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成纤维细胞通过调节间充质干细胞中 YAP 的核质穿梭和分泌 DKK1 来抑制成骨作用。

Fibroblasts inhibit osteogenesis by regulating nuclear-cytoplasmic shuttling of YAP in mesenchymal stem cells and secreting DKK1.

机构信息

Central Laboratory, First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, Fujian, China.

Department of Orthopaedics, The First Affiliated Hospital, Fujian Medical University, No. 20, Chazhong Road, Taijiang District, Fuzhou, 350005, Fujian, China.

出版信息

Biol Res. 2024 Jan 20;57(1):4. doi: 10.1186/s40659-023-00481-y.

DOI:10.1186/s40659-023-00481-y
PMID:38245803
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10799393/
Abstract

BACKGROUND

Fibrous scars frequently form at the sites of bone nonunion when attempts to repair bone fractures have failed. However, the detailed mechanism by which fibroblasts, which are the main components of fibrous scars, impede osteogenesis remains largely unknown.

RESULTS

In this study, we found that fibroblasts compete with osteogenesis in both human bone nonunion tissues and BMP2-induced ectopic osteogenesis in a mouse model. Fibroblasts could inhibit the osteoblastic differentiation of mesenchymal stem cells (MSCs) via direct and indirect cell competition. During this process, fibroblasts modulated the nuclear-cytoplasmic shuttling of YAP in MSCs. Knocking down YAP could inhibit osteoblast differentiation of MSCs, while overexpression of nuclear-localized YAP-5SA could reverse the inhibition of osteoblast differentiation of MSCs caused by fibroblasts. Furthermore, fibroblasts secreted DKK1, which further inhibited the formation of calcium nodules during the late stage of osteogenesis but did not affect the early stage of osteogenesis. Thus, fibroblasts could inhibit osteogenesis by regulating YAP localization in MSCs and secreting DKK1.

CONCLUSIONS

Our research revealed that fibroblasts could modulate the nuclear-cytoplasmic shuttling of YAP in MSCs, thereby inhibiting their osteoblast differentiation. Fibroblasts could also secrete DKK1, which inhibited calcium nodule formation at the late stage of osteogenesis.

摘要

背景

当修复骨折的尝试失败时，纤维瘢痕通常会在骨不连部位形成。然而，成纤维细胞（是纤维瘢痕的主要成分）如何阻碍成骨，其详细机制在很大程度上仍然未知。

结果

在这项研究中，我们发现成纤维细胞在人骨不连组织和 BMP2 诱导的小鼠模型异位成骨中与成骨竞争。成纤维细胞可以通过直接和间接的细胞竞争抑制间充质干细胞（MSCs）的成骨细胞分化。在此过程中，成纤维细胞调节了 MSCs 中 YAP 的核质穿梭。敲低 YAP 可以抑制 MSCs 的成骨细胞分化，而过表达核定位的 YAP-5SA 可以逆转成纤维细胞对 MSCs 的成骨细胞分化的抑制。此外，成纤维细胞分泌 DKK1，这进一步抑制了成骨后期钙结节的形成，但不影响成骨的早期阶段。因此，成纤维细胞可以通过调节 MSCs 中 YAP 的定位和分泌 DKK1 来抑制成骨。

结论

我们的研究表明，成纤维细胞可以调节 MSCs 中 YAP 的核质穿梭，从而抑制其成骨细胞分化。成纤维细胞还可以分泌 DKK1，抑制成骨后期钙结节的形成。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/279c/10799393/962dabd45c2f/40659_2023_481_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/279c/10799393/00ae6f234cd9/40659_2023_481_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/279c/10799393/8650c2dd8403/40659_2023_481_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/279c/10799393/d96a9a2c9799/40659_2023_481_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/279c/10799393/3bf3587086e9/40659_2023_481_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/279c/10799393/ce0d4a398ac5/40659_2023_481_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/279c/10799393/962dabd45c2f/40659_2023_481_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/279c/10799393/00ae6f234cd9/40659_2023_481_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/279c/10799393/8650c2dd8403/40659_2023_481_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/279c/10799393/d96a9a2c9799/40659_2023_481_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/279c/10799393/3bf3587086e9/40659_2023_481_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/279c/10799393/ce0d4a398ac5/40659_2023_481_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/279c/10799393/962dabd45c2f/40659_2023_481_Fig6_HTML.jpg

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