PTHrP suppresses BMP2-induced osteochondral differentiation and preserves cartilage phenotype in mesenchymal stem cells via inactivating PI3K-AKT signaling.
4 affiliations
- 1Department of Orthopaedic Surgery, Chongqing Municipal Health Commission Key Laboratory of Musculoskeletal Regeneration and Translational Medicine, Orthopaedic Research Laboratory, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.
- 2Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago, Medical Center, Chicago, IL 60637, USA.
- 3Medical Examination Center, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.
- 4Department of Orthopaedic Surgery, The Second People's Hospital of Chongqing Yubei District, Chongqing 401147, China.
Abstract
Bone morphogenetic protein 2 (BMP2) has the potential to drive multipotent mesenchymal stem cells (MSCs) to undergo chondral-osteogenic (including hypertrophic chondrocyte) differentiation. Parathyroid hormone-related protein (PTHrP) plays an essential role in fetal endochondral ossification, although persistent PTHrP stimulation leads to postnatal bone loss. Here, we investigated the effects of PTHrP on BMP2-induced endochondral ossification through hypertrophic chondrocyte differentiation of MSCs. We found that silencing PTHrP expression inhibited BMP2-induced chondrogenic, hypertrophic, and osteogenic differentiation of MSCs, while overexpression of PTHrP promoted BMP2-induced chondrogenic differentiation of MSCs and suppressed BMP2-induced hypertrophic differentiation of MSCs. Using stem cell implantation studies in athymic nude mice, we demonstrated that while MSCs with silenced PTHrP expression exhibited significantly reduced endochondral ossification of subcutaneous cartilage, overexpression of PTHrP promoted the growth of subcutaneous cartilage while significantly delaying ossification, leading to the preservation of cartilage phenotype. Mechanistically, we showed that exogenous PTHrP promoted BMP2-induced chondrogenic differentiation of MSCs by up-regulating Sox9 expression and inactivating PI3K-AKT signaling. Collectively, our findings strongly suggest that PTHrP may play an important role in mediating BMP2-induced chondral-osteogenic differentiation of MSCs by inactivating PI3K-AKT signaling, indicating that PTHrP may be exploited for endochondral cartilage-bone tissue engineering.
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BibTeX
@article{gao2026pthrp,
title = {{PTHrP suppresses BMP2-induced osteochondral differentiation and preserves cartilage phenotype in mesenchymal stem cells via inactivating PI3K-AKT signaling.}},
author = {Shengqiang Gao and Piao Zhao and Tingting Du and Yu Ye and Shengwen Cheng and Senrui Liu and Chengcheng Du and Tong-Chuan He and Wei Huang and Zhenglin Zhu and Wei Xu and Junyi Liao},
journal = {Genes \& diseases},
year = {2026},
month = jun,
doi = {10.1016/j.gendis.2026.102273},
url = {https://europepmc.org/article/MED/42926813},
note = {CC BY},
}
RIS
TY - JOUR
TI - PTHrP suppresses BMP2-induced osteochondral differentiation and preserves cartilage phenotype in mesenchymal stem cells via inactivating PI3K-AKT signaling.
AU - Shengqiang Gao
AU - Piao Zhao
AU - Tingting Du
AU - Yu Ye
AU - Shengwen Cheng
AU - Senrui Liu
AU - Chengcheng Du
AU - Tong-Chuan He
AU - Wei Huang
AU - Zhenglin Zhu
AU - Wei Xu
AU - Junyi Liao
PY - 2026
DA - 2026/06/05
JO - Genes & diseases
DO - 10.1016/j.gendis.2026.102273
UR - https://europepmc.org/article/MED/42926813
AB - Bone morphogenetic protein 2 (BMP2) has the potential to drive multipotent mesenchymal stem cells (MSCs) to undergo chondral-osteogenic (including hypertrophic chondrocyte) differentiation. Parathyroid hormone-related protein (PTHrP) plays an essential role in fetal endochondral ossification, although persistent PTHrP stimulation leads to postnatal bone loss. Here, we investigated the effects of PTHrP on BMP2-induced endochondral ossification through hypertrophic chondrocyte differentiation of MSCs. We found that silencing PTHrP expression inhibited BMP2-induced chondrogenic, hypertrophic, and osteogenic differentiation of MSCs, while overexpression of PTHrP promoted BMP2-induced chondrogenic differentiation of MSCs and suppressed BMP2-induced hypertrophic differentiation of MSCs. Using stem cell implantation studies in athymic nude mice, we demonstrated that while MSCs with silenced PTHrP expression exhibited significantly reduced endochondral ossification of subcutaneous cartilage, overexpression of PTHrP promoted the growth of subcutaneous cartilage while significantly delaying ossification, leading to the preservation of cartilage phenotype. Mechanistically, we showed that exogenous PTHrP promoted BMP2-induced chondrogenic differentiation of MSCs by up-regulating Sox9 expression and inactivating PI3K-AKT signaling. Collectively, our findings strongly suggest that PTHrP may play an important role in mediating BMP2-induced chondral-osteogenic differentiation of MSCs by inactivating PI3K-AKT signaling, indicating that PTHrP may be exploited for endochondral cartilage-bone tissue engineering.
SN - 2352-4820
SN - 2352-3042
ER -