Macrophage-lineage TRAP+ cells recruit periosteum-derived cells for periosteal osteogenesis and regeneration
Bo Gao, … , Zhuojing Luo, Xu Cao
Bo Gao, … , Zhuojing Luo, Xu Cao
Published April 4, 2019
Citation Information: J Clin Invest. 2019;129(6):2578-2594. https://doi.org/10.1172/JCI98857.
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Research Article Bone biology Article has an altmetric score of 6

Macrophage-lineage TRAP+ cells recruit periosteum-derived cells for periosteal osteogenesis and regeneration

Abstract

Cortical bones account for more than 80% of human bone mass. The periosteum, a thin tissue that covers almost the entire bone surface, is essential for bone formation and regeneration. However, its osteogenic and bone regenerative abilities are not well studied. In this study, we found that macrophage-lineage cells recruit periosteum-derived cells (PDCs) for cortical bone formation. Knockout of colony-stimulating factor-1 eliminated macrophage-lineage cells and resulted in loss of PDCs with impaired periosteal bone formation. Moreover, macrophage-lineage tartrate-resistant acid phosphatase–positive (TRAP+) cells induced transcriptional expression of periostin and recruitment of PDCs to the periosteal surface through secretion of PDGF-BB, where the recruited PDCs underwent osteoblast differentiation coupled with type H vessel formation. We also found that subsets of Nestin+ and LepR+CD45–Ter119–CD31– cells (LepR+ PDCs) possess multipotent and self-renewal abilities and contribute to cortical bone formation. Nestin+ PDCs are found primarily during bone development, whereas LepR+ PDCs are essential for bone homeostasis in adult mice. Importantly, conditional knockout of Pdgfr-β in LepR+ cells impaired periosteal bone formation and regeneration. These findings uncover the essential role of periosteal macrophage-lineage cells in regulating periosteum homeostasis and regeneration.

Authors

Bo Gao, Ruoxian Deng, Yu Chai, Hao Chen, Bo Hu, Xiao Wang, Shouan Zhu, Yong Cao, Shuangfei Ni, Mei Wan, Liu Yang, Zhuojing Luo, Xu Cao

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Figure 6

PDGF-BB induces periostin expression via the PDGFR-β/PI3K/AKT/-CREB signaling pathway.

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PDGF-BB induces periostin expression via the PDGFR-β/PI3K/AKT/-CREB sign...
(A and B) Representative images of coronal tibia diaphyseal periosteum sections from Trap-cre Pdgfbfl/fl mice (A, left panels) and Ctsk–/– mice (B, left panels) with their control littermates stained for periostin. Quantification of the periostin+ cells in periosteum (no. cells/periosteum). Scale bars: 20 μm (n = 5 mice/group). (C) Nestin-GFP+PDGFR-α+CD45–Ter119–CD31– PDCs and PDC-derived osteoblasts were treated with 10 ng/ml PDGF-BB or vehicle. Western blot (left panel) and qRT-PCR analysis (right panel) of periostin expression level (n = 5 mice). (D and E) Western blot (left panel) and qRT-PCR analysis (right panel) of periostin expression level in PDCs. Cells were treated with 10 ng/ml PDGF-BB or vehicle for the indicated times (D) or with the indicated doses of PDGF-BB or vehicle for 6 hours (E) (n = 5 mice). (F) Western blot analysis of the phosphorylation of PDGFR-β, PI3K, AKT, and CREB (n = 5 mice). (G) Representative images stained for p-CREB and α-Tubulin in PDC-derived osteoblasts. Scale bars: 10 μm (n = 5 mice). (H) Western blot (left panel) and qRT-PCR analysis (right panel) of periostin expression levels in PDC-derived osteoblasts. Cells were treated with 10 ng/ml PDGF-BB or vehicle in the presence or absence of various inhibitors, as indicated (n = 5 mice). (I) p-CREB binding sites on periostin promoter. (J) ChIP analysis of p-CREB on specific periostin promoter regions in the cells with PDGF-BB or vehicle treatment (n = 3 mice). Data are presented as mean ± SEM. *P < 0.05; **P < 0.01; NS, not significant as determined by 2-tailed Student t test.