膝骨关节炎合并骨质疏松症患者血清CXCL1、CCL4、CCL11与骨密度、骨代谢指标和炎性因子的关系研究

doi:10.3877/cma.j.issn.2096-0263.2026.03.007

目的

探究膝骨关节炎（KOA）合并骨质疏松症（OP）患者血清CXC趋化因子配体1（CXCL1）、CC趋化因子（CCL）4、CCL11水平，并分析其与骨密度、骨代谢指标和炎性因子的关系。

方法

前瞻性收集我院2021年9月至2023年8月收治的181例KOA患者作为研究对象，根据患者是否合并OP分为合并OP组（n=108）、未合并OP组（n=73）。收集两组患者一般资料，检测其血清CXCL1、CCL4、CCL11水平，检测全髋、股骨颈和腰椎L₁-L₄骨密度（BMD）和血清骨代谢指标、炎性因子。采用Pearson相关性分析血清CXCL1、CCL4、CCL11水平与骨密度、血清骨代谢指标、炎性因子的相关性。多因素Logistic回归分析KOA合并OP的独立影响因素，并采用受试者工作特征曲线（ROC）分析血清CXCL1、CCL4、CCL11对KOA合并OP的诊断价值。

结果

合并OP组血清CXCL1、CCL4、CCL11水平、骨代谢指标I型胶原羧基端交联肽（s-CTX）、Ⅰ型胶原氨基端前肽（PINP）、骨钙素（BGP）、骨碱性磷酸酶（BAP）、白细胞介素-1β（IL-1β）、IL-6、肿瘤坏死因子-α（TNF-α）均高于未合并OP组（P<0.05），全髋、股骨颈和腰椎L₁-L₄ BMD均低于未合并OP组（P<0.05）。采用Pearson相关性分析发现，KOA合并OP患者血清中CXCL1、CCL4、CCL11水平与骨代谢指标s-CTX、PINP、BGP、BAP和炎性因子IL-1β、IL-6、TNF-α均呈正相关性，与全髋、股骨颈和腰椎L₁-L₄ BMD呈负相关性（P<0.05）。ROC曲线分析显示：联合诊断KOA合并OP的ROC曲线下面积（AUC）为0.853，优于血清CXCL1、CCL4、CCL11水平的单独诊断效能（0.789、0.693、0.741）。

结论

CXCL1、CCL4、CCL11水平在KOA合并OP患者血清中异常升高，多因素分析证实三者为KOA合并OP的独立影响因素，其对于KOA合并OP具有一定的诊断效能，且CXCL1、CCL4、CCL11水平与骨密度呈负相关性，与骨代谢指标和炎性因子呈正相关性。

关键词: 膝骨关节炎, 骨质疏松症, CXC趋化因子配体1, CC趋化因子4, CC趋化因子11

Objective

To investigate the levels of serum CXC chemokine ligand 1 (CXCL1), CC chemokine (CCL) 4 and CCL11 in patients with knee osteoarthritis (KOA) complicated with osteoporosis (OP), and to analyze their relationship with bone density, bone metabolism indexes and inflammatory factors.

Methods

A prospective collection of 181 KOA patients admitted to our hospital from September 2021 to August 2023 were selected as research objects, patients were divided into combined OP group (n=108) and non-combined OP group (n=73) according to whether they were combined with OP. The general data of two groups were collected, and the levels of serum CXCL1, CCL4 and CCL11 were detected. The bone mineral density (BMD) of total hip, femoral neck and lumbar L1-L4, serum bone metabolism indexes and inflammatory factors were detected. The correlation between serum CXCL1, CCL4 and CCL11 levels and bone mineral density, serum bone metabolism indexes and inflammatory factors were analyzed by Pearson correlation analysis. Multivariable binary Logistic regression analysis was used to analyze the independent influencing factors of KOA combined with OP, and the diagnostic value of serum CXCL1, CCL4 and CCL11 in KOA combined with OP were analyzed by receiver operating characteristic (ROC) curve.

Results

The levels of serum CXCL1, CCL4, CCL11, bone metabolism indexs type I collagen carboxy terminal cross-linked peptide (s-CTX), type I collagen amino terminal propeptide (PINP), osteocalcin (BGP), bone alkaline phosphatase (BAP), interleukin-1β (IL-1β), IL-6 and tumor necrosis factor-α (TNF-α) in OP group were higher than those in non-combined OP group (P<0.05), and the BMD of total hip, femoral neck and lumbar L1-L4 were lower than those in non-combined OP group (P<0.05). Pearson Correlation Analysis showed that, the levels of CXCL1, CCL4 and CCL11 in serum of KOA patients with OP were positively correlated with bone metabolism indexes s-CTX, PINP, BGP, BAP and inflammatory factors IL-1β, IL-6 and TNF-α, and negatively correlated with total hip, femoral neck and lumbar L1-L4 BMD (P<0.05). ROC curve analysis showed that: the area under the ROC curve (AUC) of the combined diagnosis of KOA combined with OP was 0.853, which was better than the single diagnostic efficacy of serum CXCL1, CCL4 and CCL11 levels (0.789, 0.693, 0.741).

Conclusion

The levels of CXCL1, CCL4 and CCL11 are abnormally elevated in the serum of patients with KOA combined with OP, multivariate analysis confirms that the three are independent influencing factors of KOA combined with OP, and they have certain diagnostic efficacy for KOA combined with OP, and the levels of CXCL1, CCL4 and CCL11 are negatively correlated with bone mineral density, and positively correlated with bone metabolism indexes and inflammatory factors.

Key words: Knee osteoarthritis, Osteoporosis, CXC chemokine ligand 1, CC chemokine 4, CC chemokine 11

表1 两组KOA患者血清CXCL1、CCL4、CCL11水平比较（

±s）

组别	例数	CXCL1（ng/mL）	CCL4（pg/mL）	CCL11（pg/mL）
合并OP组	108	1.55±0.36	343.12±41.36	2.13±0.59
未合并OP组	73	1.32±0.31	259.16±35.12	1.69±0.48
t值		4.454	14.219	5.295
P值		<0.001	<0.001	<0.001

表1 两组KOA患者血清CXCL1、CCL4、CCL11水平比较（

±s）

组别	例数	CXCL1（ng/mL）	CCL4（pg/mL）	CCL11（pg/mL）
合并OP组	108	1.55±0.36	343.12±41.36	2.13±0.59
未合并OP组	73	1.32±0.31	259.16±35.12	1.69±0.48
t值		4.454	14.219	5.295
P值		<0.001	<0.001	<0.001

表2 两组KOA患者T值比较（

±s）

组别	例数	全髋	股骨颈	腰椎L₁-L₄
合并OP组	108	-2.92±0.58	-2.89±0.60	-2.83±0.62
未合并OP组	73	-2.06±0.49	-1.90±0.42	-1.95±0.59
t值		10.403	12.214	9.551
P值		<0.001	<0.001	<0.001

表2 两组KOA患者T值比较（

±s）

组别	例数	全髋	股骨颈	腰椎L₁-L₄
合并OP组	108	-2.92±0.58	-2.89±0.60	-2.83±0.62
未合并OP组	73	-2.06±0.49	-1.90±0.42	-1.95±0.59
t值		10.403	12.214	9.551
P值		<0.001	<0.001	<0.001

表3 两组KOA患者骨代谢指标比较（

±s）

组别	例数	s-CTX（µg/L）	PINP（µg/L）	BGP（ng/mL）	BAP（µg/mL）
合并OP组	108	0.79±0.12	59.62±12.65	27.36±6.41	29.31±5.69
未合并OP组	73	0.60±0.10	43.94±8.92	24.36±5.78	26.14±5.40
t值		11.158	9.159	3.212	3.753
P值		<0.001	<0.001	0.002	<0.001

表3 两组KOA患者骨代谢指标比较（

±s）

组别	例数	s-CTX（µg/L）	PINP（µg/L）	BGP（ng/mL）	BAP（µg/mL）
合并OP组	108	0.79±0.12	59.62±12.65	27.36±6.41	29.31±5.69
未合并OP组	73	0.60±0.10	43.94±8.92	24.36±5.78	26.14±5.40
t值		11.158	9.159	3.212	3.753
P值		<0.001	<0.001	0.002	<0.001

表4 两组KOA患者炎性因子水平比较（ng/L，

±s）

组别	例数	IL-1β	IL-6	TNF-α
合并OP组	108	37.39±6.03	35.16±5.12	135.15±8.79
未合并OP组	73	29.61±4.87	25.15±4.36	114.97±12.31
t值		9.181	13.682	12.867
P值		<0.001	<0.001	<0.001

表4 两组KOA患者炎性因子水平比较（ng/L，

±s）

组别	例数	IL-1β	IL-6	TNF-α
合并OP组	108	37.39±6.03	35.16±5.12	135.15±8.79
未合并OP组	73	29.61±4.87	25.15±4.36	114.97±12.31
t值		9.181	13.682	12.867
P值		<0.001	<0.001	<0.001

表5 血清CXCL1、CCL4、CCL11与骨密度、骨代谢指标和炎性因子的相关性分析

指标	CXCL1		CCL4		CCL11
指标	r值	P值	r值	P值	r值	P值
全髋BMD	-0.350	<0.001	-0.324	<0.001	-0.353	<0.001
股骨颈₄BMD	-0.408	<0.001	-0.279	<0.001	-0.335	<0.001
腰椎L₁-L₄BMD	-0.264	<0.001	-0.276	<0.001	-0.272	<0.001
s-CTX	0.345	<0.001	0.315	<0.001	0.381	<0.001
PINP	0.275	<0.001	0.305	<0.001	0.410	<0.001
BGP	0.379	<0.001	0.320	<0.001	0.301	<0.001
BAP	0.449	<0.001	0.108	<0.001	0.335	<0.001
IL-1β	0.474	<0.001	0.345	<0.001	0.408	<0.001
IL-6	0.246	<0.001	0.285	<0.001	0.402	<0.001
TNF-α	0.325	<0.001	0.373	<0.001	0.369	<0.001

表5 血清CXCL1、CCL4、CCL11与骨密度、骨代谢指标和炎性因子的相关性分析

指标	CXCL1		CCL4		CCL11
指标	r值	P值	r值	P值	r值	P值
全髋BMD	-0.350	<0.001	-0.324	<0.001	-0.353	<0.001
股骨颈₄BMD	-0.408	<0.001	-0.279	<0.001	-0.335	<0.001
腰椎L₁-L₄BMD	-0.264	<0.001	-0.276	<0.001	-0.272	<0.001
s-CTX	0.345	<0.001	0.315	<0.001	0.381	<0.001
PINP	0.275	<0.001	0.305	<0.001	0.410	<0.001
BGP	0.379	<0.001	0.320	<0.001	0.301	<0.001
BAP	0.449	<0.001	0.108	<0.001	0.335	<0.001
IL-1β	0.474	<0.001	0.345	<0.001	0.408	<0.001
IL-6	0.246	<0.001	0.285	<0.001	0.402	<0.001
TNF-α	0.325	<0.001	0.373	<0.001	0.369	<0.001

表6 KOA合并OP影响因素的多因素Logistic回归分析

变量	B值	标准误	Wald χ²值	OR值	95% CI	P值
CXCL1	1.167	0.284	16.892	3.212	1.851-5.573	<0.001
CCL4	0.018	0.006	9.215	1.018	1.007-1.030	0.002
CCL11	0.765	0.251	9.287	2.149	1.316-3.508	0.002
常量	-12.854	2.146	35.912	-	-	<0.001

表6 KOA合并OP影响因素的多因素Logistic回归分析

变量	B值	标准误	Wald χ²值	OR值	95% CI	P值
CXCL1	1.167	0.284	16.892	3.212	1.851-5.573	<0.001
CCL4	0.018	0.006	9.215	1.018	1.007-1.030	0.002
CCL11	0.765	0.251	9.287	2.149	1.316-3.508	0.002
常量	-12.854	2.146	35.912	-	-	<0.001

图1 血清CXCL1、CCL4、CCL11水平诊断KOA合并OP的ROC曲线图

表7 血清CXCL1、CCL4、CCL11水平诊断KOA合并OP的ROC曲线分析

指标	最佳截断值	AUC	95%CI	P值	灵敏度（%）	特异度（%）
CXCL1	1.48（ng/ml）	0.789	0.723~0.855	<0.001	83.33	60.27
CCL4	306.25（pg/mL）	0.693	0.616~0.770	<0.001	57.41	73.97
CCL11	1.89（pg/mL）	0.741	0.669~0.814	<0.001	58.33	75.34
联合诊断	-	0.853	0.781~0.925	<0.001	87.36	79.33

表7 血清CXCL1、CCL4、CCL11水平诊断KOA合并OP的ROC曲线分析

指标	最佳截断值	AUC	95%CI	P值	灵敏度（%）	特异度（%）
CXCL1	1.48（ng/ml）	0.789	0.723~0.855	<0.001	83.33	60.27
CCL4	306.25（pg/mL）	0.693	0.616~0.770	<0.001	57.41	73.97
CCL11	1.89（pg/mL）	0.741	0.669~0.814	<0.001	58.33	75.34
联合诊断	-	0.853	0.781~0.925	<0.001	87.36	79.33

1	Dainese P, Wyngaert KV, De Mits S, et al. Association between knee inflammation and knee pain in patients with knee osteoarthritis: a systematic review [J]. Osteoarthritis Cartilage, 2022, 30(4): 516-534.
2	Lee K, Banuls-Mirete M, Lombardi AF, et al. Infrapatellar fat pad size and subcutaneous fat in knee osteoarthritis radiographic progression: data from the osteoarthritis initiative [J]. Arthritis Res Ther, 2024, 26(1): 145.
3	李慕聪,吴婵媛,冷晓梅.小症状,大负担:骨关节炎流行病学概述[J].中华临床免疫和变态反应杂志, 2022, 16(3): 331.
4	Ayers C, Kansagara D, Lazur B, et al. Effectiveness and safety of treatments to prevent fractures in People with low bone mass or primary osteoporosis: a living systematic review and network meta-analysis for the American college of physicians [J]. Ann Intern Med, 2023, 176(2): 182-195.
5	尹伟,杨斌辉,张波,等.骨质疏松症合并膝骨性关节炎患者骨密度及血清骨代谢指标、炎症因子水平研究[J].中国骨质疏松杂志, 2019, 25(8): 1121-1124.
6	Qu Y, Chen S, Han M, et al. Osteoporosis and osteoarthritis: a bi-directional Mendelian randomization study [J]. Arthritis Res Ther, 2023, 25(1): 242.
7	Hou CH, Chen PC, Liu JF. CXCL1 enhances COX-II expression in rheumatoid arthritis synovial fibroblasts by CXCR2, PLC, PKC, and NF-κB signal pathway [J]. Int Immunopharmacol, 2023, 124(Pt B): 110909.
8	Korbecki J, Gąssowska-Dobrowolska M, Wójcik J, et al. The importance of CXCL1 in physiology and noncancerous diseases of bone, bone marrow, muscle and the nervous system [J]. Int J Mol Sci, 2022, 23(8): 4205.
9	Khurana S, Heckman MG, Craig FE, et al. Evaluation of novel targets, including CC-Chemokine receptor 4, in adult T-Cell acute lymphoblastic leukemia/lymphoma: a Mayo clinic clinical and pathologic study [J]. Arch Pathol Lab Med, 2024, 148(4): 471-475.
10	Yang W, Wang Y, Mo K, et al. Single-cell RNA sequencing reveals multiple immune cell subpopulations promote the formation of abnormal bone microenvironment in osteoporosis [J]. Sci Rep, 2024, 14(1):29493.
11	Li JQ, Li Y, Ding YZ, et al. Inverse regulation of C-C chemokine receptor 3 oligomerization by downstream proteins indicates biased signal transduction pathways [J]. J Phys Chem Lett, 2024, 15(30): 7652-7658.
12	Gregory KJ, Mason H, Casaubon J, et al. SFRP1 decreases WNT-Mediated M2 macrophage marker expression in breast tissue [J]. Cancer Immunology Immunotherapy, 2024, 73(5): 86.
13	中华医学会骨科分会关节外科学组,吴阶平医学基金会骨科学专家委员会.膝骨关节炎阶梯治疗专家共识(2018年版) [J].中华关节外科杂志:电子版, 2019, 13(1): 124-130.
14	中华医学会骨质疏松和骨矿盐疾病分会.原发性骨质疏松症诊疗指南(2022) [J].中华内分泌代谢杂志, 2023, 39(5):377-406.
15	Lin L, Luo P, Yang MY, et al. Causal relationship between osteoporosis and osteoarthritis: A two-sample Mendelian randomized study [J]. Front Endocrinol (Lausanne), 2022, 13: 1011246.
16	陈欣,刘建军,董万涛,等.膝骨性关节炎合并骨质疏松症调节机制的研究进展[J].中国骨质疏松杂志, 2022, 28(4): 607-612, 624.
17	Hu YQ, Wang L, Zhao ZJ, et al. Cytokines CCL2 and CXCL1 May be potential novel predictors of early bone loss [J]. Mol Med Rep, 2020, 22(6): 4716-4724.
18	胡鑫,王李卓,章尧,等.以CXCL1为关键靶点的糖尿病肾病差异基因分析及潜在药物预测[J].中华内分泌代谢杂志, 2023, 39(12):1056-1066.
19	Hardaway AL, Herroon MK, Rajagurubandara E, et al. Marrow adipocyte-derived CXCL1 and CXCL2 contribute to osteolysis in metastatic prostate cancer [J]. Clin Exp Metastasis, 2015, 32(4): 353-368.
20	Yang XW, Wang F, Qin RZ, et al. Elevated serum CCL4/MIP-1β levels in postmenopausal osteoporosis patients are linked with disease severity [J]. Biomark Med, 2019, 13(1): 17-25.
21	Zhao XY, Yang ZB, Zhang ZJ, et al. CCL3 serves as a potential plasma biomarker in knee degeneration (osteoarthritis) [J]. Osteoarthritis Cartilage, 2015, 23(8): 1405-1411.
22	Chen J, Zhou Y, Sun Y, et al. Bidirectional Mendelian Randomisation Analysis Provides Evidence for the Causal Involvement of Dysregulation of CXCL9, CCL11 and CASP8 in the Pathogenesis of Ulcerative Colitis [J]. J Crohns Colitis, 2023, 17(5):777-785.
23	Wang W, Huang CY, Wang ZP, et al. Serum C-C motif ligand 11/eotaxin-1 May serve as a candidate biomarker for postmenopausal osteoporosis [J]. J Med Biochem, 2019, 38(3): 353-360.
24	Wakabayashi K, Isozaki T, Tsubokura Y, et al. Eotaxin-1/CCL11 is involved in cell migration in rheumatoid arthritis [J]. Sci Rep, 2021, 11(1): 7937.
25	Ahmadi H, Khorramdelazad H, Hassanshahi G, et al. Involvement of eotaxins (CCL11, CCL24, CCL26) in pathogenesis of osteopenia and osteoporosis [J]. Iran J Public Health, 2020, 49(9): 1769-1775.
26	Rubin MR, de Boer IH, Backlund JYC, et al. Biochemical markers of bone turnover in older adults with type 1 diabetes [J]. J Clin Endocrinol Metab, 2022, 107(6): e2405-e2416.
27	Lin A, Kitaura H, Ohori F, et al. (D-Ala2)GIP Inhibits Inflammatory Bone Resorption by Suppressing TNF-α and RANKL Expression and Directly Impeding Osteoclast Formation [J]. Int J Mol Sci, 2024, 25(5):2555.
28	Chen BH, He Q, Chen CY, et al. Combination of curcumin and catalase protects against chondrocyte injury and knee osteoarthritis progression by suppressing oxidative stress [J]. Biomed Pharmacother, 2023, 168: 115751.
29	Pang J, Xin PF, Kong Y, et al. Resolvin D2 reduces chronic neuropathic pain and bone cancer pain via spinal inhibition of IL-17 secretion, CXCL1 release and astrocyte activation in mice [J]. Brain Sci, 2023, 13(1): 152.
30	Adel A, Abdul-Hamid M, Abdel-Kawi SH, et al. Bone marrow-derived mesenchymal stem cells abate CCl4-induced lung damage via their modulatory effects on inflammation, oxidative stress and apoptosis [J]. Eur Rev Med Pharmacol Sci, 2023, 27(23): 11383-11401.

[1]	吉宇通, 周月惠, 卫杨文祥, 陈镇秋, 王海彬, 周驰. 滑膜巨噬细胞铁调素诱发软骨细胞铁死亡的机制研究[J/OL]. 中华关节外科杂志(电子版), 2026, 20(03): 322-333.
[2]	李阳, 黄野, 曹光磊, 柳剑, 刘源, 龚龙, 谢文勇. 双间室膝关节单髁置换术在膝骨关节炎阶梯化治疗中的作用及研究进展[J/OL]. 中华损伤与修复杂志(电子版), 2026, 21(04): 299-303.
[3]	田井梅, 袁玉霞, 李长桂, 龙舟, 杨聚豪, 汪涓. 肺-骨轴及其在COPD并发骨质疏松症中的机制研究进展[J/OL]. 中华肺部疾病杂志(电子版), 2026, 19(01): 168-172.
[4]	宋红霞, 杨英, 陈芳. 老年COPD患者并发骨质疏松症相关危险因素的研究进展[J/OL]. 中华肺部疾病杂志(电子版), 2023, 16(06): 895-898.
[5]	肖伍豪, 刘抗寒. 晚期慢性肾脏病患者骨质疏松症的治疗研究进展[J/OL]. 中华肾病研究电子杂志, 2024, 13(02): 92-96.
[6]	张轶普, 耿霄, 王鑫光, 董子漾, 郑宇航, 田华. 机器人辅助全膝关节置换术与单髁关节置换术的研究进展[J/OL]. 中华老年骨科与康复电子杂志, 2026, 12(02): 114-122.
[7]	高广涵, 张耀南, 石磊, 王林, 王飞, 郑子天, 王鸿禹, 郭民政, 薛庆云. 膝骨关节炎患者前交叉韧带功能影像学影响因素分析[J/OL]. 中华老年骨科与康复电子杂志, 2024, 10(05): 301-307.
[8]	冉仁国, 罗政, 廖鑫, 张付民. 低频脉冲电磁场对骨质疏松性胸腰椎骨折内固定术后康复的促进作用[J/OL]. 中华老年骨科与康复电子杂志, 2024, 10(01): 39-45.
[9]	王景明, 王磊, 许小多, 陈欣, 黄伟敏. 肌少-骨质疏松症的临床诊疗进展[J/OL]. 中华临床医师杂志(电子版), 2026, 20(05): 386-392.
[10]	王茂盛, 康清源, 肖文韬, 王海东, 袁平, 张克石, 毛天明, 关振鹏. 基于遗传与代谢组学初步分析rs1426371在膝骨关节炎与动脉硬化共患病中的作用[J/OL]. 中华临床医师杂志(电子版), 2026, 20(04): 256-264.
[11]	郭格, 谢亚娜, 唐冲, 关振鹏, 李晓. 本体感觉治疗在膝骨关节炎康复中的研究进展[J/OL]. 中华临床医师杂志(电子版), 2026, 20(03): 228-233.
[12]	希龙夫, 李江涛. CXCL12及其受体CXCR4/CXCR7在肝脏相关疾病中的研究进展[J/OL]. 中华临床医师杂志(电子版), 2025, 19(09): 714-719.
[13]	肖文韬, 谢培森, 康清源, 张克石, 关振鹏. 对家族聚集性膝骨关节炎家系的基因测序及在普通人群中的初步验证[J/OL]. 中华临床医师杂志(电子版), 2025, 19(05): 337-345.
[14]	盛鹏, 柏立哲, 张靖, 李丹, 曹宏. 低聚半乳糖增强去卵巢小鼠肠道屏障功能预防骨质流失[J/OL]. 中华临床医师杂志(电子版), 2025, 19(01): 48-57.
[15]	邸文佳, 牛爱原. 基于东亚人群的肝硬化与骨质疏松症相关性研究[J/OL]. 中华老年病研究电子杂志, 2024, 11(01): 40-44.

阅读次数

全文

摘要

选择文件类型/文献管理软件名称

选择包含的内容

Study on the relationship between serum CXCL1, CCL4, CCL11 and bone density, bone metabolism indexes and inflammatory factors in patients with knee osteoarthritis and osteoporosis

模态框（Modal）标题

选择文件类型/文献管理软件名称

选择包含的内容

Study on the relationship between serum CXCL1, CCL4, CCL11 and bone density, bone metabolism indexes and inflammatory factors in patients with knee osteoarthritis and osteoporosis