TY - JOUR
T1 - RSPO2 defines a distinct undifferentiated progenitor in the tendon/ligament and suppresses ectopic ossification
AU - Tachibana, Naohiro
AU - Chijimatsu, Ryota
AU - Okada, Hiroyuki
AU - Oichi, Takeshi
AU - Taniguchi, Yuki
AU - Maenohara, Yuji
AU - Miyahara, Junya
AU - Ishikura, Hisatoshi
AU - Iwanaga, Yasuhide
AU - Arino, Yusuke
AU - Nagata, Kosei
AU - Nakamoto, Hideki
AU - Kato, So
AU - Doi, Toru
AU - Matsubayashi, Yoshitaka
AU - Oshima, Yasushi
AU - Terashima, Asuka
AU - Omata, Yasunori
AU - Yano, Fumiko
AU - Maeda, Shingo
AU - Ikegawa, Shiro
AU - Seki, Masahide
AU - Suzuki, Yutaka
AU - Tanaka, Sakae
AU - Saito, Taku
PY - 2022/8/19
Y1 - 2022/8/19
N2 - Ectopic endochondral ossification in the tendon/ligament is caused by repetitive mechanical overload or inflammation. Tendon stem/progenitor cells (TSPCs) contribute to tissue repair, and some express lubricin [proteoglycan 4 (PRG4)]. However, the mechanisms of ectopic ossification and association of TSPCs are not yet known. Here, we investigated the characteristics of Prg4-positive (+) cells and identified that R-spondin 2 (RSPO2), a WNT activator, is specifically expressed in a distinct Prg4+ TSPC cluster. The Rspo2+ cluster was characterized as mostly undifferentiated, and RSPO2 overexpression suppressed ectopic ossification in a mouse Achilles tendon puncture model via chondrogenic differentiation suppression. RSPO2 expression levels in patients with ossification of the posterior longitudinal ligament were lower than those in spondylosis patients, and RSPO2 protein suppressed chondrogenic differentiation of human ligament cells. RSPO2 was induced by inflammatory stimulation and mechanical loading via nuclear factor κB. Rspo2+ cells may contribute to tendon/ligament homeostasis under pathogenic conditions.
AB - Ectopic endochondral ossification in the tendon/ligament is caused by repetitive mechanical overload or inflammation. Tendon stem/progenitor cells (TSPCs) contribute to tissue repair, and some express lubricin [proteoglycan 4 (PRG4)]. However, the mechanisms of ectopic ossification and association of TSPCs are not yet known. Here, we investigated the characteristics of Prg4-positive (+) cells and identified that R-spondin 2 (RSPO2), a WNT activator, is specifically expressed in a distinct Prg4+ TSPC cluster. The Rspo2+ cluster was characterized as mostly undifferentiated, and RSPO2 overexpression suppressed ectopic ossification in a mouse Achilles tendon puncture model via chondrogenic differentiation suppression. RSPO2 expression levels in patients with ossification of the posterior longitudinal ligament were lower than those in spondylosis patients, and RSPO2 protein suppressed chondrogenic differentiation of human ligament cells. RSPO2 was induced by inflammatory stimulation and mechanical loading via nuclear factor κB. Rspo2+ cells may contribute to tendon/ligament homeostasis under pathogenic conditions.
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U2 - 10.1126/sciadv.abn2138
DO - 10.1126/sciadv.abn2138
M3 - Article
C2 - 35984875
AN - SCOPUS:85136229111
SN - 2375-2548
VL - 8
SP - eabn2138
JO - Science advances
JF - Science advances
IS - 33
ER -