CD1530, selective RARγ agonist, facilitates Achilles tendon healing by modulating the healing environment including less chondrification in a mouse model

Yimiti, Dilimulati; Uchibe, Kenta; Toriyama, Minoru; Hayashi, Yuta; Ikuta, Yasunari; Nakasa, Tomoyuki; Akiyama, Haruhiko; Watanabe, Hitomi; Kondoh, Gen; Takimoto, Aki; Shukunami, Chisa; Adachi, Nobuo; Miyaki, Shigeru

Affiliations

¹Department of Orthopaedic Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan

²Department of Maxillofacial Anatomy and Neuroscience, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan

³Department of Musculoskeletal Traumatology and Reconstructive Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan

⁴Department of Artificial Joints and Biomaterials, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan

⁵Department of Orthopaedic Surgery, Gifu University Graduate School of Medicine, Gifu, Japan

⁶Laboratory of Integrative Biological Science, Institute for Life and Medical Sciences (LIME), Kyoto University, Kyoto, Japan

⁷Department of Molecular Biology and Biochemistry, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan

⁸Medical Center for Translational and Clinical Research, Hiroshima University Hospital, Hiroshima, Japan

Abstract and keywords

Heterotopic ossification (HO) in Achilles tendon often arises due to endochondral ossification during the healing process following trauma. Retinoic acid receptor γ (RARγ) plays a critical role in this phenomenon. This study aims to elucidate the therapeutic effects of CD1530, an RARγ selective agonist, along with the contributing cells, in Achilles tendon healing, utilizing a cell lineage tracing system. Local injection of CD1530 facilitated histological tendon healing by inhibiting chondrification in a mouse Achilles rupture model. Resident Scleraxis (Scx)+ cells in Achilles tendon were not found to be actively involved in HO or　tendon healing following injury. Instead, these processes were primarily driven by tendon stem/progenitor cells (TSPC)-like cells. Furthermore, an in vitro assay revealed that CD1530 attenuated inflammation in injured Achilles tendon-derived tendon fibroblasts (iATF) and inhibited the chondrogenesis of iATF. This dual effect suggests the potential of CD1530 in effectively modulating the healing environment during tendon healing. Together, the present study demonstrated that the local administration of CD1530 accelerated tendon healing by modulating the healing environment, including reducing chondrification via targeting TSPC-like cells in a mouse Achilles tendon rupture model. These results suggest that CD1530 may have the potential to be a novel tendon therapy that offers benefits via the inhibition of chondrogenesis.

Keywords: Achilles tendon healing; chondrification; ossification; retinoic acid receptor γ selective agonist; tendon stem/progenitor cells

Links

DOI: 10.1002/jor.26006

PubMed: 39513493

WoS: 001357363900001

History

Received: 2024-02-27

Revised: 2024-09-19

Accepted: 2024-09-27

Cited Works (2)

Year	Entry
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