Differential effects of fibroblast growth factor (FGF) 9 and FGF2 on proliferation, differentiation and terminal differentiation of chondrocytic cells in vitro

Weksler, Nicole B.; Lunstrum, Gregory P.; Reid, Eric S.; Horton, William A.

doi:10.1042/bj3420677

Cited by 56 publications

(19 citation statements)

References 38 publications

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“…23 We collected the culture medium from cells expressing either WT or mutant FGF9 and assessed their activity on chondrocyte proliferation and differentiation. Consistent with previously reports, 14 conditioned medium containing FGF9 promoted cell proliferation of rat calvaria chondrogenic cell line (RCJ 3.1 C5.18 cells) ( Figure 3B), as well as mouse primary chondrocytes ( Figure S3A). In contrast, no such effect was observed when FGF9 S99N -containing medium was used, suggesting that S99N mutation compromised FGF9 to promote chondrogenic cell proliferation.…”

Section: Abnormal Cell Proliferation and Differentiation Associated Wsupporting

confidence: 92%

Multiple Synostoses Syndrome Is Due to a Missense Mutation in Exon 2 of FGF9 Gene

Huang

et al. 2009

The American Journal of Human Genetics

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Fibroblast growth factors (FGFs) play diverse roles in several developmental processes. Mutations leading to deregulated FGF signaling can cause human skeletal dysplasias and cancer.(1,2) Here we report a missense mutation (Ser99Asp) in exon 2 of FGF9 in 12 patients with multiple synostoses syndrome (SYNS) in a large Chinese family. In vitro studies demonstrate that FGF9(S99N) is expressed and secreted as efficiently as wild-type FGF9 in transfected cells. However, FGF9(S99N) induces compromised chondrocyte proliferation and differentiation, which is accompanied by enhanced osteogenic differentiation and matrix mineralization of bone marrow-derived mesenchymal stem cells (BMSCs). Biochemical analysis reveals that S99N mutation in FGF9 leads to significantly impaired FGF signaling, as evidenced by diminished activity of Erk1/2 pathway and decreased beta-catenin and c-Myc expression when compared with wild-type FGF9. Importantly, the binding of FGF9(S99N) to its receptor is severely impaired although the dimerization ability of mutant FGF9 itself or with wild-type FGF9 is not detectably affected, providing a basis for the defective FGFR signaling. Collectively, our data demonstrate a previously uncharacterized mutation in FGF9 as one of the causes of SYNS, implicating an important role of FGF9 in normal joint development.

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Section: Abnormal Cell Proliferation and Differentiation Associated Wsupporting

confidence: 92%

Multiple Synostoses Syndrome Is Due to a Missense Mutation in Exon 2 of FGF9 Gene

Huang

et al. 2009

The American Journal of Human Genetics

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“…We believe that a large amount of elastic chondrocytes is necessary for the use of clinical facial reconstruction. We thus developed a multilayered culture system in which, first, fibroblast growth factor-2 (FGF2), [19][20][21][22][23][24] known as a proliferation promoter of chondrocytes, is added to a medium to make cells multiply and undergo sufficient expansion, and these cells are then layered on top of each other and seeded. [1][2][3][4] With this system, a large volume of chondrocytes was obtained, since the cells are prevented from becoming dispersed and are connected mutually by being multilayered.…”

Section: Introductionmentioning

confidence: 99%

Cell-Engineered Human Elastic Chondrocytes Regenerate Natural Scaffold In Vitro and Neocartilage with Neoperichondrium in the Human Body Post-Transplantation

Yanaga¹,

Imai

Koga³

et al. 2012

Tissue Engineering Part A

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We have developed a unique method that allows us to culture large volumes of chondrocyte expansion from a small piece of human elastic cartilage. The characteristic features of our culturing method are that fibroblast growth factor-2 (FGF2), which promotes proliferation of elastic chondrocytes, is added to a culture medium, and that cell-engineering techniques are adopted in the multilayered culture system that we have developed. We have subsequently discovered that once multilayered chondrocytes are transplanted into a human body, differentiation induction that makes use of surrounding tissue occurs in situ, and a large cartilage block is obtained through cartinogenesis and matrix formation. We have named this method two-stage transplantation. We have clinically applied this transplantation method to the congenital ear defect, microtia, and reported successful ear reconstruction. In our present study, we demonstrated that when FGF2 was added to elastic chondrocytes, the cell count increased and the level of hyaluronic acid, which is a major extracellular matrix (ECM) component, increased. We also demonstrated that these biochemical changes are reflected in the morphology, with the elastic chondrocytes themselves producing a matrix and fibers in vitro to form a natural scaffold. We then demonstrated that inside the natural scaffold thus formed, the cells overlap, connect intercellularly to each other, and reconstruct a cartilage-like three-dimensional structure in vitro. We further demonstrated by immunohistochemical analysis and electron microscopic analysis that when the multilayered chondrocytes are subsequently transplanted into a living body (abdominal subcutaneous region) in the two-stage transplantation process, neocartilage and neoperichondrium of elastic cartilage origin are regenerated 6 months after transplantation. Further, evaluation by dynamic mechanical analysis showed the regenerated neocartilage to have the same viscoelasticity as normal auricular cartilage. Using our multilayered culture system supplemented with FGF2, elastic chondrocytes produce an ECM and also exhibit an intercellular network; therefore, they are able to maintain tissue integrity post-transplantation. These findings realized a clinical application for generative cartilage surgery.

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“…This method has been used in other studies for quantifying GAG levels in bone sections (75,76) and in cultured cells. (77,78) This histochemical method was utilized to verify the results obtained from bone powder samples using enzyme digestion approaches. Because the powder samples were prepared manually, it was hard to keep the consistent size and shape distributions of the powders for each individual donor.…”

Section: Discussionmentioning

confidence: 99%

Age‐Related Deterioration of Bone Toughness Is Related to Diminishing Amount of Matrix Glycosaminoglycans (GAGs)

et al. 2018

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Hydration status significantly affects the toughness of bone. In addition to the collagen phase, recent evidence shows that glycosaminoglycans (GAGs) of proteoglycans (PGs) in the extracellular matrix also play a pivotal role in regulating the tissue-level hydration status of bone, thereby affecting the tissue-level toughness of bone. In this study, we hypothesized that the amount of GAGs in bone matrix decreased with age and such changes would lead to reduction in bound water and subsequently result in a decrease in the tissue-level toughness of bone. To test the hypothesis, nanoscratch tests were conducted to measure the tissue-level toughness of human cadaveric bone specimens, which were procured only from male donors in three different age groups: young (26 ± 6 years old), mid-aged (52 ± 5 years old) and elderly (73 ± 5 years old), with six donors in each group. Biochemical and histochemical assays were performed to determine the amount and major subtypes of GAGs and proteoglycans in bone matrix. In addition, low-field NMR measurements were implemented to determine bound water content in bone matrix. The results demonstrated that aging resulted in a statistically significant reduction (17%) of GAGs in bone matrix. Concurrently, a significant deterioration (20%) of tissue-level toughness of bone with age was observed. Most importantly, the deteriorated tissue-level toughness of bone was associated significantly with the age-related reduction (40%) of bound water, which was partially induced by the decrease of GAGs in bone matrix. Furthermore, we identified that chondroitin sulfate (CS) was a major subtype of GAGs and the amount of CS decreased with aging in accompany with a decrease of biglycan that is a major subtype of PGs in bone. The findings of this study suggests that reduction of GAGs in bone matrix is likely one of the molecular origins for age-related deterioration of bone quality.

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Differential effects of fibroblast growth factor (FGF) 9 and FGF2 on proliferation, differentiation and terminal differentiation of chondrocytic cells in vitro

Cited by 56 publications

References 38 publications

Multiple Synostoses Syndrome Is Due to a Missense Mutation in Exon 2 of FGF9 Gene

Multiple Synostoses Syndrome Is Due to a Missense Mutation in Exon 2 of FGF9 Gene

Cell-Engineered Human Elastic Chondrocytes Regenerate Natural Scaffold In Vitro and Neocartilage with Neoperichondrium in the Human Body Post-Transplantation

Age‐Related Deterioration of Bone Toughness Is Related to Diminishing Amount of Matrix Glycosaminoglycans (GAGs)

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