Mechanical stimulation improves rotator cuff tendon-bone healing via activating IL-4/JAK/STAT signaling pathway mediated macrophage M2 polarization

Yuqian Liu; Linfeng Wang; Shengcan Li; Tao Zhang; Can Chen; Jianzhong Hu; Deyi Sun; Hongbin Lu

Journal of Orthopaedic Translation (Nov 2022)

Mechanical stimulation improves rotator cuff tendon-bone healing via activating IL-4/JAK/STAT signaling pathway mediated macrophage M2 polarization

Yuqian Liu,
Linfeng Wang,
Shengcan Li,
Tao Zhang,
Can Chen,
Jianzhong Hu,
Deyi Sun,
Hongbin Lu

Affiliations

Yuqian Liu: Department of Sports Medicine, Xiangya Hospital, Central South University, Changsha, China; Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province, Changsha, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
Linfeng Wang: Department of Sports Medicine, Xiangya Hospital, Central South University, Changsha, China; Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province, Changsha, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
Shengcan Li: Department of Sports Medicine, Xiangya Hospital, Central South University, Changsha, China; Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province, Changsha, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
Tao Zhang: Department of Sports Medicine, Xiangya Hospital, Central South University, Changsha, China; Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province, Changsha, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
Can Chen: Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province, Changsha, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
Jianzhong Hu: Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province, Changsha, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China; Department of Spine Surgery and Orthopedics, Xiangya Hospital, Central South University, Changsha, China
Deyi Sun: Department of Sports Medicine, Xiangya Hospital, Central South University, Changsha, China; Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province, Changsha, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China; Corresponding author. Xiangya Hospital, Central South University, No. 87, Xiangya Road, Kaifu District, Changsha, 410008, China.
Hongbin Lu: Department of Sports Medicine, Xiangya Hospital, Central South University, Changsha, China; Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province, Changsha, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China; Corresponding author. Xiangya Hospital, Central South University, No. 87, Xiangya Road, Kaifu District, Changsha, 410008, China.

Journal volume & issue: Vol. 37
pp. 78 – 88

Abstract

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Background: It is well known that appropriate mechanical stimulation benefits tendon-bone (T-B) healing, however, the mechanisms behind this are still uncovered completely. Here, we aimed to explore whether the IL-4/JAK/STAT signaling pathway mediated macrophage polarization was involved in mechanical stimulation induced T-B healing. Method: C57BL/6 mice rotator cuff (RC) repair model was established, and the mice were randomly allocated to the following group. 1. Mice were allowed for free cage activities after surgery (FC group); 2. Mice received treadmill running initiated on postoperative day 7 (TR group); 3. Mice only received a local injection of hydrogel containing IL-4 neutralizing antibody without postoperative intervention (FC + AF-404-SP group); 4. Mice received a local injection of hydrogel containing IL-4 neutralizing antibody and postoperative treadmill running (TR + AF-404-SP group). The expression of IL-4 within supraspinatus tendon (SST) enthesis was measured by Enzyme-linked immunosorbent assay (ELISA). In addition, the activation of JAK/STAT signaling pathway in macrophages and identification of macrophage phenotype at the RC insertion site was detected by Flow cytometry and qRT-PCR. T-B healing quality in this RC repair model was evaluated by histological staining, Micro-computed tomography (Micro-CT) scanning, and biomechanical testing. Result: In this study, using the RC repair model, we confirmed that generation of IL-4, activation of the JAK/STAT signaling pathway in macrophages, the ability of macrophages to polarize towards M2 subtype, and T-B healing quality were significantly enhanced in TR group compared to FC group. When comparing FC + AF-404-SP group with TR + AF-404-SP group, it was found that the mechanical stimulation induced this effect was depleted following the blockade of the IL-4/JAK/STAT signaling pathway. Conclusion: Our finding suggested that mechanical stimulation could accelerate T-B healing via activating the IL-4/JAK/STAT signaling pathway that modulates macrophages to polarize towards M2 subtype. The translational potential of this article: This is the first study to reveal a significant role of mechanical stimulation in the IL-4/JAK/STAT signaling pathway activation and macrophage polarization during RC T-B healing, which highlights the IL-4/JAK/STAT signaling pathway as a potential target to mediate macrophage M2 polarization and improves T-B healing for RC repair.

Published in Journal of Orthopaedic Translation

ISSN: 2214-031X (Print); 2214-0328 (Online)
Publisher: Elsevier
Country of publisher: Hong Kong
LCC subjects: Medicine: Internal medicine: Specialties of internal medicine: Diseases of the musculoskeletal system
Website: http://www.journals.elsevier.com/journal-of-orthopaedic-translation/

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