Pharmacological Inhibition of Rac1 Activity Prevents Pathological Calcification and Enhances Tendon Regeneration

Long Yang; Chenqi Tang; Yangwu Chen; Dengfeng Ruan; Erchen Zhang; Zi Yin; Xiao Chen; Yangzi Jiang; Youzhi Cai; Yang Fei; Shouan Zhu; Huanhuan Liu; Jiajie Hu; Boon Chin Heng; Weishan Chen; Weiliang Shen; Hongwei Ouyang

doi:10.1021/acsbiomaterials.9b00335

Pharmacological Inhibition of Rac1 Activity Prevents Pathological Calcification and Enhances Tendon Regeneration

ACS Biomater Sci Eng. 2019 Jul 8;5(7):3511-3522. doi: 10.1021/acsbiomaterials.9b00335. Epub 2019 Jun 7.

Authors

Long Yang^{1

2

3}, Chenqi Tang^{1

2

4

5}, Yangwu Chen^{1

2

4

5}, Dengfeng Ruan^{4

5}, Erchen Zhang^{1

2}, Zi Yin^{1

2}, Xiao Chen^{1

2

6}, Yangzi Jiang^{1

2

7

8}, Youzhi Cai^{2

9}, Yang Fei^{4

5}, Shouan Zhu^{1

2}, Huanhuan Liu^{1

2}, Jiajie Hu^{1

2}, Boon Chin Heng¹⁰, Weishan Chen^{4

5}, Weiliang Shen^{1

2

4

5

6

7}, Hongwei Ouyang^{1

2

6

7

11}

Affiliations

¹ Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cells and Regenerative Medicine, School of Medicine, Zhejiang University, Hangzhou, China.
² Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, School of Medicine, Zhejiang University, Hangzhou, China.
³ The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China.
⁴ Department of Orthopaedics, Second Affiliated Hospital, Zhejiang University, Hangzhou, China.
⁵ Orthopaedics Research Institute of Zhejiang University, Hangzhou, China.
⁶ China Orthopedic Regenerative Medicine Group (CORMed), Hangzhou, China.
⁷ Department of Sports Medicine, School of Medicine, Zhejiang University, Hangzhou, China.
⁸ Center for Cellular and Molecular Engineering, Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15219, United States.
⁹ Center for Sport Medicine, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
¹⁰ Faculty of Dentistry, Department of Endodontology, The University of Hong Kong, Pokfulam, Hong Kong.
¹¹ State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.

PMID: 33405734
DOI: 10.1021/acsbiomaterials.9b00335

Abstract

Tendinopathy is a common disease, which is characterized by pain, swelling, and dysfunction. At the late stage of tendinopathy, pathological changes may occur, such as tendon calcification. Previously, we have shown that in situ tendon stem/progenitor cells (TSPCs) underwent osteogenesis in the inflammatory niche in diseased tendons. In this study, we demonstrate that this process is accompanied by the activation of Ras-related C3 botulinum toxin substrate 1 (Rac1) signaling. A specific inhibitor NSC23766 significantly downregulated catabolic factors and calcification-related genes and rescued the tenogenesis gene expression of TSPCs under the influence of Interleukin (IL)-1β in vitro. For in vivo evaluation, we further developed a drug delivery system to encapsulate Rac1 inhibitor NSC23766. Chitosan/β-glycerophosphate hydrogel encapsulated NSC23766 effectively impeded tendon calcification and enhanced tendon regeneration in rat Achilles tendinosis. Our findings indicated that inhibiting Rac1 signaling could act as an effective intervention for tendon pathological calcification and promote tendon regeneration, thus providing a new therapeutic strategy.

Keywords: NSC23766; Rac1; chitosan/β-glycerophosphate; tendon calcification; tendon stem progenitor cells.