Knockout of nuclear high molecular weight FGF2 isoforms in mice modulates bone and phosphate homeostasis.
We previously reported that targeted overexpression of the fibroblast growth factor 2 (FGF2) high molecular weight (HMW) isoforms in osteoblastic lineage cells in mice resulted in phenotypic changes, including dwarfism, rickets, osteomalacia, hypophosphatemia, increased serum parathyroid hormone, and increased levels of the phosphatonin FGF23 in serum and bone. This study examined the effects of genetically knocking out the FGF2HMW isoforms (HMWKO) on bone and phosphate homeostasis. HMWKO mice were not dwarfed and had significantly increased bone mineral density and bone mineral content in femurs and lumbar vertebrae when compared with the wild-type (WT) littermates. Micro-computed tomography analysis of femurs revealed increased trabecular bone volume, thickness, number, and connective tissue density with decreased trabecular spacing compared with WT. In addition, there was significantly decreased cortical porosity and increased cortical thickness and sub-periosteal area in femurs of HMWKO. Histomorphometric analysis demonstrated increased osteoblast activity and diminished osteoclast activity in the HMWKO. In vitro bone marrow stromal cell cultures showed there was a significant increase in alkaline phosphatase-positive colony number at 1 week in HMWKO. At 3 weeks of culture, the mineralized area was also significantly increased. There was increased expression of osteoblast differentiation marker genes and reduced expression of genes associated with impaired mineralization, including a significant reduction in Fgf23 and Sost mRNA. Normal serum phosphate and parathyroid hormone were observed in HMWKO mice. This study demonstrates a significant negative impact of HMWFGF2 on biological functions in bone and phosphate homeostasis in mice.
From the Department of Medicine, Institute for Systems Genomics, University of Connecticut Health Center, Farmington, Connecticut 06030 and.
Collin
C
Homer-Bouthiette
the B105 Institute and Department Cellular and Molecular Medicine, University of Arizona, Tucson, Arizona 85724-5217.
Thomas
T
Doetschman
From the Department of Medicine, Institute for Systems Genomics, University of Connecticut Health Center, Farmington, Connecticut 06030 and xiao@uchc.edu.
Liping
L
Xiao
From the Department of Medicine, Institute for Systems Genomics, University of Connecticut Health Center, Farmington, Connecticut 06030 and hurley@nso1.uchc.edu.
Marja M
MM
Hurley
D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D015519:Bone Density; D001854:Bone Marrow Cells / Q000201:enzymology; D001842:Bone and Bones / Q000378:metabolism*; D002478:Cells, Cultured; D016222:Fibroblast Growth Factor 2 / Q000235:genetics* / Q000378:metabolism; D000089703:Fibroblast Growth Factor-23; D006706:Homeostasis; D008297:Male; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D008970:Molecular Weight; D010006:Osteoblasts / Q000378:metabolism; D010710:Phosphates; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism
C000717428:Fgf23 protein, mouse; D010710:Phosphates; D020033:Protein Isoforms; D016222:Fibroblast Growth Factor 2; D000089703:Fibroblast Growth Factor-23; D000469:Alkaline Phosphatase
Bone; Fibroblast Growth Factor (FGF); RNA; Transcription Regulation; Wnt Signaling