PDGF Modulates BMP2‐Induced Osteogenesis in Periosteal Progenitor Cells

Wang, Xi; Matthews, Brya G.; Yu, Jungeun; Novak, Sanja; Grčević, Danka; Sanjay, Archana; Kalajzić, Ivo

doi:10.1002/jbm4.10127

Cited by 39 publications

(51 citation statements)

References 42 publications

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“…Mouse periosteal cells were isolated from either WT or Osterix-conditional YAP/TAZ deficient (YAP cKOi ;TAZ cKOi ) femurs on 4 dpf and cultured at 37°C and 5% O2, as described previously (29) . Briefly, mice were anesthetized by carbon dioxide inhalation and euthanized via cervical dislocation.…”

Section: Periosteal Cell Isolation and Osteogenic Differentiationmentioning

confidence: 99%

“…To elucidate if inducible YAP/TAZ deletion regulated periosteal osteoprogenitor differentiation, we isolated activated periosteal progenitor cells at 4 dpf ( Fig. 7G) (28,29) . Following culture for 21 days in osteogenic media, inducible, Osterix-conditional YAP/TAZ deletion reduced mineral deposition stained with Alizarin Red (Fig.…”

Section: Inducible Osterix-conditional Yap/taz Deletion Reduced Periomentioning

confidence: 99%

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YAP and TAZ promote periosteal osteoblast precursor expansion and differentiation for fracture repair

Kegelman

Nijsure

Moharrer

et al. 2020

Preprint

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In response to bone fracture, periosteal progenitor cells proliferate, expand, and differentiate to form cartilage and bone in the fracture callus. These cellular functions require the coordinated activation of multiple transcriptional programs, and the transcriptional regulators Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) regulate osteochondroprogenitor activation during endochondral bone development.However, recent observations raise important distinctions between the signaling mechanisms used to control bone morphogenesis and repair. Here, we tested the hypothesis that YAP and TAZ regulate osteochondroprogenitor activation during endochondral bone fracture healing. Constitutive YAP and/or TAZ deletion from Osterixexpressing cells impaired both cartilage callus formation and subsequent mineralization. However, this could be explained either by direct defects in osteochondroprogenitor differentiation after fracture, or by developmental deficiencies in the progenitor cell pool prior to fracture. Consistent with the second possibility, we found that developmental YAP/TAZ deletion produced long bones with impaired periosteal thickness and cellularity. Therefore, to remove the contributions of developmental history, we next generated adult onset-inducible knockout mice (using Osx1-Cre tetOff ) in which YAP and TAZ were deleted prior to fracture, but after normal development. Adult onset-induced YAP/TAZ deletion had no effect on cartilaginous callus formation, but impaired bone formation at 14 days post-fracture (dpf). Earlier, at 4 dpf, adult onset-induced YAP/TAZ deletion impaired the proliferation and expansion of osteoblast precursor cells located in the shoulder of the callus. Further, activated periosteal cells isolated from this region at 4 dpf exhibited impaired osteogenic differentiation in vitro upon YAP/TAZ deletion. Finally, confirming the effects on osteoblast function in vivo, adult onset-induced YAP/TAZ deletion impaired bone formation in the callus shoulder at 7 dpf, prior to the initiation of endochondral ossification. Together, these data show that YAP and TAZ promote the expansion and differentiation of periosteal osteoblast precursors to accelerate bone fracture healing.

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Section: Periosteal Cell Isolation and Osteogenic Differentiationmentioning

confidence: 99%

Section: Inducible Osterix-conditional Yap/taz Deletion Reduced Periomentioning

confidence: 99%

YAP and TAZ promote periosteal osteoblast precursor expansion and differentiation for fracture repair

Kegelman

Nijsure

Moharrer

et al. 2020

Preprint

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“…Interestingly, of the major growth factor receptors involved in fracture healing, PI3K can only directly bind PDGF-receptors (PDGFRs). Additionally, it has been recently published that a majority of murine periosteal cells post-fracture express the homodimer PDGFRβ or the heterodimer PDGFRα/β, while few express PDGFRα alone [20]. While a direct interaction between PI3K and PDGFRs is critical for skeletal development [21–23], this requirement in the context of periosteal response to fracture healing has never been studied.…”

Section: Introductionmentioning

confidence: 99%

A PDGFRβ-PI3K signaling axis mediates periosteal cell activation during fracture healing

Doherty

Wang

et al. 2019

PLoS ONE

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Insufficient and delayed fracture healing remain significant public health problems with limited therapeutic options. Phosphoinositide 3-kinase (PI3K) signaling, a major pathway involved in regulation of fracture healing, promotes proliferation, migration, and differentiation of osteoprogenitors. We have recently reported that knock-in mice with a global increase in PI3K signaling (gCblYF) show enhanced femoral fracture healing characterized by an extraordinary periosteal response to injury. Interestingly, of all growth factor receptors involved in fracture healing, PI3K directly binds only to PDGFR. Given these findings, we hypothesized a PDGFR-PI3K interaction is necessary for mediating robust periosteal cell activation following fracture. In this study, we isolated primary periosteal cells from gCblYF mice to analyze cross-talk between the PDGFRβ and PI3K signaling pathways. We found PDGFRβ signaling contributes to robust Akt phosphorylation in periosteal cells in comparison with other growth factor signaling pathways. Additionally, we performed femoral fractures on gCblYF mice with a conditional removal of PDGFRβ in mesenchymal progenitors using inducible alpha smooth muscle actin (αSMA) CreERT2 mice. Our studies showed that depletion of PDGFRβ signaling within these progenitors in the early phase of fracture healing significantly abrogates PI3K-mediated periosteal activation and proliferation three days after fracture. Combined, these results suggest that PDGFRβ signaling through PI3K is necessary for robust periosteal activation in the earliest phases of fracture healing.

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“…We used two murine strains of MSCs in the current study to investigate the co-expression GM MSCs. It is been reported that PDGF-BB enhanced the proliferation of several cell types including endothelial cells [6] and populations of MSCs [31,32]. By studying the cell proliferation and cell viability, the results showed that the presence of PDGF-BB from GM MSCs or exogenous PDGF-BB protein in BALB/c MSCs increased cell proliferation and cell viability.…”

Section: Discussionmentioning

confidence: 91%

“…Recombinant human PDGF-BB (rhPDGF-BB) in combination with an osteoinductive tricalcium phosphate (TCP)-collagen matrix has been applied clinically in ankle and hindfoot arthrodesis, and was shown to be a safe and effective alternative to autograft [33,34]. In vitro and in vivo studies have previously demonstrated the capacity for PDGF-BB to facilitate osteogenesis by stem cells [7,31,32]. Furthermore, PDGF-BB secreted by preosteoclasts induced angiogenesis during coupling with osteogenesis [6].…”

Section: Discussionmentioning

confidence: 99%

PDGF-BB and IL-4 co-overexpression is a potential strategy to enhance mesenchymal stem cell-based bone regeneration

Zhang

Utsunomiya

et al. 2020

Preprint

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Background Mesenchymal stem cell (MSC)-based therapy has the potential for immunomodulation and enhancement of tissue regeneration. Genetically modified (GM) MSCs that over-express specific cytokines, growth factors or chemokines have shown great promise in pre-clinical studies. In this regard, the anti-inflammatory cytokine Interleukin (IL)-4 converts pro-inflammatory M1 macrophages into an anti-inflammatory M2 phenotype; M2 macrophages could potentially enhance osteogenesis by MSC lineage cells. However, IL-4 inhibits osteogenesis during the acute inflammatory period. Platelet-derived growth factor (PDGF)-BB has been shown to enhance osteogenesis of MSCs with a dose-dependent effect. Methods In this study, we generated a lentiviral vector that produces PDGF-BB under a weak promoter (phosphoglycerate kinase, PGK) and lentiviral vector producing IL-4 under a strong promoter (cytomegalovirus, CMV). We infected the MSCs with the PDGF-BB and IL-4-producing lentiviral vectors separately or in combination to investigate protein expression, cell proliferation and viability as well as the capability for osteogenesis. Results Co-overexpression of PDGF-BB and IL-4 was observed in the co-infected MSCs and shown to enhance cell proliferation and viability, and osteogenesis compared to IL-4 overexpressing MSCs alone. Conclusions Thus, overexpression of both PDGF-BB and IL-4 may be a potential strategy to facilitate osteogenesis in scenarios of both acute and chronic inflammation.

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PDGF Modulates BMP2‐Induced Osteogenesis in Periosteal Progenitor Cells

Cited by 39 publications

References 42 publications

YAP and TAZ promote periosteal osteoblast precursor expansion and differentiation for fracture repair

YAP and TAZ promote periosteal osteoblast precursor expansion and differentiation for fracture repair

A PDGFRβ-PI3K signaling axis mediates periosteal cell activation during fracture healing

PDGF-BB and IL-4 co-overexpression is a potential strategy to enhance mesenchymal stem cell-based bone regeneration

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