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Fibroblast Growth Factor 2 (FGF-2)

Fibroblast Growth Factor 2 (FGF-2) is an intercellular signaling molecule that plays a role in multiple developmental and biological processes.[1] These include induction of differentiation, stimulation of mitosis (Mitogenesis), and stimulation of blood vessel formation (angiogenesis).[2] FGF-2 is part of a family of Fibroblast Growth Factor molecules that, in humans, has 23 members[3]. FGFs are present in vertebrate and invertebrate species[4], indicating that they have been highly conserved throughout evolution. Fibroblast growth factors are among the first growth factors that were discovered.[3]

Background

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FGFs are polypeptide molecules[4] that share a homologous core region and are primarily distinguished by their N-terminus and C-terminus sequences.[5] FGF-2 is most closely related to FGF-1[3], although FGF-2 is basic whereas FGF-1 is acidic.[3]

FGF-2 is a paracrine factor that induces other molecules to differentiate. FGF-2 binds to a membrane-bound tyrosine kinase receptor to initiate an intracellular signal transduction cascade that culminates in transcription factors altering transcription in the nucleus. FGF-2 can also bind to heparan sulfate proteoglycan receptors, which enable it to bind more readily to its receptors. The effect of FGF-2 is concentration dependent – different concentrations will induce molecules to have different fates.[4] FGF-2 signaling is important both in embryonic development and adulthood.[6]

In the chick embryo, FGF-2 is secreted by the notochord, as well as by neuroepithelium.[7]

Because of its angiogenic and mitogenic capabilities, multiple therapeutic applications of FGF-2 have been considered. Studies suggest that FGF-2 could reduce vasoconstriction surrounding a spinal injury and increase the formation of new blood vessels.[8] Other studies have indicated that FGF-2 could alleviate hypertension.[9] FGF-2 has also been found to be effective against cartilage loss due to osteoarthritis.[10]

Functions

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Figure 1 - Secreted isoforms of FGF-2 bind to the FGFR to activate a signal transduction pathway. (View in full size)
Figure 2 - Bounded FGF-2 to FGFR can internalize into the nucleus (View in full size)
Figure 3 - HMW Isoforms of FGF-2 affects cell phenotype by localizing into the nucleus (View in full size)

FGF-2 can induce cells to undergo mitosis.[8] FGF-2 is also able to regulate cell fate specification.[2] FGF-2 has an impact on the development of mesodermal, ectodermal, and endodermal tissue. In the embryo, it has been shown to influence blood vessel formation, neuron formation, pancreas formation, glial cell formation, lung development, limb development, embryonic morphogenesis, and organ morphogenesis, among other things. Studies in Xenopus have indicated that FGF-2 acts even before gastrulation as a mesoderm inducer.[11] Post-gastrulation, FGF-2 acts on mesenchymal and endothelial cells to induce the formation of differentiated blood vessels.[3] Studies have hypothesized that FGF-2 also has an important role in limb bud growth and development in chick embryos.[12] In adults, FGF-2 continues to act on mesodermally derived tissues; studies have suggested it has some control over blood vessel formation[1] and influences wound healing.[13]

FGF-2 Isoforms

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The mRNA of FGF-2 has been found to have multiple translational start sites. Depending on where the translation begins, the protein products that result will have different localization regions, molecular weight, and will ultimately function in different pathways.[14] Translation of the original start site at the AUG (methionine) start codon will produce the low molecular weight (LMW) FGF-2 protein.[14] The 18kDa extracellular protein remains in the cytosol or is secreted from the FGF-2 producing cell.[14] There are also at least 4 other CUG (leucine) start codons which result in translated products that are considered as heavy molecular weight (HMW) proteins and their sizes are 22kDa, 22.5kDa, 24kDa, and 34kDa.[14] These HMW isoforms have further specific interactions to alter cell phenotype and most are able to localize into the nucleus due to a nuclear localization sequence.[14]

Mechanisms

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Secretion of the FGF-2 protein is said to be completed through an ER-Golgi independent pathway because FGF-2 does not contain a classical secretion signal.[15] The structure of FGF-2 is similar to IL-1β and it is hypothesized that their excretion mechanisms are similar. [15] Not much is known about the secretion mechanism for FGF-2 but it is done by exocytosis and is energy-dependent.[15]

Secreted isoforms interact with high affinity tyrosine-kinase FGF receptors (FGFRs) and low affinity heparan sulphate proteoglycans receptors (HSPGs).[14] Most binding models suggest FGF-2 interacts with the free HSPGs, which prevent FGF-2 from inactivating and modulates the dimerization of FGF-2. The dimerization activates FGF receptor tyrosine kinase (FGFRs) and initiates a number of biological responses including angiogenesis and cell proliferation.[16] -- See Figure 1

Besides inducing FGF receptor signal transduction, the 18kDa protein can internalize with the active FGFR into the nucleus by using a non classical bipartite NLS in the C-terminus. [17] Accumulation of 18kDa FGF-2 in the nucleolus is related to protein kinase CKII activation which can initiate ribosomal gene transcription as well as other functions such as cell-cycle progression and proliferation.[17] --- See Figure 2

There are blockers for HSPG, FGF-2 and FGFR interaction and such inhibitors prevent angiogenesis, endothelial cell growth, migration, and tumour growth in vivo.[16] Removing either the HSPGs or the FGFR component inhibits cell-cell interaction and growth. [16]

However, not all FGF-2 isoforms are secreted. Most of HMW FGF-2 are localized in the nucleus after translation.[18] A signal sequence, 37 amino region upstream of the AUG start site acts as a nuclear targeting sequence on the N-terminus of the protein.[15] This signal interacts with intracellular effectors in the cell in a FGFR-independent manner and regulates the expression of target genes.[14] --- See Figure 3

Expression of the various isoforms have different patterns of expression depending on the cell conditions, the developmental stage and species. A specific example is seen in rats, where HMW isoforms are found in high concentrations during the development of the heart in the neonatal stage whereas LMW isoforms are found in high concentrations during the adult heart stages.[14]

Regeneration

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The FGF-2 is found to be extremely influential in cell proliferation, which suggests a potentially important role in regenerative medicine. Although cell differentiation seems to be inhibited by higher levels of FGF-2 (it induces inhibitory factors), growth differentiation factors and other known differentiation inducers could be used to drive cells towards a specific cell lineage. Multiple papers have found that FGF-2 has an effect on proliferation and repair in certain tissues.

The optic tectum, cartilage, peripheral glial cells, oocytes and mesenchymal cells were all proven to be affected by FGF-2 by numerous experiments. The retinal ganglion cells in the optic tectum treated with FGF-2 were found to have an increased regeneration and survival rate after an optic nerve injury [19]. Cartilage homeostasis[20] was found to be regulated by FGF-2 and other FGF family members , which may be a very effective treatment for osteoarthritis and degenerative disc diseases. The bone marrow-derived cell-secreted FGF-2 highly upregulates early proliferation of glial cells in the peripheral nervous system [21]. This may be important in the regeneration of nerves and ganglia, which could be effective treatment for neurodegenerative diseases. Mammalian oocytes production (or folliculogenesis) was increased with the addition of FGF-2 [22].

Since so many lineages are affected by FGF-2, it may be a very useful treatment as regenerative medicine for tissue or organ damage and degenerative diseases, and also tissue engineering purposes.

FGF-2 in Cartilage & Bone Regeneration as Osteoarthritis Treatment

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Globally, approximately 1 in 2 people may develop osteoarthritic knee by age 85 years [23] , making it a devastating problem in aging populations all over the world. Osteoarthritis is caused by the degeneration of articular cartilage and subcondral bone around a joint [24]. The disappearance of cartilage causes pain and damage to bones due to increased friction between bones during movement. Cartilage is a combination of secreted extracellular matrix of collagen (structural protein), proteoglycans and non-collagenous proteins, and 80% water [25]. This extracellular matrix is secreted by chondrocytes, a mesenchymal stem cell derivative. Mesenchymal stem cells (MSCs) are derived from bone marrow stem cells and are progenitors for different connective tissue cells, including osteoblasts (for bone formation), chondrocytes (for cartilage formation), myotube (for muscle formation) and fibroblasts (for tendon and ligament formation).[10]

Currently, the possibility of tissue engineering in conjunction with stem cell therapy is being researched to increase of cartilage production, and thus providing more protection for joints. FGF-2 at the appropriate concentrations has been shown to keep certain types of stem cells at a highly plastic state, a key characteristic of effective tissue engineering. [10][26] [26][27].



See also

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References

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  1. ^ a b Slavin J (1995). “Fibroblast growth factors: at the heart of angiogenesis.” Cell Biology International 19 (5): 431-44. PMID 7543787.
  2. ^ a b Uniprot C (2012). “FGF2_HUMAN” Uniprot Knowledge Base. Primary (citable) accession number: P09038
  3. ^ a b c d e Rovensky J, Payer J, ed (2009). “Fibroblast growth factors (FGF)” Dictionary of Rheumatology. Vienna: Springer Vienna. p. 66-67. DOI 10.1007/978-3-211-79280-3_371 ONLINE ISBN 978-3-211-79280-3
  4. ^ a b c Bottcher RT, Niehrs C (2005). “Fibroblast Growth Factor Signaling during Early Vertebrate Development.” Endocrine Reviews 26 (1): 63-77. doi 10.1210/er.2003-0040
  5. ^ Beenken A, Mohammadi M (2009). “The FGF family: biology, pathophysiology and therapy.” Nature Reviews, Drug Discovery 8(3): 235. doi 10.1038/nrd2792
  6. ^ Amaya E, Musci TJ, Kirschner MW (1991). “Expression of a dominant negative mutant of the FGF receptor disprupts mesoderm formation in Xenopus embryos” Cell 66 (2): 257-270. DOI 10.1016/0092-8674(91)90616-7. PMID 1649700
  7. ^ Madern AL, Desmond M (2011). “The primary regulator of early embryonic brain growth in the chick: Intraluminal pressure or FGF2?” Development Biology 356 (1): 151. doi http://dx.doi.org/10.1016/j.ydbio.2011.05.175
  8. ^ a b Kang CE, Baumann MD, Tator CH, Shoichet MS (2012). “Localized and Sustained Delivery of Fibroblast Growth Factor-2 from a Nanoparticle-Hydrogel Composite for Treatment of Spinal Cord Injury.” Cell Tissue Organs. Epub ahead of print. PMID 22796886
  9. ^ (2009) “Fibroblast growth factor-2 (FGF2; FGF-2).” SciBX 2 (7); online. doi 10.1038/scibx.2009.276
  10. ^ a b c Solchaga, L.A., Penick, K.,Porter, J.D., Goldberg, V.M., Caplan, A.I., and Welter, J.F. (2004). "FGF-2 enhances the mitotic and chondrogenic potentials of human adult bone marrow-derived mesenchymal stem cells." J Cell Phys 203(2):398-409.
  11. ^ Kimelman D, Abraham JA, Haaparanta T, Palisi TM, Kirschner MW (1988). “The presence of fibroblast growth factor in the frog egg: its role as a natural mesoderm inducer.” Science 242 (4881): 1053-1056. DOI 10.1126/science.3194757
  12. ^ Savage, M., Hart, C., Riley, B., Sasse, J., Olwin, B., & Fallon, J. (1993). "Distribution of FGF-2 Suggests It Has a Role in Chick Limb Bud Growth." Developmental Dynamics. 198: 159-170. doi:10.1002/aja.1001980302
  13. ^ Nugent MA, Renator VI (2000). “Fibroblast growth factor-2.” The International Journal of Biochemistry and Cell Biology 32 (2): 115-120. doi http://dx.doi.org/10.1016/S1357-2725(99)00123-5
  14. ^ a b c d e f g h Delrieu,I. (2000). "The high molecular weight isoforms of basic fibroblast growth factor (FGF-2): an insight into intracrine mechanism". FEBS Letters 468(1): 6-10. PMID 10683430.
  15. ^ a b c d Powers, C.J., McLeskey, S.W., Wellstein, A. (2000). "Fibroblast growth factors, their receptors and signaling". Endocrine-Related Cancers 7: 165-197. doi: 1351-0088/00/007–165.
  16. ^ a b c Presta, M. (1998). "Examining new models for the study of autocrine and paracrine mechanisms of angiogenesis through fgf2-transfected endothelial and tumor cells". Retrieved from http://www.med.unibs.it/~airc/iir/framefgf2.html
  17. ^ a b Sheng, N., Lewis, J.A., Chirico, W.J. (2004). "Nuclear and Nucleolar Localization of 18-kDa Fibroblast Growth Factor-2 Is Controlled by C-terminal Signal". Journal Of Biological Chemistry 279(38): 40153-40160.
  18. ^ Chlebova, K., Bryja, V., Dvorak, P., Kozubik, A., Wilcox, W.R., Krejci, P. (2009). "High molecular weight FGF2: the biology of a nuclear growth factor". Cell Mol Life 66(2): 225-235. doi:10.1007/s00018-008-8440-4.
  19. ^ Duprey-Díaz, M.V., Blagburn, J.M. and Blanco, R.E. (2012). “Changes in fibroblast growth factor-2 and FGF receptors in the frog visual system during optic nerve regeneration.” J Chem Neuroanat. pii: S0891-0618 (12): 00049-X. doi: 10.1016.
  20. ^ Ellman, M., Yan, D., Ahmadinia, K., Chen, D., An, H., and Im H.(2012). "Fibroblast growth factor control of cartilage homeostasis." J Cell Biochem doi: 10.1002/jcb.24418
  21. ^ Ribeiro de Resende, V.T., Carrier-Ruiz, A., Lemes, R.M., Reis, R.A. and Mendez-Otero, R. (2012). “Bone marrow-derived fibroblast growth factor-2 induces glial cell proliferation in the regenerating peripheral nervous system.” Mol Neurodegener. 7 (1): 34.
  22. ^ Chaves, R.N., de Matos, M.H., Buratini, J Jr. and de Figueiredo,JR. (2012). “The fibroblast growth factor family: involvement in the regulation of folliculogenesis.” Reprod. Fertil. Dev. 24 (7): 905-15. doi: 10.1071/RD11318.
  23. ^ Murphy, L., Schwartz, T.A., Helmick, C.G., Renner, J.B, Tudor, G., Koch, G., Dragomir, A., Kalsbeek, W.D., Luta, G., Jordan, J.M.(2008). "Lifetime risk of symptomatic knee osteoarthritis". Arthritis Rheum 59(9):1207-1213.
  24. ^ PubMed Health A.D.A.M. Medical Encyclopedia. (2011). “Osteoarthritis.” Retrieved from http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001460/
  25. ^ International Cartilage Repair Society. (2012). “What is Cartilage?” Retrieved from http://www.cartilage.org/index.php?pid=22
  26. ^ a b Lai,W.T., Krishnappa, V., and Phinney, D.G. (2011). "Fgf2 Inhibits Differentiation of Mesenchymal Stem Cells by Inducing Twist2 and Spry4, Blocking Extracellular Regulated Kinase Activation and Altering Fgfr Expression Levels." Stem Cells. 29(7):1102-1111. doi: 10.1002/stem.661
  27. ^ Nakamura, Y., Tensho, K., Nakaya, H., Nawata, M., Okabe, T., and Wakitani, S. (2005). “Low dose fibroblast growth factor-2 (FGF-2) enhances bone morphogenetic protein-2 (BMP-2)-induced ectopic bone formation in mice.” Bone. 36(3):399-407. PMID:15777655
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