What Can We Learn from FGF-2 Isoform-Specific Mouse Mutants? Differential Insights into FGF-2 Physiology In Vivo
Abstract
:1. Introduction
2. FGF-2 Isoforms in the Cardiovascular System
Strain | FGF-2 LMWko (FGF-2tm2Doe) | FGF-2 HMWko (FGF-2tm3Doe) | FGF-2HMWtg Overexpressed Human 24 kDa Driven by PGK Promoter | FGF-2LMWtg Overexpressed Rat 18 kDa Driven by RSV Promoter |
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Phenotype | ♂ ↑ left atrial dimensions ↓ E/A ratio ↓ decline in left ventricular pressure ↑ isovolumic relaxation time (impaired elaxation filling patterns) (Nusayr and Doetschman 2013) [50] ↑ α-SMA expression (Nusayr, Sadideen et al., 2013) [51] ♀ ↑ body weight ↑ heart hypoplasia ↓ LV posterior mass and wall thickness in iastole and systole ↑ LV volume in systole and diastole ↑ LV internal dimension in diastole ↑ E/A ratio ↑ myocardial stiffnessrestrictive diastolic filling patterns (Nusayr and Doetschman 2013) [50] ♀ ↑ ANF expression (Nusayr, Sadideen et al., 2013) [51] ♀ ↑ angiogenesis mediated by 17β-estradiol § (Garmy-Susini, Delmas et al., 2004) [42] | ♂/♀ ↑ FGF-2LMW protein levels in heart tissue, capillaries and vessels (Azhar, Yin et al., 2009) [43], (Liao, Bodmer et al., 2010) [44] ♂ ↓ LV volume in systole ↓ LV internal dimensions in systole ↑ systolic function indicated by greater cardiac output, stroke volume and fractional shortening ↑ flow velocity in the pulmonary artery ↑ mitral valve flow mean velocity and mitral valve flow mean pressure gradient (Nusayr and Doetschman 2013) [50] ♀ ↑ ANF expression (Nusayr, Sadideen et al., 2013) [51] ♀ no alterations compared to wt littermates (Nusayr and Doetschman 2013) [50] (Nusayr, Sadideen et al., 2013) [51] | ♂/♀ no alteration regarding heart growth, vasculogenesis/ angiogenesis or endogenous FGF-2 protein expression (Liao, Bodmer et al., 2010) [44] | ♂/♀ ↑ capillary density ↑ levels of phosphorylated c-Jun ↑ levels of phosphorylated p38MAPK ↑ levels of phosphorylated membrane associated PKCα and cytosolic PKCε (Sheikh, Sontag et al., 2001) [48] |
Atherosclerosis | FGF-2tm2Doe x ApoEko ♂ ↓ atherosclerotic lesions in the aorta ↓ macrophage infiltration ↓ MCP-1, VCAM-1, Nox4 and p47phox expression (Liang, Wang et al., 2018) [60] |
3. FGF-2 Isoforms in Bone Physiology
(A) | ||||
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Strain | FGF-2LMWko (FGF-2tm2Doe) | FGF-2HMWko (FGF-2tm3Doe) | FGF-2HMWtg Overexpressed Human 22, 23, 24 kDa Driven by Col3.6 Promoter | FGF-2LMWtg Overexpressed Human 18 kDa Driven by Col3.6 Promoter |
Phenotype | ♂ ↓ vertebral bone mineral density and content ↑ sFRP1 protein levels in trabecular bones (Xiao, Liu et al., 2009) [47] | ♂ ↑ whole body bone mineral density and content ↑ vertebral, femoral bone mineral density and content ↑ femoral bone volume, trabecular thickness, number (cortical bone area, thickness, cortical mask) ↓ femoral trabecular spacing ↑ connective tissue density ↓ cortical porosity, bone resorption (↓ osteoclast surface, number) ↑ bone formation in cortical periosteum, trabecular bone (↑ osteoblast surface, inter-label thickness, mineral apposition rate) ↑ tibial Col1a1, Runx2, osterix, oc, op, Dmp1 gene expression ↓ femoral Sost gene expression ↓ serum sclerostin, protein levels ↓ tibial Fgf-2, Fgf-23 gene expression (Homer-Bouthiette, Doetschman et al., 2014) [78] | ♂ dwarfism, osteomalacia ↓ body weight ↓ whole body bone mineral density and content ↓ femoral bone length ↓ vertebral volume, bone mineral density and content ↓ femoral bone volume, trabecular number, thickness ↑ femoral trabecular spacing ↑ bone resorption (↑ osteoclast surface, number) ↓ bone formation (↓ osteoblast, mineralization surface, bone formation rate) ↓ tibial Col1a1, Oc gene expression ↑ tibial Op, Mgp gene expression↓ serum phosphate ↑ serum PTH, CTX, FGF-23 ↑ tibial, femoral Fgf-23, Phex gene expression, protein levels ↑ renal Fgfr-1c, Fgfr-3c, Klotho gene expression ♂ with continuous phosphate diet ↑ body weight, bone mineral content and density ↑ serum phosphate to a normal level ↑ serum FGF-23 (Xiao, Naganawa et al., 2010) [45] ♂ ↓ tibia bone mineral density and content ↑ renal FGFR-1, FGFR-3, Klotho, C-Fos, activated ERK protein levels ↑ renal C-fos, Egr1 gene expression ↓ renal Npt2 gene expression ↑ renal Cyp24, Cyp27b1 gene expression ↓ renal Npt2 protein levels (Du, Xiao et al., 2017) [83] ♂ ↓ tail length ↓ femoral length ↑ urinary phosphate level ↑ cortical porosity, trabecular spacing, osteoid volume ↓ cortical thickness, tissue ↓ endosteal/periosteal perimeter, subendosteal area ↓ mineralization of cortical bone area, metaphyseal cancellous bone volume, trabecular number ↑ femoral Fgfr-3c, Pthr1, Op, Mgp gene expression (Xiao, Du et al., 2017) [84] | ♂ ↑ vertebral, tibial, femoral bone mineral density and content ↑ femoral bone volume, trabecular thickness, cortical bone area, thickness ↓ sFrp1 gene expression, protein levels in trabecular bones ↑ β-catenin gene expression, protein levels (Xiao, Liu et al., 2009) [47] ♂ ↑ Fgfr-1, Fgfr2, oc, β-catenin gene expression in calvaria bone ↓ sFrp1 gene expression in calvaria bone ↑ calvarial inter-label thickness, mineral apposition rate (Xiao, Ueno et al., 2014) [77] |
Phenotype | ♀ ↓ body weight ↓ femoral, tibial, vertebral bone mineral density and content ↓ serum phosphate ↑ serum FGF-23, 1,25D ↑ urinary phosphate level ↑ renal FGFR-1, En-1, klotho protein levels ↑ renal Klotho, Sostdc-1, En-1, Cyp24 gene expression ↑ activated renal ERK, Gsk-3β (Tr216) protein levels ↓ renal Npt2, Akt gene expression ↓ activated renal Gsk-3β (Ser9), active β-catenin and Akt protein levels (Du, Xiao et al., 2016) [82] ♀ ↓ femur length, cortical density, mineral apposition rate ↑ cortical porosity ↓ femoral bone volume, trabecular number ↑ femoral trabecular spacing ↑ osteoid volume ↑ serum ALP ↓ serum TNAP ↓ TNAP activity in osteocytes ↑ renal Fgfr-1c, Fgfr-3 gene expression ↑ tibia Fgf-2, Fgfr-1c, Col1a1, Mgp, Dmp4, Phex, Mepe, Enpp1, SLc20a1 gene expression ↓ tibia Dmp1, Rankl, Oc gene expression ↑ femur cortical ERK, FGFR-1 protein levels (Xiao, Homer-Bouthiette et al., 2018) [79] | |||
(B) | ||||
Strain | FGF-2 LMWko (FGF-2tm2Doe) | FGF-2 HMWko (FGF-2tm3Doe) | FGF-2HMWtg Overexpressed Human 22, 23, 24 kDa Driven by Col3.6 Promoter | FGF-2LMWtg Overexpressed Human 18 kDa Driven by Col3.6 Promoter |
Aging/Osteo-arthritis | ♂/♀ ↑ OA in knee joints (flattening of tibial plateau, osteophyte formation) ♂ ↓ femoral, tibial bone volume, trabecular number, thickness ↑ femoral, tibial trabecular spacing ↓ proteoglycan content, cartilage thickness in knee joint ↑ tendonitis, arthritis ↑ MMP-13, ADAMTS-5, FGF-2, FGF-23, FGFR-1 protein levels in articular cartilages ↑ Igf1, IL-1β, Bmp4, Hif1α, Bax, Fgf-2, Fgf-23, Fgfr-3 Vegf, Col10 gene expression in knee joints ↑ activated ERK protein levels in articular cartilage ↓ activated FGFR-3 in articular cartilage ↑ signs of OA following tibial loading (loss of proteoglycan content, thinning of subchondral bone) (Burt, Xiao et al., 2019) [71] | ♂/♀ no radiographical signs of OA in knee joints ♂ ↑ activated FGFR-3 protein levels in knees ↓ FGF-2 protein levels in articular cartilage (Burt, Xiao et al., 2019) [71] | ♂ ↑ OA in knee joints (flattening of tibial plateau, osteophyte formation, femoral subchondral bone thinning, sclerotic bone development, narrowing of the patellofemoral space, loss of trabeculae, sclerosis of femur) ↓ epiphyseal bone volume density, trabecular thickness, number in femur, tibiae ↓ proteoglycan content, cartilage thickness in knee joint ↑ Mmp13, Col10, ADAMTS-5 gene expression in articular cartilages ↑ Igf1, IL-1β, Bmp2, Bmp4, Hif1α, Bax, Sox9, Vegf gene expression in knee joints ↑ FGF-23, FGFR-1 protein levels in knee joints↓ mineralization of hypertrophic chondrocytes (Meo Burt, Xiao et al., 2016) [89] ♂ ↓ Sost, Dkk1, Lrp6 gene expression in knee joints ↑ Wnt5a, Axin2, Lef1 gene expression in knee joints ↓ Sost, Lrp6 protein levels in knee joints ↑ Wnt7b, Wnt5a, Lrp5, Axin2, Gsk-3β, Lef1, nuclear β-catenin protein levels in knee joints ↑ Mmp9 gene expression in femoral cartilage (Meo Burt, Xiao et al., 2018) [87] ♂/♀ ↑ signs of OA in knee joints (flattening of tibial plateau, osteophyte formation, sclerosis) ↓ femoral, tibial bone volume, trabecular number, thickness ↓ proteoglycane content, cartilage thickness in knee joints ↑ cartilage calcification in knee cartilage ♂ ↑ Fgfr-1c, Fgf-18 gene expression in knee joints ↓ Fgfr-3c gene expression in knee joints ↑ FGF-2 protein level in subchondral bone ↑ MMP-13, SOX9, ADAMTS-5 protein level in articular cartilages ↓ Dkk1 Lrp6, Sost protein levels in articular cartilage (Xiao, Williams et al., 2020) [92] | ♂ no radiographical signs of OA in knee joints (Meo Burt, Xiao et al., 2016) [89] |
4. FGF-2 Isoforms in the Central Nervous System
Strain | FGF-2 LMWko (FGF-2tm2Doe) | FGF-2 HMWko (FGF-2tm3Doe) |
---|---|---|
Phenotype | ♂/♀ no FGF-2HMW protein expression can be found in the embryonic nigrostriatal system ↑ number of DA precursor cells in the rostral subventricular zone at E14.5 ↑ signs of regulatory apoptosis in DA neurons of the ventral midbrain at P0 ↑ number of DA neurons in the adult female SNpc ↓ explorative behavior of adult male mice (von Hövel, Leiter et al., 2019) [22] | ♂/♀ ↑ FGF-2LMW protein in brain tissue (Azhar, Yin et al., 2009) [43] ♂/♀ ↑ FGF-2LMW protein expression in the nigrostriatal pathway from P0 through development ↑ number of DA precursor cells in the rostral subventricular zone at E14.5 ↑ signs of apoptosis in DA neurons of the ventral midbrain at P0 ↑ number of DA neurons in the adult female SNpc ↑ explorative behavior of adult male mice (von Hövel, Leiter et al., 2019) [22] |
ALS mouse model | ♂/♀ SOD1G93A × FGF-2LMWko ↓ body weight, general condition score, and survival rate from 17 weeks onwards ↓ performance in the rotarod test in weeks 14–17 ↓ runtime in the footprint track with 21 weeks ↓ EGF mRNA expression in the gastrocnemius muscle at 21 weeks (Kefalakes, Sarikidi et al., 2019) [113] | ♂/♀ SOD1G93A × FGF-2HMWko ↑ performance in the rotarod test in weeks 17, 18, 19, 20 and 21 (Kefalakes, Sarikidi et al., 2019) [113] |
In vitro model | ♂/♀ ↓ RIG-1 protein level in MEF independent of IAV infection ↑ INF-α, INF-β, IL-6, and TNF-α expression in macrophages and MEFs following polyIC or SeV stimulation ↑ phosphorylation of IRF3 following SeV infection (Liu, Luo et al., 2015) [122] |
5. Outlook
Supplementary Materials
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Freiin von Hövel, F.; Kefalakes, E.; Grothe, C. What Can We Learn from FGF-2 Isoform-Specific Mouse Mutants? Differential Insights into FGF-2 Physiology In Vivo. Int. J. Mol. Sci. 2021, 22, 390. https://doi.org/10.3390/ijms22010390
Freiin von Hövel F, Kefalakes E, Grothe C. What Can We Learn from FGF-2 Isoform-Specific Mouse Mutants? Differential Insights into FGF-2 Physiology In Vivo. International Journal of Molecular Sciences. 2021; 22(1):390. https://doi.org/10.3390/ijms22010390
Chicago/Turabian StyleFreiin von Hövel, Friederike, Ekaterini Kefalakes, and Claudia Grothe. 2021. "What Can We Learn from FGF-2 Isoform-Specific Mouse Mutants? Differential Insights into FGF-2 Physiology In Vivo" International Journal of Molecular Sciences 22, no. 1: 390. https://doi.org/10.3390/ijms22010390