PGE2 combined with IL-6 promote non-tenogenic and inhibit tenogenic differentiation of tendon stem cell via the SMAD pathways
- 1Department of Orthopaedics, Jinan Fifth People’s Hospital
- 2Department of Spine Surgery, The Second Hospital of Shandong University
Abstract
As vital healing cells, inappropriate differentiation of tendon stem cells (TSCs) in persistent inflammation wound cause injured tendons to difficult healing, eventually developing into tendinopathy. The key inflammation cytokines Prostaglandin E2 (PGE2) and Interleukin-(IL-)6 are increased in injured tendons and the SMAD signaling pathways play key role in regulating stem cell activity. However the combined effects of PGE2 and IL-6 on TSC differentiation and the molecular mechanism in it have not been unexplored. In the current study, we found that PGE2 combined with IL-6 promote osteogenic, chondrogenic, and adipogenic differentiation of TSCs, inhibited tenogenic differentiation of TSCs, and activated the SMAD1/5/8 and SMAD2/3 signaling, while the SMAD inhibitors LDN 193,189 combined with SB431542 reversed those effects. SB431542 inhibited IL-6-induced SMAD2/3 signaling and up-regulated the phosphorylation level of SMAD1/5/8 induced by PGE2, which was consistent with the results that IL-6 inhibited PGE2-induced adipogenic differentiation of TSC. In vivo, LDN 193,189 combined with SB431542 prevented tendon injury induced by treadmill running in mice, and suppressed the expression of non-tenogenic differentiation markers and enhanced the tenogenic marker expression in injured tendons. Collectively, the present study demonstrated that PGE2 combined with IL-6 promoted non-tenogenic differentiation and inhibited tenogenic differentiation of TSCs via the SMAD1/5/8 and SMAD2/3 pathway. Additionally, we confirmed the positive effects of the SMAD inhibitors LDN193189 and SB431542 in preventing tendon injury in vivo and provide a novel strategy for preventing and treating tendon injuries.
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BibTeX
@article{fu2026pge2,
title = {{PGE2 combined with IL-6 promote non-tenogenic and inhibit tenogenic differentiation of tendon stem cell via the SMAD pathways}},
author = {Shenglong Fu and Dongjin Wu and Hu Li and Lijun Zhang and Yunting Bai and Zhiwei Fang and Jun Zhang},
journal = {Scientific Reports},
year = {2026},
month = aug,
doi = {10.1038/s41598-026-65599-x},
url = {https://doi.org/10.1038/s41598-026-65599-x},
note = {CC BY},
}
RIS
TY - JOUR
TI - PGE2 combined with IL-6 promote non-tenogenic and inhibit tenogenic differentiation of tendon stem cell via the SMAD pathways
AU - Shenglong Fu
AU - Dongjin Wu
AU - Hu Li
AU - Lijun Zhang
AU - Yunting Bai
AU - Zhiwei Fang
AU - Jun Zhang
PY - 2026
DA - 2026/08/01
JO - Scientific Reports
DO - 10.1038/s41598-026-65599-x
UR - https://doi.org/10.1038/s41598-026-65599-x
AB - As vital healing cells, inappropriate differentiation of tendon stem cells (TSCs) in persistent inflammation wound cause injured tendons to difficult healing, eventually developing into tendinopathy. The key inflammation cytokines Prostaglandin E2 (PGE2) and Interleukin-(IL-)6 are increased in injured tendons and the SMAD signaling pathways play key role in regulating stem cell activity. However the combined effects of PGE2 and IL-6 on TSC differentiation and the molecular mechanism in it have not been unexplored. In the current study, we found that PGE2 combined with IL-6 promote osteogenic, chondrogenic, and adipogenic differentiation of TSCs, inhibited tenogenic differentiation of TSCs, and activated the SMAD1/5/8 and SMAD2/3 signaling, while the SMAD inhibitors LDN 193,189 combined with SB431542 reversed those effects. SB431542 inhibited IL-6-induced SMAD2/3 signaling and up-regulated the phosphorylation level of SMAD1/5/8 induced by PGE2, which was consistent with the results that IL-6 inhibited PGE2-induced adipogenic differentiation of TSC. In vivo, LDN 193,189 combined with SB431542 prevented tendon injury induced by treadmill running in mice, and suppressed the expression of non-tenogenic differentiation markers and enhanced the tenogenic marker expression in injured tendons. Collectively, the present study demonstrated that PGE2 combined with IL-6 promoted non-tenogenic differentiation and inhibited tenogenic differentiation of TSCs via the SMAD1/5/8 and SMAD2/3 pathway. Additionally, we confirmed the positive effects of the SMAD inhibitors LDN193189 and SB431542 in preventing tendon injury in vivo and provide a novel strategy for preventing and treating tendon injuries.
SN - 2045-2322
ER -