Extracellular HMGB-1 activates inflammatory signaling in tendon cells and tissues

Chuanxin Zhang; Xinfeng Gu; Guangyi Zhao; Wang Wang; Jiahua Shao; Jun Zhu; Ting Yuan; Jiuyi Sun; Daibang Nie; Yiqin Zhou

doi:10.1177/2040622320956429

Extracellular HMGB-1 activates inflammatory signaling in tendon cells and tissues

Ther Adv Chronic Dis. 2020 Sep 11:11:2040622320956429. doi: 10.1177/2040622320956429. eCollection 2020.

Authors

Chuanxin Zhang¹, Xinfeng Gu², Guangyi Zhao³, Wang Wang⁴, Jiahua Shao¹, Jun Zhu¹, Ting Yuan⁵, Jiuyi Sun⁶, Daibang Nie⁷, Yiqin Zhou¹

Affiliations

¹ Department of Joint Surgery and Sports Medicine, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China.
² Department of Joint Surgery and Sports Medicine, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China Department of Bone and Joint, Shuguang Hospital Affiliated to Shanghai University of Tradition Chinese Medicine, Shanghai, China.
³ Department of Pathology, University of Pittsburgh School of Medicine, University of Pittsburgh Cancer Institute Pittsburgh, PA, USA.
⁴ Department of Immunology, College of Basic Medicine, Chongqing Medical University, Chongqing, China.
⁵ Department of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
⁶ Department of Joint Surgery and Sports Medicine, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China Department of Orthropaedics, Navy Medical Center of PLA, Shanghai, China.
⁷ Department of Immunology, College of Basic Medicine, Chongqing Medical University, #1 Yixueyuan Road, Yuzhong District, Chongqing, 400016, China.

Abstract

Background: Increasing evidence indicates that secretion of high mobility group box 1 protein (HMGB-1) is functionally associated with tendinopathy development. However, the underlying effect and mechanism of extracellular HMGB-1 on tendon cells are unclear.

Methods: We tested the effect of exogenous HMGB-1 on cell growth, migration, and inflammatory signaling responses with isolated rat Achilles tendon cells. Also, we studied the role of extracellular HMGB-1, when administrated alone or in combination with mechanical overloading induced by intensive treadmill running (ITR), in stimulating inflammatory effects in tendon tissues.

Results: By using in vitro and in vivo models, we show for the first time that exogenous HMGB-1 dose-dependently induces inflammatory reactions in tendon cells and tendon tissue. Extracellular HMGB-1 promoted redistribution of HMGB-1 from the nucleus to the cytoplasm, and activated canonical nuclear factor kappa B (NF-κB) signaling and mitogen-activated protein kinase (MAPK) signaling. Short-term administration of HMGB-1 induced hyper-cellularity of rat Achilles tendon tissues, accompanied with enhanced immune cell infiltration. Additional ITR to HMGB-1 treatment worsens these responses, and application of HMGB-1 specific inhibitor glycyrrhizin (GL) completely abolishes such inflammatory effects in tendon tissues.

Conclusion: Collectively, these results confirm that HMGB-1 plays key roles in the induction of tendinopathy. Our findings improve the understanding of the molecular and cellular mechanisms during tendinopathy development, and provide essential information for potential targeted treatments of tendinopathy.

Keywords: HMGB1; tendinopathy.