Gli1 identifies osteogenic progenitors for bone formation and fracture repair

Shi, Yu; He, Guangxu; Lee, Wen‐Chih; McKenzie, Janice M.; Silva, Matthew J.; Long, Fanxin

doi:10.1038/s41467-017-02171-2

Cited by 264 publications

(334 citation statements)

References 40 publications

(35 reference statements)

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“…Recent studies have used inducible Cre reporter mice to track osteoblast lineage cells in skeletal development and fracture repair . Osteoblasts are derived from mesenchymal progenitor cells, which differentiate into osteoprogenitors (or preosteoblasts), and then mature osteoblasts .…”

Section: Introductionmentioning

confidence: 99%

“…Recent studies have used inducible Cre reporter mice to track osteoblast lineage cells in skeletal development and fracture repair. (10)(11)(12)(13)(14)(15) Osteoblasts are derived from mesenchymal progenitor cells, which differentiate into osteoprogenitors (or preosteoblasts), and then mature osteoblasts. (16) The cells of the osteoblast lineage responsible for bone formation can be well-visualized on the periosteal surface of the tibia.…”

Section: Introductionmentioning

confidence: 99%

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Proliferation and Activation of Osterix‐Lineage Cells Contribute to Loading‐Induced Periosteal Bone Formation in Mice

Zannit

Silva

2019

JBMR Plus

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Mechanical loading stimulates bone formation. Bone‐lining‐cell activation and cell proliferation have been implicated in this process. However, the origin of osteoblasts that form bone following mechanical stimulation remains unknown. Our objective was to identity the contributions of activation, differentiation, and proliferation of osteoblast lineage cells to loading‐induced periosteal bone formation. Tamoxifen‐inducible Osx‐Cre‐ERT2;Ai9/TdTomato reporter mice (male and female) were aged to young adult (5 months) and middle age (12 months), and were administered tamoxifen for 5 consecutive days to label osterix‐lineage cells. Following a 3‐week clearance period, mice were subjected to five consecutive bouts of unilateral axial tibial compression. We first confirmed this protocol stimulated an increase in periosteal bone formation that was primarily lamellar apposition. Next, mice received 5‐bromo‐2′‐deoxyuridine (BrdU) in their drinking water daily to label proliferating cells; calcein was given to label active mineralizing surfaces. Tibias were harvested after the fifth loading day and processed for frozen undecalcified histology. The middiaphyseal periosteal surface in the region of peak bone formation was analyzed. Histology revealed both nonloaded and loaded tibias were covered in osterix positive (Osx+) cells on the periosteal surface of both 5‐ and 12‐month‐old animals. There was a significant increase in the mineralizing surface (calcein+) covered with Osx+ cells in loaded versus control limbs. Furthermore, nearly all of the mineralizing surfaces (>95%) were lined with Osx+ cells. We also observed approximately 30% of Osx+ cells were also BrdU+, indicating they arose via proliferation. These results show that following mechanical loading, pre‐existing cells of the Osx lineage cover the vast majority of surfaces where there is active loading‐induced bone formation, and a portion of these cells proliferated in the 5‐day loading period. We conclude the initial anabolic response after mechanical loading is based on the activation and proliferation of Osx lineage cells, not the differentiation of progenitor cells. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Proliferation and Activation of Osterix‐Lineage Cells Contribute to Loading‐Induced Periosteal Bone Formation in Mice

Zannit

Silva

2019

JBMR Plus

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“…SSCs are endogenous stem cells in skeletal tissues. Increasing evidence has demonstrated that SSCs are closely involved in bone homeostasis . These cells respond to tissue stress and migrate to sites of injury, supplying new osteoblasts during fracture healing .…”

Section: Discussionmentioning

confidence: 99%

“…Skeletal stem cells (SSCs) have been defined as tissue-specific stem cells in skeletons and have been demonstrated to play pivotal roles in maintaining and repairing skeletal tissues. [1][2][3][4][5][6][7][8] By determining unique cell surface maker profiles and performing rigorous functional characterizations, previous researchers have identified a number of subpopulations of stem and progenitor cells from skeletal tissues, including bone, cartilage, and tendon. [1][2][3][4][5][6][7][8] Chan et al showed the presence of CD45-Ter119-Tie2-AlphaV+ multipotent stem cells in murine bone and identified cells and factors in the SSC niches that regulate its activity.…”

Section: Introductionmentioning

confidence: 99%

Skeletal stem cell-mediated suppression on inflammatory osteoclastogenesis occurs via concerted action of cell adhesion molecules and osteoprotegerin

Ding

Wang

et al. 2019

Stem Cells Translational Medicine

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In the current study, we investigated how skeletal stem cells (SSCs) modulate inflammatory osteoclast (OC) formation and bone resorption. Notably, we found that intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and osteoprotegerin (OPG) play a synergistic role in SSC-mediated suppression of inflammatory osteoclastogenesis. The effect of SSCs on inflammatory osteoclastogenesis was investigated using a lipopolysaccharide-induced mouse osteolysis model in vivo and human osteoarthritis synovial fluid (OASF) in vitro. OC formation was determined by tartrate-resistant acid phosphatase staining. Bone resorption was evaluated by microcomputerized tomography, serum C-terminal telopeptide assay, and pit formation assay. The expression of ICAM-1, VCAM-1, and OPG in SSCs and their contribution to the suppression of osteoclastogenesis were determined by flow cytometry or enzyme linked immunosorbent assay. Gene modification, neutralization antibodies, and tumor necrosis factor-α knockout mice were used to further explore the mechanism. The results demonstrated that SSCs remarkably inhibited inflammatory osteoclastogenesis in vivo and in vitro. Mechanistically, inflammatory OASF stimulated ICAM-1 and VCAM-1 expression as well as OPG secretion by SSCs. In addition, ICAM-1 and VCAM-1 recruited CD11b + OC progenitors to proximity with SSCs, which strengthened the inhibitory effects of SSC-derived OPG on osteoclastogenesis. Furthermore, it was revealed that tumor necrosis factor α is closely involved in the suppressive effects. In summary, SSCs express a higher level of ICAM-1 and VCAM-1 and produce more OPG in inflammatory microenvironments, which are sufficient to inhibit osteoclastogenesis in a "capture and educate" manner. These results may represent a synergistic mechanism to prevent bone erosion during joint inflammation by SSCs.

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“…Ihh regulates osteogenic differentiation by modulating Runx2‐controlled osteoblastic cell fates . Gli1‐positive cells located beneath the growth plate contribute to both chondrocytes and osteoblasts during bone fracture healing . Ihh signaling also plays a critical role in osteoblast differentiation by regulating Runx2 and Runx3 activity .…”

Section: Introductionmentioning

confidence: 99%

Identification of Gli1‐interacting proteins during simvastatin‐stimulated osteogenic differentiation of bone marrow mesenchymal stem cells

Chi

Fan

et al. 2019

J of Cellular Biochemistry

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Simvastatin has been shown to promote osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). Our study aimed to illuminate the underlying mechanism, with a specific focus on the role of Hedgehog signaling in this process. BMSCs cultured with or without 10−7 mol/L simvastatin were subjected to evaluation of osteogenic differentiation capacity. Osteogenic markers such as type 1 collagen (COL1) and osteocalcin (OCN), as well as key molecules of Hedgehog signaling molecules, were examined by Western blot and real‐time polymerase chain reaction (PCR). Co‐immunoprecipitation and mass spectrometry assays were applied to screen for Gli1‐interacting proteins. Cyclopamine (Cpn) was used as a Hedgehog signaling inhibitor. Our results indicated that simvastatin increased alkaline phosphatase (ALP) activity; mineralization of extracellular matrix; mRNA expression of ALP, COL1, and OCN; and expression and nuclear translocation of Gli1. Contrasting effects were observed in Cpn‐exposed groups, but were partially rescued by the simvastatin treatment. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses indicated that Gli1‐interacting proteins were primarily associated with mitogen‐activated protein kinase (MAPK) (P = 7.04E−04), hippo, insulin, and glucagon signaling. Further, hub genes identified by protein‐protein interaction network analysis included Gli1‐interacting proteins such as Ppp2r1a, Rac1, Etf1, and XPO1/CRM1. In summary, the current study showed that the mechanism by which simvastatin stimulates osteogenic differentiation of BMSCs involves activation of Hedgehog signaling, as indicated by interactions with Gli1 and, most notably, the MAPK signaling pathway.

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Gli1 identifies osteogenic progenitors for bone formation and fracture repair

Cited by 264 publications

References 40 publications

Proliferation and Activation of Osterix‐Lineage Cells Contribute to Loading‐Induced Periosteal Bone Formation in Mice

Proliferation and Activation of Osterix‐Lineage Cells Contribute to Loading‐Induced Periosteal Bone Formation in Mice

Skeletal stem cell-mediated suppression on inflammatory osteoclastogenesis occurs via concerted action of cell adhesion molecules and osteoprotegerin

Identification of Gli1‐interacting proteins during simvastatin‐stimulated osteogenic differentiation of bone marrow mesenchymal stem cells

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