共查询到20条相似文献,搜索用时 31 毫秒
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Patience M. Burt Liping Xiao Thomas Doetschman Marja M. Hurley 《Journal of cellular physiology》2019,234(4):4418-4431
FGF2 is an essential growth factor implicated in osteoarthritis (OA), and deletion of full-length FGF2 (Fgf2ALLKO) leads to murine OA. However, the FGF2 gene encodes both high-molecular-weight (HMW) and low-molecular-weight (LMW) isoforms, and the effects of selectively ablating individual isoforms, as opposed to total FGF2, has not been investigated in the context of OA. We undertook this study to examine whether mice lacking HMW FGF2 (Fgf2HMWKO) or LMW FGF2 (Fgf2LMWKO) develop OA and to further characterize the observed OA phenotype in Fgf2ALLKO mice. Fgf2HMWKO mice never developed OA, but 6- and 9-month-old Fgf2LMWKO and Fgf2ALLKO mice displayed signs of OA, including eroded articular cartilage, altered subchondral bone and trabecular architecture, and increased OA marker enzyme levels. Even with mechanical induction of OA, Fgf2HMWKO mice were protected against OA, whereas Fgf2LMWKO and Fgf2ALLKO displayed OA-like changes of the subchondral bone. Before exhibiting OA symptoms, Fgf2LMWKO or Fgf2ALLKO joints displayed differential expression of genes encoding key regulatory proteins, including interleukin-1β, insulin-like growth factor 1, bone morphogenetic protein 4, hypoxia-inducible factor 1, B-cell lymphoma 2, Bcl2-associated X protein, a disintegrin and metalloproteinase with thrombospondin motifs 5, ETS domain-containing protein, and sex-determining region Y box 9. Moreover, Fgf2LMWKO OA cartilage exhibited increased FGF2, FGF23, and FGFR1 expression, whereas Fgf2HMWKO cartilage had increased levels of FGFR3, which promotes anabolism in cartilage. These results demonstrate that loss of LMW FGF2 results in catabolic activity in joint cartilage, whereas absence of HMW FGF2 with only the presence of LMW FGF2 offers protection from OA. 相似文献
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Naganawa T Xiao L Abogunde E Sobue T Kalajzic I Sabbieti M Agas D Hurley MM 《Biochemical and biophysical research communications》2006,339(2):490-498
We previously reported that deletion of the Fgf2 gene (Fgf2-/-) resulted in decreased bone mass in adult mice. This study examines the effect of haplo-insuffiency (Fgf2+/-) on bone loss in vertebrae from these mutant mice. Fgf2+/+ mice attained peak bone mass at 8-9 months of age. In contrast BMD was significantly reduced in vertebrae from adult (8-9) Fgf2+/- mice. Exogenous FGF-2 rescued reduced bone nodule formation in Fgf2+/- and Fgf2-/- cultures. Runx2 mRNA was reduced in cultures from Fgf2+/- and Fgf2-/- mice. FGF receptor2 mRNA and protein were markedly reduced in Fgf2+/- and Fgf2-/- mice. Decreased bone formation in Fgf2 mutant mice may correlate with impaired FGFR signaling, decreased Runx2 gene expression. 相似文献
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Fei Y Xiao L Doetschman T Coffin DJ Hurley MM 《The Journal of biological chemistry》2011,286(47):40575-40583
Fibroblast growth factor 2 (FGF2) positively modulates osteoblast differentiation and bone formation. However, the mechanism(s) is not fully understood. Because the Wnt canonical pathway is important for bone homeostasis, this study focuses on modulation of Wnt/β-catenin signaling using Fgf2(-/-) mice (FGF2 all isoforms ablated), both in the absence of endogenous FGF2 and in the presence of exogenous FGF2. This study demonstrates a role of endogenous FGF2 in bone formation through Wnt signaling. Specifically, mRNA expression for the canonical Wnt genes Wnt10b, Lrp6, and β-catenin was decreased significantly in Fgf2(-/-) bone marrow stromal cells during osteoblast differentiation. In addition, a marked reduction of Wnt10b and β-catenin protein expression was observed in Fgf2(-/-) mice. Furthermore, Fgf2(-/-) osteoblasts displayed marked reduction of inactive phosphorylated glycogen synthase kinase-3β, a negative regulator of Wnt/β-catenin pathway as well as a significant decrease of Dkk2 mRNA, which plays a role in terminal osteoblast differentiation. Addition of exogenous FGF2 promoted β-catenin nuclear accumulation and further partially rescued decreased mineralization in Fgf2(-/-) bone marrow stromal cell cultures. Collectively, our findings suggest that FGF2 stimulation of osteoblast differentiation and bone formation is mediated in part by modulating the Wnt pathway. 相似文献
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Impaired osteoclast formation in bone marrow cultures of Fgf2 null mice in response to parathyroid hormone 总被引:3,自引:0,他引:3
Okada Y Montero A Zhang X Sobue T Lorenzo J Doetschman T Coffin JD Hurley MM 《The Journal of biological chemistry》2003,278(23):21258-21266
Fibroblast growth factor (FGF)-2 and parathyroid hormone (PTH) are potent inducers of osteoclast (OCL) formation, and PTH increases FGF-2 mRNA and protein expression in osteoblasts. To elucidate the role of endogenous FGF-2 in PTH responses, we examined PTH-induced OCL formation in bone marrow cultures from wild type and mice with a disruption of the Fgf2 gene. FGF-2-induced OCL formation was similar in marrow culture from both genotypes. In contrast, PTH-stimulated OCL formation in bone marrow cultures or co-cultures of osteoblast-spleen cells from Fgf2-/mice was significantly impaired. PTH increased RANKL mRNA expression in osteoblasts cultures from both genotypes. After 6 days of treatment, osteoprotegerin protein in cell supernatants was 40-fold higher in vehicle-treated and 30-fold higher in PTH-treated co-cultures of osteoblast and spleen cells from Fgf2-/mice compared with Fgf2+/+ mice. However, a neutralizing antibody to osteoprotegerin did not rescue reduced OCL formation in response to PTH. Injection of PTH caused hypercalcemia in Fgf2+/+ but not Fgf2-/mice. We conclude that PTH stimulates OCL formation and bone resorption in mice in part by endogenous FGF-2 synthesis by osteoblasts. Because RANKL- and interleukin-11-induced OCL formation was also reduced in bone marrow cultures from Fgf2-/mice, we further conclude that endogenous FGF-2 is necessary for maximal OCL formation by multiple bone resorbing factors. 相似文献
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Deficiency of inducible nitric oxide synthase exacerbates hepatic fibrosis in mice fed high-fat diet
Yi Chen Sadaaki Sawamura Naoto Fukuyama Tetsuya Mine Ryuzaburo Tanino Hiroe Nakazawa 《Biochemical and biophysical research communications》2004,326(1):45-51
The role of inducible nitric oxide synthase (iNOS) in the progression of fibrosis during nonalcoholic steatohepatitis remains to be elucidated. This study examined the role of iNOS in the progression of fibrosis during steatohepatitis by comparing iNOS knockout (iNOS−/−) and wild-type (iNOS+/+) mice that were fed a high-fat diet. Severe fatty metamorphosis developed in the liver of iNOS+/+ and iNOS−/− mice. Fibrotic changes were marked in iNOS−/− mice. Gelatin zymography showed that pro MMP-2 and pro MMP-9 protein expressions were more highly induced in iNOS+/+ mice than in iNOS−/− mice. Active forms of MMP-2 and MMP-9 were clearly present only in the liver tissue of iNOS+/+ mice. In situ zymography showed strong gelatinolytic activities in the liver tissue of iNOS+/+ mice, but only spotty activity in iNOS−/−mice. iNOS may attenuate the progression of liver fibrosis in steatohepatitis, in part by inducing MMP-2 and MMP-9 expression and augmenting their activity. 相似文献
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Hironori Adachi Tatsuya Kondo Rei Ogawa Norio Ishii Keishi Miyata Hiroyuki Motoshima Kaku Tsuruzoe Motohiro Takeya Gou Young Koh Toshio Suda Eiichi Araki 《Biochemical and biophysical research communications》2009,379(4):806-355
Angiopoietin-like protein family 4 (Angptl 4) has been shown to regulate lipoprotein metabolism through the inhibition of lipoprotein lipase (LPL). We generated ApoE−/−Angptl 4−/− mice to study the effect of Angptl 4 deficiency on lipid metabolism and atherosclerosis. Fasting and postolive oil-loaded triglyceride (TG) levels were largely decreased in ApoE−/−Angptl 4−/− mice compared with and ApoE−/−Angptl 4+/+ mice. There was a significant (75 ± 12%) reduction in atherosclerotic lesion size in ApoE−/−Angptl 4−/− mice compared with ApoE−/− Angptl 4+/+ mice. Peritoneal macrophages, isolated from Angptl 4−/− mice to investigate the foam cell formation, showed a significant decrease in newly synthesized cholesteryl ester (CE) accumulation induced by acetyl low-density lipoprotein (acLDL) compared with those from Angptl 4+/+ mice. Thus, genetic knockout of Angptl 4 protects ApoE−/− mice against development and progression of atherosclerosis and strongly suppresses the ability of the macrophages to become foam cells in vitro. 相似文献