Earliest phases of chondrogenesis are dependent upon angiogenesis during ectopic bone formation in mice

Bragdon, Beth; Lam, Stephanie; Aly, Sherif; Femia, Alexandra; Clark, Abigail H.; Hussein, Amira I.; Morgan, Elise F.; Gerstenfeld, Louis C.

doi:10.1016/j.bone.2017.04.002

Cited by 30 publications

(30 citation statements)

References 53 publications

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“…5A). Although VEGFA signaling has been shown to be important for chondrocyte survival and differentiation, (13,36,71) our UBC cKO full fracture calluses demonstrated elevated relative amounts of cartilage compared with controls, with chondrocytes that appeared hypertrophic at day 14 via morphology (Fig. 3B, C).…”

Section: Journal Of Bone and Mineral Researchmentioning

confidence: 86%

“…(15,22,(28)(29)(30) Therefore, VEGFA's role in promoting ossification following bone injury is thought to be caused by its role in supporting both angiogenesis and osteoblast function, two processes necessary for bone formation in vivo. (31)(32)(33)(34)(35) However, the nonspecific nature of anti-VEGFA treatments used to block bone repair in vivo (32,36,37) have not shed light on which cell types are critical sources of VEGFA for this process.…”

Section: Introductionmentioning

confidence: 99%

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VEGFA From Early Osteoblast Lineage Cells (Osterix+) Is Required in Mice for Fracture Healing

Buettmann

McKenzie

Migotsky

et al. 2019

Journal of Bone and Mineral Research

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Bone formation via intramembranous and endochondral ossification is necessary for successful healing after a wide range of bone injuries. The pleiotropic cytokine, vascular endothelial growth factor A (VEGFA) has been shown, via nonspecific pharmacologic inhibition, to be indispensable for angiogenesis and ossification following bone fracture and cortical defect repair. However, the importance of VEGFA expression by different cell types during bone healing is not well understood. We sought to determine the role of VEGFA from different osteoblast cell subsets following clinically relevant models of bone fracture and cortical defect. Ubiquitin C (UBC), Osterix (Osx), or Dentin matrix protein 1 (Dmp1) Cre‐ERT2 mice (male and female) containing floxed VEGFA alleles (VEGFAfl/fl) were either given a femur full fracture, ulna stress fracture, or tibia cortical defect at 12 weeks of age. All mice received tamoxifen continuously starting 2 weeks before bone injury and throughout healing. UBC Cre‐ERT2 VEGFAfl/fl (UBC cKO) mice, which were used to mimic nonspecific inhibition, had minimal bone formation and impaired angiogenesis across all bone injury models. UBC cKO mice also exhibited impaired periosteal cell proliferation during full fracture, but not stress fracture repair. Osx Cre‐ERT2 VEGFAfl/fl (Osx cKO) mice, but not Dmp1 Cre‐ERT2 VEGFAfl/fl (Dmp1 cKO) mice, showed impaired periosteal bone formation and angiogenesis in models of full fracture and stress fracture. Neither Osx cKO nor Dmp1 cKO mice demonstrated significant impairments in intramedullary bone formation and angiogenesis following cortical defect. These data suggest that VEGFA from early osteolineage cells (Osx+), but not mature osteoblasts/osteocytes (Dmp1+), is critical at the time of bone injury for rapid periosteal angiogenesis and woven bone formation during fracture repair. Whereas VEGFA from another cell source, not from the osteoblast cell lineage, is necessary at the time of injury for maximum cortical defect intramedullary angiogenesis and osteogenesis. © 2019 American Society for Bone and Mineral Research.

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Section: Journal Of Bone and Mineral Researchmentioning

confidence: 86%

Section: Introductionmentioning

confidence: 99%

VEGFA From Early Osteoblast Lineage Cells (Osterix+) Is Required in Mice for Fracture Healing

Buettmann

McKenzie

Migotsky

et al. 2019

Journal of Bone and Mineral Research

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“…In the callus, new vessel formation provides a nutrient supply for cells, facilitates removal of cartilage by the delivery of osteoclast precursors, and contributes to healing by producing mediators . Vascular cells produce a number of paracrine factors that impact chondrocytes and osteoblasts and affect bone production and the formation and maintenance of bone marrow . An important angiogenic factor is vascular endothelial growth factor‐A (VEGFA), which is produced by mesenchymal stem cells, vascular cells, chondrocytes and osteoblasts …”

Section: Introductionmentioning

confidence: 99%

“…(11) Vascular cells produce a number of paracrine factors that impact chondrocytes and osteoblasts and affect bone production and the formation and maintenance of bone marrow. (12)(13)(14) An important angiogenic factor is vascular endothelial growth factor-A (VEGFA), which is produced by mesenchymal stem cells, vascular cells, chondrocytes and osteoblasts. (1,15,16) FOXO1 is a forkhead box-O (FOXO) transcription factor that is expressed in chondrocytes and has been shown to modulate downstream gene targets in chondrocytes or chondrocyte activity.…”

Section: Introductionmentioning

confidence: 99%

Chondrocytes Promote Vascularization in Fracture Healing Through a FOXO1-Dependent Mechanism

Zhang¹,

Feinberg²,

Alharbi³

et al. 2018

Journal of Bone and Mineral Research

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Chondrocytes play an essential role in fracture healing by producing cartilage, which forms an anlage for endochondral ossification that stabilizes the healing fracture callus. More recently it has been appreciated that chondrocytes have the capacity to produce factors that may affect the healing process. We examined the role of chondrocytes in angiogenesis during fracture healing and the role of the transcription factor forkhead box‐O 1 (FOXO1), which upregulates wound healing in soft tissue. Closed fractures were induced in experimental mice with lineage‐specific FOXO1 deletion by Cre recombinase under the control of a collagen‐2α1 promoter element (Col2α1Cre+FOXO1L/L) and Cre recombinase negative control littermates containing flanking loxP sites (Col2α1Cre–FOXO1L/L). Experimental mice had significantly reduced CD31+ new vessel formation. Deletion of FOXO1 in chondrocytes in vivo suppressed the expression of vascular endothelial growth factor‐A (VEGFA) at both the protein and mRNA levels. Overexpression of FOXO1 in chondrocytes in vitro increased VEGFA mRNA levels and VEGFA transcriptional activity whereas silencing FOXO1 reduced it. Moreover, FOXO1 interacted directly with the VEGFA promoter and a deacetylated FOXO1 mutant enhanced VEGFA expression whereas an acetylated FOXO1 mutant did not. Lastly, FOXO1 knockdown by siRNA significantly reduced the capacity of chondrocytes to stimulate microvascular endothelial cell tube formation in vitro. The results indicate that chondrocytes play a key role in angiogenesis which is FOXO1 dependent and that FOXO1 in chondrocytes regulates a potent angiogenic factor, VEGFA. These studies provide new insight into fracture healing given the important role of vessel formation in the fracture repair process. © 2018 American Society for Bone and Mineral Research.

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“…RNA extraction was performed by tissue dissociation and chemical extraction as previously described (Bragdon et al, 2017). Briefly, samples were snap frozen in QIAzol R Lysis Reagent and lysed with the Qiagen R Tissue Lyser II.…”

Section: Rna Extraction and Quantitative Reverse Transcriptase Pcrmentioning

confidence: 99%

An in vivo Comparison Study Between Strontium Nanoparticles and rhBMP2

Montagna

Cristofaro

Fassina

et al. 2020

Front. Bioeng. Biotechnol.

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The osteoinductive property of strontium was repeatedly proven in the last decades. Compelling in vitro data demonstrated that strontium hydroxyapatite nanoparticles exert a dual action, by promoting osteoblasts-driven matrix secretion and inhibiting osteoclasts-driven matrix resorption. Recombinant human bone morphogenetic protein 2 (rhBMP2) is a powerful osteoinductive biologic, used for the treatment of vertebral fractures and critically-sized bone defects. Although effective, the use of rhBMP2 has limitations due its recombinant morphogen nature. In this study, we examined the comparison between two osteoinductive agents: rhBMP2 and the innovative strontium-substituted hydroxyapatite nanoparticles. To test their effectiveness, we independently loaded Gelfoam sponges with the two osteoinductive agents and used the sponges as agent-carriers. Gelfoam are FDA-approved biodegradable medical devices used as delivery system for musculoskeletal defects. Their porous structure and spongy morphology make them attractive in orthopedic field. The abiotic characterization of the loaded sponges, involving ion release pattern and structure investigation, was followed by in vivo implantation onto the periosteum of healthy mice and comparison of the effects induced by each implant was performed. Abiotic analysis demonstrated that strontium was continuously released from the sponges over 28 days with a pattern similar to rhBMP2. Histological observations and gene expression analysis showed stronger endochondral ossification elicited by strontium compared to rhBMP2. Osteoclast activity was more inhibited by strontium than by rhBMP2. These results demonstrated the use of sponges loaded with strontium nanoparticles as potential bone grafts might provide better outcomes for complex fractures. Strontium nanoparticles are a novel and effective non-biologic treatment for bone injuries and can be used as novel powerful therapeutics for bone regeneration.

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Earliest phases of chondrogenesis are dependent upon angiogenesis during ectopic bone formation in mice

Cited by 30 publications

References 53 publications

VEGFA From Early Osteoblast Lineage Cells (Osterix+) Is Required in Mice for Fracture Healing

VEGFA From Early Osteoblast Lineage Cells (Osterix+) Is Required in Mice for Fracture Healing

Chondrocytes Promote Vascularization in Fracture Healing Through a FOXO1-Dependent Mechanism

An in vivo Comparison Study Between Strontium Nanoparticles and rhBMP2

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