Critical implication of the PTEN/PI3K/AKT pathway during BMP2-induced heterotopic ossification

Dong,Jun; Xu,Xiqiang; Zhang,Qingyu; Yuan,Zenong; Tan,Bingyi

doi:10.3892/mmr.2021.11893

Critical implication of the PTEN/PI3K/AKT pathway during BMP2-induced heterotopic ossification

Authors:
- Jun Dong
- Xiqiang Xu
- Qingyu Zhang
- Zenong Yuan
- Bingyi Tan
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Affiliations: Department of Orthopaedics, Shandong Provincial Hospital, Affiliated to Shandong First Medical University, Jinan, Shandong 250021, P.R. China
Published online on: February 3, 2021 https://doi.org/10.3892/mmr.2021.11893
Article Number: 254
Copyright: © Dong et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Heterotopic ossification (HO) is characterized by extraskeletal ossification in soft tissue. Thus far, there is a lack of effective drug therapy against HO. Loss of PTEN in osteoblasts has been reported to accumulate bone mass in skeletal development and promote fracture healing in association with the activation of the PI3K/AKT pathway. However, the role of the PTEN/PI3K/AKT signaling in HO pathogenesis remains unknown. The present study investigated the implication of this pathway during BMP2‑induced osteogenic differentiation and ectopic bone formation. It was shown that overexpression of PTEN inhibited proliferation but stimulated apoptosis in mesenchymal pluripotent C3H10T1/2 cells. PTEN also inhibited BMP2‑induced osteoblast differentiation, whereas BMP2 repressed PTEN expression and subsequently activated PI3K/AKT. The PI3K inhibitor, LY294002, blocked BMP2‑induced osteoblastogenesis, suggesting that the PI3K/AKT pathway is critically required for BMP2 to initiate osteoblastogenesis. In vivo, implantation of BMP2 in muscle induced ectopic endochondral ossification. Strikingly, this bone‑forming capacity was notably suppressed by the PI3K inhibitor LY294002. Hence, the results of the present study demonstrated that the PI3K/AKT signaling activity is indispensable for BMP2 to induce ectopic new bone. Targeting the PI3K/AKT pathway using inhibitor(s) may represent a potential molecular therapy for the treatment against HO.

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