Periodontal ligament fibroblasts as a cell model to study osteogenesis and osteoclastogenesis in fibrodysplasia ossificans progressiva

Vries, Teun J. de; Schoenmaker, Ton; Micha, Dimitra; Hogervorst, Jolanda M. A.; Bouskla, Siham; Forouzanfar, Tim; Pals, Gerard; Netelenbos, Coen; Eekhoff, Elisabeth M. W.; Bravenboer, Nathalie

doi:10.1016/j.bone.2017.07.007

Cited by 30 publications

(39 citation statements)

References 31 publications

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“…Therefore, studies were often based on overexpression strategies that may result in experimental artifacts. Other approaches have been pursued, including the collection of stem cells from human exfoliated deciduous teeth (SHED), or fibroblasts isolated from either the skin or periodontal ligaments . In parallel, different groups have engineered a number of FOP animal models.…”

Section: Discussionmentioning

confidence: 99%

“…Despite the recent generation of induced pluripotent stem cell (iPSC) lines from FOP somatic tissues in past years, the establishment and maintenance of such lines remains time‐ and resource‐consuming, and is restricted to groups with expertise in iPSC technology. Therefore, new model systems making use of different cell types are progressively arising …”

Section: Introductionmentioning

confidence: 99%

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Development of Macrocycle Kinase Inhibitors for ALK2 Using Fibrodysplasia Ossificans Progressiva‐Derived Endothelial Cells

Sánchez‐Duffhues

Williams

Benderitter³

et al. 2019

JBMR Plus

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Fibrodysplasia ossificans progressiva (FOP) is an extremely rare congenital form of heterotopic ossification (HO), caused by heterozygous mutations in the activin A type I receptor (ACVR1), that encodes the bone morphogenetic protein (BMP) type I receptor ALK2. These mutations enable ALK2 to induce downstream signaling in response to activins, thereby turning them into bone‐inducing agents. To date, there is no cure for FOP. The further development of FOP patient‐derived models may contribute to the discovery of novel biomarkers and therapeutic approaches. Nevertheless, this has traditionally been a challenge, as biopsy sampling often triggers HO. We have characterized peripheral blood‐derived endothelial colony‐forming cells (ECFCs) from three independent FOP donors as a new model for FOP. FOP ECFCs are prone to undergo endothelial‐to‐mesenchymal transition and exhibit increased ALK2 downstream signaling and subsequent osteogenic differentiation upon stimulation with activin A. Moreover, we have identified a new class of small molecule macrocycles with potential activity against ALK2 kinase. Finally, using FOP ECFCs, we have selected OD36 and OD52 as potent inhibitors with excellent kinase selectivity profiles that potently antagonize mutant ALK2 signaling and osteogenic differentiation. We expect that these results will contribute to the development of novel ALK2 clinical candidates for the treatment of FOP. © 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: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Development of Macrocycle Kinase Inhibitors for ALK2 Using Fibrodysplasia Ossificans Progressiva‐Derived Endothelial Cells

Sánchez‐Duffhues

Williams

Benderitter³

et al. 2019

JBMR Plus

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“… Each number behind the cell type refers to a unique donor: From 5 individuals, 7 primary cell cultures were retrieved from liquid nitrogen and used in the current experiments …”

Section: Methodsmentioning

confidence: 99%

Effects of L‐PRF and A‐PRF+ on periodontal fibroblasts in in vitro wound healing experiments

Pitzurra

Jansen

Vries

et al. 2019

J of Periodontal Research

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Objective To determine whether leukocyte‐platelet‐rich fibrin (L‐PRF) and advanced platelet‐rich fibrin (A‐PRF+) differ in their in vitro capacity to induce proliferation and migration of periodontal fibroblasts. Background L‐PRF and A‐PRF + are autologous materials used in periodontal regenerative surgery. They derive from blood from patients, but have different characteristics. The literature is controversial regarding the effects of the two PRF preparations on periodontal tissue fibroblasts. Materials and methods L‐PRF and A‐PRF + membranes were prepared from eight patients and incubated in 3 mL of culture medium for 2 days. Gingival fibroblasts (G‐F) and periodontal ligament fibroblast (PDL‐F) primary cells were retrieved from 7 donors. These cells were pre‐cultured for 1 day in wound healing experiment plates leaving a gap of 500 ± 50 µm in a concentration of 3.3 x 105 cells/mL. 70 µL of the cell suspension was placed in each half of the well. Thereafter, the pre‐cultured L‐PRF and A‐PRF + supernatants were added to the experimental plates, and the fibroblasts were incubated for another 24 h. Medium alone (NEG) and fibroblast growth factor II (FGF) were used as controls. Subsequently, cell migration was registered for 24 h with live cell imaging in a time frame microscope at 5% CO2 in air at 37°C. Images were analyzed using ImageJ. Cell proliferation and cell viability were measured. Results L‐PRF and A‐PRF + induced higher cell proliferation than FGF and NEG. Both A‐PRF + and L‐PRF induced significant faster artificial wound closure than controls. Both PRF conditioned media induced faster cell migration in the initial phase (P < .01), but in the stoppage phase, the induced migration was higher for the A‐PRF+, compared with L‐PRF (P < .01). Conclusion L‐PRF and A‐PRF + have a stimulatory effect on migration and proliferation of periodontal fibroblasts, and artificial wound closure was longer sustained by A‐PRF + than L‐PRF.

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“…These processes are tightly controlled and coupled together to ensure an overall bone homeostasis . Especially cells that are attached to teeth after tooth extraction, are enriched with stem cells that can be propagated for many passages and that can contribute to both osteogenic or bone formation and osteoclastogenic or bone degradation pathways.…”

Section: Introductionmentioning

confidence: 99%

“…Osteogenesis can be studied by analyzing alkaline phosphatase expression over time in cultures that are supplemented with β‐glycerophosphate and vitamin C. Typically, periodontal ligament cells express more alkaline phosphatase than gingiva cells. At later stages of mineralization experiments the deposited bone matrix can be visualized with alizarin red staining . Early marker genes for osteoblast such as RUNX2, Collagen 1, and later markers such as Osteonectin and Dentin matrix protein 1 (DMP1) can be identified by quantitative PCR.…”

Section: Introductionmentioning

confidence: 99%

Osteogenic and osteoclastogenic potential of jaw bone‐derived cells—A case study

Ruppeka‐Rupeika

Hogervorst

Wouters

et al. 2018

J of Cellular Biochemistry

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Though the stem cell properties of tooth-derived periodontal ligament and gingival cells have been widely documented, surprisingly little is known about both the osteogenic and osteoclastogenic differentiation capacities of the more clinically relevant jaw bone-derived cells. These cells could be considered being recruited during bone healing such as after tooth extraction, after placing an implant, or after surgical or traumatic injury. Here, we compared the osteoblast and osteoclastogenesis features of four consecutive bone outgrowths with periodontal ligament and gingiva cells. For osteogenesis assay, cells were cultured in osteogenic medium, whereas in osteoclastogenesis assays, cells were cultured in the presence of human peripheral blood mononuclear cells (PBMCs) as a source of osteoclast precursors. After osteogenic stimulus, all six cell types responded by an increased expression of osteoblast markers RUNX2 and DMP1. Periodontal ligament cells expressed significantly higher levels of RUNX2 compared to all bone outgrowths. Alkaline phosphatase enzyme levels in periodontal ligament cells reached earlier and higher peak expression. Mineral deposits were highest in periodontal ligament, gingiva and the first bone outgrowth. Osteoclastogenesis revealed a stepwise increase of secreted pro-osteoclastogenesis proteins M-CSF, IL-1β, and TNF-α in the last three consecutive bone cultures. OPG mRNA showed the opposite: high expression in periodontal and gingiva cells and the first outgrowth. Osteoclast numbers were similar between the six cultures, both on bone and on plastic. This first study reveals that jaw bone outgrowths contain bone remodelling features that are slightly different from tooth-associated cells.

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Periodontal ligament fibroblasts as a cell model to study osteogenesis and osteoclastogenesis in fibrodysplasia ossificans progressiva

Cited by 30 publications

References 31 publications

Development of Macrocycle Kinase Inhibitors for ALK2 Using Fibrodysplasia Ossificans Progressiva‐Derived Endothelial Cells

Development of Macrocycle Kinase Inhibitors for ALK2 Using Fibrodysplasia Ossificans Progressiva‐Derived Endothelial Cells

Effects of L‐PRF and A‐PRF+ on periodontal fibroblasts in in vitro wound healing experiments

Osteogenic and osteoclastogenic potential of jaw bone‐derived cells—A case study

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