Gli1 identifies osteogenic progenitors for bone formation and fracture repair

• Published in: Nature communications Vol. 8; no. 1; pp. 2043 - 12
• Main Authors: Shi, Yu, He, Guangxu, Lee, Wen-Chih, McKenzie, Jennifer A, Silva, Matthew J, Long, Fanxin
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 11.12.2017; Nature Publishing Group UK; Nature Portfolio
• Subjects: Adipocytes; Adipogenesis; Adipose tissue; Animals; beta Catenin - genetics; beta Catenin - metabolism; Biocompatibility; Biomedical materials; Bone growth; Bone healing; Bone marrow; Cancellous bone; CD44 antigen; Cells (biology); Chondrocytes; Chondrocytes - cytology; Chondrocytes - metabolism; Continuous production; Fetuses; Fracture Healing; Fractures; Fractures, Bone - genetics; Fractures, Bone - metabolism; Growth plate; Mesenchymal Stem Cells - cytology; Mesenchymal Stem Cells - metabolism; Mesenchyme; Mice; Mice, Knockout; Mice, Transgenic; Osteoblastogenesis; Osteoblasts; Osteoblasts - cytology; Osteoblasts - metabolism; Osteogenesis; Osteopenia; Osteoprogenitor cells; Receptor, Platelet-Derived Growth Factor alpha - genetics; Receptor, Platelet-Derived Growth Factor alpha - metabolism; Repair; Ribonucleic acid; RNA; Signaling; Stromal cells; Vitamin D; Zinc Finger Protein GLI1 - genetics; Zinc Finger Protein GLI1 - metabolism; β-Catenin
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-017-02171-2

Bone formation in mammals requires continuous production of osteoblasts throughout life. A common molecular marker for all osteogenic mesenchymal progenitors has not been identified. Here, by lineage-tracing experiments in fetal or postnatal mice, we discover that Gli1 cells progressively produce osteoblasts in all skeletal sites. Most notably, in postnatal growing mice, the Gli1 cells residing immediately beneath the growth plate, termed here "metaphyseal mesenchymal progenitors" (MMPs), are essential for cancellous bone formation. Besides osteoblasts, MMPs also give rise to bone marrow adipocytes and stromal cells in vivo. RNA-seq reveals that MMPs express a number of marker genes previously assigned to mesenchymal stem/progenitor cells, including CD146/Mcam, CD44, CD106/Vcam1, Pdgfra, and Lepr. Genetic disruption of Hh signaling impairs proliferation and osteoblast differentiation of MMPs. Removal of β-catenin causes MMPs to favor adipogenesis, resulting in osteopenia coupled with increased marrow adiposity. Finally, postnatal Gli1 cells contribute to both chondrocytes and osteoblasts during bone fracture healing. Thus Gli1 marks mesenchymal progenitors responsible for both normal bone formation and fracture repair.