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PTEN/PI3K/AKT 通路在 BMP2 诱导异位骨化中的关键意义。

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

机构信息

Department of Orthopaedics, Shandong Provincial Hospital, Affiliated to Shandong First Medical University, Jinan, Shandong 250021, P.R. China.

出版信息

Mol Med Rep. 2021 Apr;23(4). doi: 10.3892/mmr.2021.11893. Epub 2021 Feb 4.

DOI:10.3892/mmr.2021.11893
PMID:33537834
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7893754/
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.

摘要

异位骨化（HO）的特征是在软组织中出现骨骼外骨化。到目前为止，针对 HO 还没有有效的药物治疗方法。已有研究报道，成骨细胞中 PTEN 的缺失会在骨骼发育过程中积累骨量，并通过激活 PI3K/AKT 通路促进骨折愈合。然而，PTEN/PI3K/AKT 信号通路在 HO 发病机制中的作用尚不清楚。本研究探讨了该通路在 BMP2 诱导的成骨分化和异位骨形成过程中的作用。结果表明，PTEN 的过表达抑制了间充质多能 C3H10T1/2 细胞的增殖，但刺激了其凋亡。PTEN 还抑制 BMP2 诱导的成骨分化，而 BMP2 抑制了 PTEN 的表达，继而激活了 PI3K/AKT。PI3K 抑制剂 LY294002 阻断了 BMP2 诱导的成骨作用，表明 PI3K/AKT 通路对 BMP2 启动成骨作用至关重要。在体内，BMP2 在肌肉中的植入诱导了异位软骨内成骨。引人注目的是，这种成骨能力被 PI3K 抑制剂 LY294002 显著抑制。因此，本研究结果表明，PI3K/AKT 信号活性对于 BMP2 诱导异位新骨形成是必不可少的。使用抑制剂靶向 PI3K/AKT 通路可能代表针对 HO 的潜在分子治疗方法。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b17c/7893754/6b055515a4ac/mmr-23-04-11893-g04.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b17c/7893754/6da6f54c8820/mmr-23-04-11893-g00.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b17c/7893754/9b8f77aa4c12/mmr-23-04-11893-g01.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b17c/7893754/fd4e641cdec1/mmr-23-04-11893-g02.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b17c/7893754/090cd20d918d/mmr-23-04-11893-g03.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b17c/7893754/6b055515a4ac/mmr-23-04-11893-g04.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b17c/7893754/6da6f54c8820/mmr-23-04-11893-g00.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b17c/7893754/9b8f77aa4c12/mmr-23-04-11893-g01.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b17c/7893754/fd4e641cdec1/mmr-23-04-11893-g02.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b17c/7893754/090cd20d918d/mmr-23-04-11893-g03.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b17c/7893754/6b055515a4ac/mmr-23-04-11893-g04.jpg

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