Bone marrow-derived fibroblast migration via periostin causes irreversible arthrogenic contracture after joint immobilization

Hirotaka Iura; Kazu Kobayakawa; Hirokazu Saiwai; Daijiro Konno; Masatake Tanaka; Kazuhiro Hata; Tetsuya Tamaru; Yohei Haruta; Gentaro Ono; Kazuki Kitade; Ken Kijima; Kensuke Kubota; Yutaka Inagaki; Masato Ohtsuka; Ken Okazaki; Koji Murakami; Shusaku Matsuda; Masami Tokunaga; Takaaki Yoshimoto; Takeshi Maeda; Yasuharu Nakashima; Seiji Okada

doi:10.1096/fj.202201598R

Bone marrow-derived fibroblast migration via periostin causes irreversible arthrogenic contracture after joint immobilization

FASEB J. 2023 May;37(5):e22842. doi: 10.1096/fj.202201598R.

Authors

Hirotaka Iura¹, Kazu Kobayakawa¹, Hirokazu Saiwai¹, Daijiro Konno², Masatake Tanaka³, Kazuhiro Hata¹, Tetsuya Tamaru¹, Yohei Haruta¹, Gentaro Ono¹, Kazuki Kitade¹, Ken Kijima¹, Kensuke Kubota⁴, Yutaka Inagaki⁵, Masato Ohtsuka^{6

7}, Ken Okazaki⁸, Koji Murakami⁹, Shusaku Matsuda⁹, Masami Tokunaga⁹, Takaaki Yoshimoto⁹, Takeshi Maeda⁴, Yasuharu Nakashima¹, Seiji Okada¹⁰

Affiliations

¹ Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
² Faculty of Science and Engineering, Graduate School of Science and Engineering, Kindai University, Osaka, Japan.
³ Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
⁴ Department of Orthopaedic Surgery, Spinal Injuries Center, Iizuka, Japan.
⁵ Center for Matrix Biology and Medicine, Graduate School of Medicine, Tokai University, Isehara, Japan.
⁶ Department of Molecular Life Science, Division of Basic Medical Science and Molecular Medicine, Tokai University School of Medicine, Isehara, Japan.
⁷ The Institute of Medical Sciences, Tokai University, Isehara, Japan.
⁸ Department of Orthopaedic Surgery, Graduate School of Medicine, Tokyo Women's Medical University, Tokyo, Japan.
⁹ Department of Orthopaedic Surgery, Fukuoka Orthopaedic Hospital, Fukuoka, Japan.
¹⁰ Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Osaka University, Suita, Japan.

PMID: 37000501
DOI: 10.1096/fj.202201598R

Abstract

Joint contracture causes distressing permanent mobility disorder due to trauma, arthritis, and aging, with no effective treatment available. A principal and irreversible cause of joint contracture has been regarded as the development of joint capsule fibrosis. However, the molecular mechanisms underlying contracture remain unclear. We established a mouse model of knee joint contracture, revealing that fibrosis in joint capsules causes irreversible contracture. RNA-sequencing of contracture capsules demonstrated a marked enrichment of the genes involved in the extracellular region, particularly periostin (Postn). Three-dimensional magnetic resonance imaging and immunohistological analysis of contracture patients revealed posterior joint capsule thickening with abundant type I collagen (Col1a2) and POSTN in humans. Col1a2-GFP^TG ; Postn^-/- mice and chimeric mice with Col1a2-GFP^TG ; tdTomato^TG bone marrow showed fibrosis in joint capsules caused by bone marrow-derived fibroblasts, and POSTN promoted the migration of bone marrow-derived fibroblasts, contributing to fibrosis and contracture. Conversely, POSTN-neutralizing antibody attenuated contracture exacerbation. Our findings identified POSTN as a key inducer of fibroblast migration that exacerbates capsule fibrosis, providing a potential therapeutic strategy for joint contracture.

Keywords: fibroblast; fibrosis; joint contracture; migration; periostin.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Bone Marrow* / pathology
Contracture* / drug therapy
Contracture* / genetics
Fibroblasts / pathology
Fibrosis
Humans
Mice
Range of Motion, Articular

Substances

Collagen Type I, alpha2 Subunit