FGFR3 in Periosteal Cells Drives Cartilage-to-Bone Transformation in Bone Repair

Julien, Anaïs; Perrin, Simon; Lageneste, Oriane Duchamp de; Carvalho, Caroline; Bensidhoum, Morad; Legeai-Mallet, Laurence; Colnot, Céline

doi:10.1016/j.stemcr.2020.08.005

Cited by 28 publications

(29 citation statements)

References 33 publications

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“…In a stabilized fracture model, mice lacking Fgfr3 had increased cartilaginous callus, accelerated endochondral ossification, and callus mineralization (Xie et al, 2017). In contrast, mice expressing activating mutations in Fgfr3 in periosteal cells had impaired bone healing attributed to a failure of cartilage-to-bone transformation that is required for remodeling of the fracture callus (Julien et al, 2020). Fgfr3 Ach mice express activated FGFR3 (p.G380R) in chondrocytes driven by the Col2A1 promoter (Naski et al, 1998).…”

Section: Fgf Signaling In Bone Repairmentioning

confidence: 99%

New developments in the biology of fibroblast growth factors

Ornitz

Itoh

2022

WIREs Mechanisms of Disease

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The fibroblast growth factor (FGF) family is composed of 18 secreted signaling proteins consisting of canonical FGFs and endocrine FGFs that activate four receptor tyrosine kinases (FGFRs 1-4) and four intracellular proteins (intracellular FGFs or iFGFs) that primarily function to regulate the activity of voltagegated sodium channels and other molecules. The canonical FGFs, endocrine FGFs, and iFGFs have been reviewed extensively by us and others. In this review, we briefly summarize past reviews and then focus on new developments in the FGF field since our last review in 2015. Some of the highlights in the past 6 years include the use of optogenetic tools, viral vectors, and inducible transgenes to experimentally modulate FGF signaling, the clinical use of small molecule FGFR inhibitors, an expanded understanding of endocrine FGF signaling, functions for FGF signaling in stem cell pluripotency and differentiation, roles for FGF signaling in tissue homeostasis and regeneration, a continuing elaboration of mechanisms of FGF signaling in development, and an expanding appreciation of roles for FGF signaling in neuropsychiatric diseases.

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Section: Fgf Signaling In Bone Repairmentioning

confidence: 99%

New developments in the biology of fibroblast growth factors

Ornitz

Itoh

2022

WIREs Mechanisms of Disease

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“…Bone regeneration begins with an inflammatory response, the formation of a fibrous callus and the deposition of cartilage and bone tissues that are then remodeled to reconstitute the initial shape and function of the injured bone. Skeletal stem/progenitor cells activated by the bone injury differentiate into chondrocytes preferentially in the center of the callus where endochondral ossification occurs through the replacement of cartilage by bone 1 , 2 . At the callus periphery where bone forms via intramembranous ossification, skeletal stem/progenitor cells differentiate directly into osteoblasts.…”

Section: Introductionmentioning

confidence: 99%

Direct contribution of skeletal muscle mesenchymal progenitors to bone repair

et al. 2021

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Bone regenerates by activation of tissue resident stem/progenitor cells, formation of a fibrous callus followed by deposition of cartilage and bone matrices. Here, we show that mesenchymal progenitors residing in skeletal muscle adjacent to bone mediate the initial fibrotic response to bone injury and also participate in cartilage and bone formation. Combined lineage and single-cell RNA sequencing analyses reveal that skeletal muscle mesenchymal progenitors adopt a fibrogenic fate before they engage in chondrogenesis after fracture. In polytrauma, where bone and skeletal muscle are injured, skeletal muscle mesenchymal progenitors exhibit altered fibrogenesis and chondrogenesis. This leads to impaired bone healing, which is due to accumulation of fibrotic tissue originating from skeletal muscle and can be corrected by the anti-fibrotic agent Imatinib. These results elucidate the central role of skeletal muscle in bone regeneration and provide evidence that skeletal muscle can be targeted to prevent persistent callus fibrosis and improve bone healing after musculoskeletal trauma.

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“…Platelet‐derived growth factor‐BB, secreted by pre‐osteoclasts, can induce type H vessels during bone modeling and remodeling 27 . FGFR3 in periosteal cells is a crucial regulator of the cartilage‐to‐bone transformation process for bone repair 28 . STING signaling pathway may directly act on these cells, like osteoclastogenesis, 29 thereby influencing angiogenesis progress.…”

Section: Discussionmentioning

confidence: 99%

“…27 FGFR3 in periosteal cells is a crucial regulator of the cartilage-to-bone transformation process for bone repair. 28 STING signaling pathway may directly act on these cells, like osteoclastogenesis, 29 thereby influencing angiogenesis progress. Nevertheless, this requires further investigation.…”

Section: Sting Inhibition Promoted Angiogenesis In Vitromentioning

confidence: 99%

STING inhibition accelerates the bone healing process while enhancing type H vessel formation

Chen

Sun

et al. 2021

The FASEB Journal

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The stimulator of interferon genes (STING), one of the critical factors of innate immunity, is indicated to be closely related to angiogenesis. This study examined STING's role in angiogenesis and the formation of type H vessels, a specific subtype of bone vessels that regulates bone healing. Different concentrations of 2′,3′-cGAMP, and H-151 or C-176 were applied to activate or inhibit STING, respectively. Human umbilical vein endothelial cells were used to examine the effect of STING on angiogenesis in vitro; cell viability, cell migration, and quantitative real-time polymerase chain reactions were performed. Also, the metatarsal experiment was applied as ex vivo proof. Bone fracture or defect mice models were used to examine the effect of STING in vivo; the bone healing process was evaluated by radiography weekly and by μCT on the 14th day after surgery. The formation of type H vessels (CD31 hi Emcn hi endothelial cells) and osteogenesis (OCN-positive cells) was assessed using the cryosection and paraffin section.STING activation inhibited angiogenesis both in vitro and ex vivo and slowed down the bone healing process in vivo. Histological analysis showed an increased callus formation, fewer type H vessels, and almost no callus mineralization in the STING activation group compared to the control group. By contrast, H-151 (a hsSTING inhibitor) promoted angiogenesis at a low dose. Moreover, inhibition of mmSTING by C-176 enhanced type H vessels' formation, implying osteogenesis promotion in bone healing (higher bone volume density and more OCN-positive cells). Our data suggested that STING inhibition accelerates the bone healing process while enhancing type H vessel formation.

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FGFR3 in Periosteal Cells Drives Cartilage-to-Bone Transformation in Bone Repair

Cited by 28 publications

References 33 publications

New developments in the biology of fibroblast growth factors

New developments in the biology of fibroblast growth factors

Direct contribution of skeletal muscle mesenchymal progenitors to bone repair

STING inhibition accelerates the bone healing process while enhancing type H vessel formation

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