PCR showed that the mRNA expression levels of two osteoclast differentiation markers OCSTAMP and NFATC1 in the osteocrin group were significantly lower than those in the control group (OCSTAMP: 4T1, t=10.018, P=0.001; MC-38, t=24.537, P<0.001; NFATC1: 4T1, t=3.356, P=0.028; MC-38, t=3.377, P=0.028). Compared with the control group, the phosphorylation level of AKT protein in the osteocrin group was significantly decreased (4T1: t=3.289, P=0.030; MC-38: t=5.363, P=0.006). Treatment with SC79 (AKT pathway activator) reversed the ability of osteocrin to inhibit osteoclast formation (4T1: F=8.598, P=0.005; MC-38: F=9.125, P=0.007). Micro-CT scanning showed that bone marrow density was significantly improved after treatment of osteocrin in bone metastasis models of BC or CRC, respectively.

Conclusions

Osteocrin can prevent osteolytic lesions during bone metastasis of BC and CRC through directly inhibiting osteoclast formation via downregulation of AKT pathway.

Key words: Breast neoplasms, Colorectal neoplasms, Metastasis, Osteoclasts
表1 实时荧光定量PCR引物序列
基因名称 上游引物序列(5′-3′) 下游引物序列(5′-3′)
GAPDH AGGTCGGTGTGAACGGATTTG TGTAGACCATGTAGTTGAGGTCA
OCSTAMP GTCTTCCCGCTGGCCATGAACTAC GGAAGCGTGTGAGGCGGTAGTAGG
NFATC1 AGTACTGCCATCCGAGAGA GAATGCCAGTGAGAGCAGAG
图1 骨织素干预后4T1或MC-38细胞条件培养基中破骨细胞形成情况(TRAP染色　×40)　a、b图分别为在4T1细胞条件培养基中对照组、骨织素组的破骨细胞形成情况；c、d图分别为在MC-38细胞条件培养基中对照组、骨织素组的破骨细胞形成情况
表2 骨织素干预后4T1或MC-38细胞条件培养基中诱导形成的破骨细胞数(个/视野，±s)
条件培养基 样本数 对照组 骨织素组 t值 P值
4T1 5 10.60±1.67 4.60±1.14 6.626 <0.001
MC-38 5 10.20±1.92 4.00±1.00 6.395 <0.001
表3 骨织素干预后4T1和MC-38细胞条件培养基中的TRAP蛋白表达量(U/L，±s)
条件培养基 样本数 对照组 骨织素组 t值 P值
4T1 3 41.66±1.38 35.24±0.32 7.843 0.001
MC38 3 44.58±1.54 33.71±0.69 11.142 <0.001
表4 实时荧光定量PCR法检测4T1和MC-38条件培养基中破骨分化标志物的相对表达量(±s)
标志物 条件培养基 样本数 对照组 骨织素组 t值 P值
OCSTAMP 4T1 3 1.00±0.15 0.08±0.04 10.018 0.001
  MC-38 3 1.00±0.07 0.06±0.01 24.537 <0.001
NFATC1 4T1 3 1.00±0.46 0.10±0.03 3.356 0.028
  MC-38 3 1.00±0.18 0.53±0.16 3.377 0.028
图2 骨织素干预注射4T1细胞后骨转移模型中不同时间点的破骨细胞形成情况(TRAP染色　×40) a、b图分别为第14天对照组、骨织素组的破骨细胞形成情况；c、d图分别为第21天对照组、骨织素组的破骨细胞形成情况
图3 骨织素干预注射MC-38细胞后骨转移模型中不同时间点的破骨细胞形成情况(TRAP染色　×40)　a、b图分别为第14天对照组、骨织素组的破骨细胞形成情况；c、d图分别为第21天对照组、骨织素组的的破骨细胞形成情况
表5 4T1细胞构建的小鼠胫骨骨转移模型中破骨细胞面积与骨小梁面积百分比(%，±s)
组别 样本数 第14天 第21天
对照组 4 12.79±1.08 16.96±2.00
骨织素组 4 5.55±1.56 7.21±1.41
t值   7.640 7.966
P值   <0.001 0.001
表6 MC-38细胞构建的小鼠胫骨骨转移模型中破骨细胞面积与骨小梁面积百分比(%，±s)
组别 样本数 第14天 第21天
对照组 4 10.69±0.64 15.53±2.81
骨织素组 4 5.57±0.87 8.47±0.86
t值   9.500 4.805
P值   <0.001 0.003
图4 骨织素干预4T1细胞或MC-38细胞条件培养基诱导破骨细胞形成时AKT通路蛋白表达条带注：a为对照组4T1细胞；b为对照组MC-38细胞；c为骨织素组4T1细胞；b为对照组MC-38细胞；p-AKT为磷酸化AKT蛋白；t-AKT为总AKT蛋白：β-actin为内参照物
表7 骨织素处理后4T1或MC-38条件培养基破骨细胞分化过程中磷酸化AKT蛋白与总AKT蛋白的比值(±s)
条件培养基 样本数 对照组 骨织素组 t值 P值
4T1 3 0.97±0.32 0.33±0.10 3.289 0.030
MC-38 3 0.94±0.19 0.33±0.06 5.363 0.006
图5 骨织素或骨织素联用SC79干预后4T1或MC-38细胞条件培养基中破骨细胞形成情况(TRAP染色　×40)　a~c图分别为在4T1细胞条件培养基中对照组、骨织素组和骨织素＋SC79组的破骨细胞形成情况；d~f图分别为在MC-38细胞条件培养基中对照组、骨织素组和和骨织素＋SC79组的破骨细胞形成情况
表8 骨织素或骨织素联用SC79干预后4T1或MC-38细胞条件培养基中破骨细胞形成数量(个/视野，±s)
条件培养基 样本数 对照组 骨织素组 骨织素＋SC79组 F值 P值
4T1 5 10.20±1.92b 5.60±1.95ac 8.80±1.48b 8.598 0.005
MC-38 4 10.00±2.16b 5.50±1.29ac 9.50±1.29b 9.125 0.007
图6 骨织素干预注射4T1细胞后小鼠骨转移模型中骨小梁形成情况(番红固绿染色　×40)　a、b图分别为注射后第14天对照组、骨织素组的骨小梁情况；c、d图分别为第21天对照组、骨织素组的骨小梁情况
图7 显微CT检测骨织素处理后小鼠乳腺癌骨转移第21天的骨量情况　a、b、c图分别表示溶剂处理后胫骨的三维重建、矢状面和冠状面扫描结果；d、e、f图分别表示骨织素处理后胫骨的三维重建、矢状面和冠状面扫描结果
表9 骨织素处理后小鼠乳腺癌骨转移第14天和第21天骨小梁面积(%，±s)
组别 样本数 第14天 第21天
对照组 4 16.91±1.18 11.00±2.55
骨织素组 4 23.54±1.60 17.08±1.53
t值   －6.670 －4.097
P值   0.001 0.006
表10 骨织素处理后小鼠乳腺癌骨转移第21天骨相关指标比较(±s)
骨相关指标 样本数 对照组 骨织素组 t值 P值
骨密度(g/cm3) 3 0.08±0.01 0.19±0.05 －3.837 0.019
骨小梁数量a 3 0.45±0.11 1.41±0.32 －4.929 0.008
骨体积分数(%) 3 2.22±0.81 7.43±1.08 －6.670 0.003
骨小梁厚度(mm) 3 0.05±0.01 0.08±0.004 －7.270 0.002
骨小梁分离度(mm) 3 0.63±0.09 0.30±0.09 4.492 0.011
图8 骨织素干预注射MC-38细胞后小鼠骨转移模型中骨小梁情况(番红固绿染色　×40)　a、b图分别为注射后第14天时对照组、骨织素组的骨小梁情况；c、d图分别为第21天时对照组、骨织素组的的骨小梁情况
图9 结直肠癌骨转移第21天小鼠胫骨显微CT扫描图　a、b、c图分别表示溶剂处理后胫骨的三维重建、矢状面和冠状面扫描图；d、e、f图分别表示骨织素处理后胫骨的三维重建、矢状面和冠状面扫描图
表11 骨织素处理后小鼠结直肠癌骨转移第14天和第21天骨小梁面积(%，±s)
骨小梁面积定量 样本数 第14天 第21天
对照组 4 18.63±2.07 13.14±1.72
骨织素组 4 23.25±1.50 20.85±3.09
t值   －3.615 －4.360
P值   0.011 0.005
表12 骨织素处理后小鼠结直肠癌骨转移第21天骨相关指标比较(±s)
骨相关指标 样本数 对照组 骨织素组 t值 P值
骨密度(g/cm3) 3 0.09±0.004 0.14±0.02 －5.495 0.005
骨小梁数量a 3 0.59±0.13 1.60±0.45 －3.764 0.020
骨体积分数(%) 3 9.20±3.54 1.74±1.16 3.472 0.026
骨小梁厚度(mm) 3 0.07±0.002 0.05±0.001 14.899 <0.001
骨小梁分离度(mm) 3 0.25±0.09 0.64±0.16 －3.630 0.022
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