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OBJECTIVES

Excessive inflammation contributes to the pathogenesis of tendinopathy. Fatty acid binding protein 4 (FABP4) is a pro-inflammatory adipokine mediating various metabolic and inflammatory diseases. This study aimed to examine the expression of FABP4 and its association with the expressions of inflammatory cytokines in tendinopathy. The effects of a single injection of FABP4 on tendon pathology and inflammation were examined. The effect of FABP4 on the expressions of inflammatory cytokines and the effect of IL-1β on the expression of FABP4 in tendon-derived stem/progenitor cells (TDSCs) were also investigated.

METHODS

Clinical patellar tendinopathy samples, healthy hamstring tendon samples, and healthy patellar tendon samples, 2) rotator cuff tendinopathy samples and healthy hamstring tendon samples; and 3) Achilles tendons of mice after saline or collagenase injection (CI) were stained for FABP4, IL-1β, IL-6, TNF-α and IL-10 by immunohistochemistry (IHC). For the rotator cuff tendinopathy samples, co-localization of FABP4 with IL-1β and TNF-α was done by immunofluorescent staining (IF). Mouse Achilles tendons injected with FABP4 or saline were collected for histology and IHC as well as microCT imaging post-injection. TDSCs were isolated from human and mouse tendons. The mRNA expressions of inflammatory cytokines in human and mouse TDSCs after the addition of FABP4 was quantified by qRT-PCR. The expression of FABP4 in TDSCs isolated from rotator cuff tendinopathy samples and healthy hamstring tendon samples was examined by IF. Mouse Achilles TDSCs were treated with IL-1β. The mRNA and protein expressions of FABP4 were examined by qRT-PCR and IF, respectively.

RESULTS

There was significant upregulation of FABP4 in the patellar tendinopathy samples and rotator cuff tendinopathy samples compared to their corresponding controls. FABP4 was mainly expressed in the pathological areas including blood vessels, hypercellular and calcified regions. The expressions of IL-1β and TNF-α increased in human rotator cuff tendinopathy samples and co-localized with the expression of FABP4. Collagenase induced tendinopathic-like histopathological changes and ectopic calcification in the mouse Achilles tendinopathy model. The expressions of inflammatory cytokines (IL-1β, IL-6, TNF-α, IL-10) and FABP4 increased in hypercellular region, round cells chondrocyte-like cells and calcified regions in the mouse Achilles tendons post-collagenase injection. A single injection of FABP4 in mouse Achilles tendons induced histopathological changes resembling tendinopathy, with increased cell rounding, loss of collagen fiber alignment, and additionally presence of chondrocyte-like cells and calcification post-injection. The expressions of IL1-β, IL-6, TNF-α and IL-10 increased in mouse Achilles tendons post-FABP4 injection. FABP4 increased the expressions of , , and in human TDSCs as well as the expressions of , , and in mouse TDSCs. Human tendinopathy TDSCs expressed higher level of FABP4 compared to healthy hamstring TDSCs. Besides, IL-1β increased the expression of FABP4 in mouse TDSCs.

CONCLUSION

In conclusion, an upregulation of FABP4 is involved in excessive inflammation and pathogenesis of tendinopathy. TDSCs is a potential source of FABP4 during tendon inflammation.

TRANSLATION POTENTIAL OF THIS ARTICLE

FABP4 can be a potential treatment target of tendinopathy.

OBJECTIVES

METHODS

Clinical patellar tendinopathy samples, healthy hamstring tendon samples, and healthy patellar tendon samples, 2) rotator cuff tendinopathy samples and healthy hamstring tendon samples; and 3) Achilles tendons of mice after saline or collagenase injection (CI) were stained for FABP4, IL-1β, IL-6, TNF-α and IL-10 by immunohistochemistry (IHC). For the rotator cuff tendinopathy samples, co-localization of FABP4 with IL-1β and TNF-α was done by immunofluorescent staining (IF). Mouse Achilles tendons injected with FABP4 or saline were collected for histology and IHC as well as microCT imaging post-injection. TDSCs were isolated from human and mouse tendons. The mRNA expressions of inflammatory cytokines in human and mouse TDSCs after the addition of FABP4 was quantified by qRT-PCR. The expression of FABP4 in TDSCs isolated from rotator cuff tendinopathy samples and healthy hamstring tendon samples was examined by IF. Mouse Achilles TDSCs were treated with IL-1β. The mRNA and protein expressions of FABP4 were examined by qRT-PCR and IF, respectively.

RESULTS

CONCLUSION

In conclusion, an upregulation of FABP4 is involved in excessive inflammation and pathogenesis of tendinopathy. TDSCs is a potential source of FABP4 during tendon inflammation.

TRANSLATION POTENTIAL OF THIS ARTICLE

FABP4 can be a potential treatment target of tendinopathy.

目的

过度炎症反应参与肌腱病的发病机制。脂肪酸结合蛋白4（FABP4）是一种促炎脂肪因子，介导多种代谢和炎症性疾病。本研究旨在检测FABP4在肌腱病中的表达及其与炎症细胞因子表达的关系。研究单次注射FABP4对肌腱病理和炎症的影响。同时也研究FABP4对炎症细胞因子表达的影响以及白细胞介素-1β（IL-1β）对肌腱来源的干/祖细胞（TDSCs）中FABP4表达的影响。

方法

1）临床髌腱病样本、健康绳肌腱样本和健康髌腱样本；2）肩袖肌腱病样本和健康绳肌腱样本；3）对注射生理盐水或胶原酶（CI）后的小鼠跟腱进行免疫组织化学（IHC）染色，检测FABP4、IL-1β、IL-6、肿瘤坏死因子-α（TNF-α）和IL-10。对于肩袖肌腱病样本，通过免疫荧光染色（IF）检测FABP4与IL-1β和TNF-α的共定位。收集注射FABP4或生理盐水后的小鼠跟腱进行组织学检查、IHC以及注射后微计算机断层扫描（microCT）成像。从人及小鼠肌腱中分离TDSCs。通过定量逆转录聚合酶链反应（qRT-PCR）定量检测添加FABP4后人及小鼠TDSCs中炎症细胞因子的mRNA表达。通过IF检测从肩袖肌腱病样本和健康绳肌腱样本中分离的TDSCs中FABP4的表达。用IL-1β处理小鼠跟腱TDSCs。分别通过qRT-PCR和IF检测FABP4的mRNA和蛋白表达。

结果

与相应对照相比，髌腱病样本和肩袖肌腱病样本中FABP4显著上调。FABP4主要表达于包括血管、细胞增多和钙化区域在内的病理区域。人肩袖肌腱病样本中IL-1β和TNF-α的表达增加，并与FABP4的表达共定位。胶原酶在小鼠跟腱病模型中诱导出类似肌腱病的组织病理学变化和异位钙化。胶原酶注射后，小鼠跟腱中细胞增多区域、圆形细胞、软骨样细胞和钙化区域中炎症细胞因子（IL-1β、IL-6、TNF-α、IL-10）和FABP4的表达增加。在小鼠跟腱中单次注射FABP4可诱导出类似肌腱病的组织病理学变化，注射后细胞变圆增加、胶原纤维排列紊乱，此外还出现软骨样细胞和钙化。FABP4注射后小鼠跟腱中IL1-β、IL-6、TNF-α和IL-10的表达增加。FABP4增加人TDSCs中IL-1β、IL-6、TNF-α和IL-10的表达以及小鼠TDSCs中IL-1β、IL-6、TNF-α和IL-10的表达。与健康绳肌腱TDSCs相比，人肌腱病TDSCs表达更高水平的FABP4。此外，IL-1β增加小鼠TDSCs中FABP4的表达。