Effects of basic fibroblast growth factor (bFGF) on bone formation in growing rats

Nagai, Hirofumi; Tsukuda, Ryoichi; Mayahara, Hiroshi

doi:10.1016/8756-3282(94)00049-2

Cited by 132 publications

(75 citation statements)

References 25 publications

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“…The ability of bFGF to stimulate the proliferation and differentiation of mesenchymal stem cells and osteoblast-like cells in vitro (Canalis et al, 1988;Globus et al, 1988;Pitaru et al, 1993;Martin et al, 1997) suggested that this growth factor may stimulate bone formation. Subsequent in vivo studies showed that IV treatment with bFGF markedly increased the osteoblast population and augmented bone mass in intact rats (Mayahara et al, 1993;Nagai et al, 1995;Nakamura et al, 1995). These initial findings were confirmed in ovariectomized (OVX) rats, a well-established animal model for postmenopausal bone loss (Kalu, 1991).…”

Section: Introductionsupporting

confidence: 51%

Selected Extraskeletal Effects of Systemic Treatment with Basic Fibroblast Growth Factor in Ovariectomized Rats

2005

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Basic fibroblast growth factor (bFGF) is a pleiotropic mitogen with a potent bone-forming effect, rendering it a potential osteoporosis therapy. This study examined selected extraskeletal effects of bFGF in ovariectomized rats, a well-established model of human postmenopausal osteopenia, to more fully characterize side effects associated with bFGF treatment. Five-month-old, osteopenic, ovariectomized rats were injected subcutaneously with vehicle or bFGF (1 mg/kg) daily for 3 weeks. Hematologic and biochemical analyses were performed; and kidneys, livers, and proximal tibiae were examined histologically and histomorphometrically. bFGF administration resulted in anemia that was due to a shift toward granulocyte production in the bone marrow. Increased granulocyte production was also observed in the liver of bFGF-treated rats, which exhibited a markedly increased number and area of hematopoietic foci. bFGF administration also caused mild glomerular hypertrophy that was not attended by significant biochemical evidence of glomerular dysfunction. The bone anabolic effect of subcutaneous bFGF administration was confirmed in the proximal tibia, and was associated with a significant decrease in urine fractional excretion of calcium in bFGF-treated rats. Though bFGF strongly stimulates bone formation at osteopenic skeletal sites, its extraskeletal effects may restrict the long-term use of bFGF in its current form as an osteoporosis therapy.

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Section: Introductionsupporting

confidence: 51%

Selected Extraskeletal Effects of Systemic Treatment with Basic Fibroblast Growth Factor in Ovariectomized Rats

2005

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“…Given at high concentrations, bFGFs and other growth factors have a toxic effect. Their biological efficacy after a one-dose local application at the concentrations we selected, namely 1-100 ng bFGF, and also at much higher doses, has been verified in numerous publications (Joseph-Silverstein and Rifkin 1987, Sprugel et al 1987, Broadley et al 1989, Burges 1989, Rifkin and Moscatelli 1989, Klingbeil et al 1991, Albertson et al 1993, Kawaguchi et al 1994, Nagai et al 1995, Okumura et al 1996, Leunig et al 1997, Kato et al 1998, McGee et al 1998. With the exception of one study , local application of the appropriate growth factor led to an acceleration of wound and fracture healing in all of the above studies.…”

Section: Discussionmentioning

confidence: 98%

“…In this regard, Nagai et al (1995) were able to prove both stimulatory and inhibitory effects on terminal osteoblast differentiation in the rat model, depending on the dose of bFGF and the duration of local application. Bland et al (1995) were the only research group unable to demonstrate accelerated fracture healing after the application of bFGF.…”

Section: Discussionmentioning

confidence: 98%

“…Clinical and animal experiments have shown that local application of growth factors may accelerate this restoration of vascularization/perfusion and lead to improvement of wound and fracture healing (Mustoe et al 1987, Sprugel et al 1987, Rifkin andMoscatelli 1989, Klingbeil et al 1991, Yasko et al 1992, Albertson et al 1993, Lind et al 1993, Kawaguchi et al 1994, Nash et al 1994, Nielsen et al 1994, Steenfos et al 1994, Heckman et al 1995, Nagai et al 1995, Richard et al 1995, Okumura et al 1996, Wang and Aspenberg 1996, Beer et al 1997, Davidson et al 1997, Leunig et al 1997, Bostrom and Camacho 1998, Kato et al 1998, McGee et al 1998, Wieman et al 1998, Corral et al 1999, Radomsky et al 1999, Bouxein et al 2001, Govender et al 2002, Luppen et al 2002, Einhorn et al 2003, Hom and Manivel 2003.…”

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confidence: 99%

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Local application of basic fibroblast growth factor increases the risk of local infection after trauma: An in-vitro and in-vivo study in rats

et al. 2007

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Introduction Local application of growth factors to stimulate wound and fracture healing is attracting increasing interest. We studied the effect of local application of a potent angiogenic growth factor, basic fibroblast growth factor (bFGF), on resistance to local infection after soft tissue trauma.Methods For in-vitro and in-vivo experiments, we used recombinant human bFGF. The in-vitro investigations were performed by isolation of human leukocyte fractions, cytokine analysis, phagocytosis assay, flow cytometry, and LDH assay. For the in-vivo investigation, a paired comparison of infection rates was carried out on Sprague-Dawley rats after standardized, closed soft tissue trauma and local, percutaneous bacterial inoculation of different concentrations of Staphylococcus aureus (2 × 10 4 to 2 × 10 7 colony-forming units (cfu)). The lower leg was treated with 1, 10 or 100 ng bFGF (16 animals for each concentration) and without bFGF (16 animals).Results Cytotoxic reactions due to the concentrations of bFGF used could be excluded in the in-vitro tests since incubations of isolated peripheral blood mononuclear cells (PBMCs) with increasing concentrations of bFGF for 24 h did not lead to an increase in the release of lactate dehydrogenase in the culture supernatants compared to corresponding control incubations without any bFGF added. A significant increase in cytokine release was observed after the co-incubation of PBMCs with 100 or 200 ng of the same bFGF that was used for the animal experiments. Furthermore, the capacity of

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“…FGF2 can act at several stages of osteoblast differentiation to differentially affect osteoblast function (Marie, 2003). In vivo, short-term administration of recombinant FGF2 has been shown to increase bone formation in intact rats (Nakamura et al, 1995;Nagai et al, 1995) and to exhibit bone anabolic effects on ovariectomized rats (Liang et al, 1999), presumably through the recruitment and expansion of osteo-progenitor populations. Genetic ablation of FGF2 results in impaired trabecular bone formation associated with decreased mineral apposition and bone formation rates, and stromal cells isolated from FGF2 null mice have a markedly reduced mineralization potential (Montero et al, 2000).…”

mentioning

confidence: 99%

Connexin43 Potentiates Osteoblast Responsiveness to Fibroblast Growth Factor 2 via a Protein Kinase C-Delta/Runx2–dependent Mechanism

Lima

Niger

Hebert

et al. 2009

MBoC

100

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In this study, we examine the role of the gap junction protein, connexin43 (Cx43), in the transcriptional response of osteocalcin to fibroblast growth factor 2 (FGF2) in MC3T3 osteoblasts. By luciferase reporter assays, we identify that the osteocalcin transcriptional response to FGF2 is markedly increased by overexpression of Cx43, an effect that is mediated by Runx2 via its OSE2 cognate element, but not by a previously identified connexin-responsive Sp1/Sp3-binding element. Furthermore, disruption of Cx43 function with Cx43 siRNAs or overexpression of connexin45 markedly attenuates the response to FGF2. Inhibition of protein kinase C delta (PKC␦) with rottlerin or siRNA-mediated knockdown abrogates the osteocalcin response to FGF2. Additionally, we show that upon treatment with FGF2, PKC␦ translocates to the nucleus, PKC␦ and Runx2 are phosphorylated and these events are enhanced by Cx43 overexpression, suggesting that the degree of activation is enhanced by increased Cx43 levels. Indeed, chromatin immunoprecipitations of the osteocalcin proximal promoter with antibodies against Runx2 demonstrate that the recruitment of Runx2 to the osteocalcin promoter in response to FGF2 treatment is dramatically enhanced by Cx43 overexpression. Thus, Cx43 plays a critical role in regulating the ability of osteoblasts to respond to FGF2 by impacting PKC␦ and Runx2 function. INTRODUCTIONBone formation and remodeling is a tightly organized and dynamic process that requires the coordinated action of osteoblasts, osteocytes, and osteoclasts to maintain bone homeostasis. It is hypothesized that osteoblasts and osteocytes coordinate their activities, at least in part, through direct cell-to-cell communication through gap junctions. Gap junctions are composed of connexins, a family of transmembrane proteins that constitute the intercellular gap junction channels (Beyer et al., 1990). Six connexins assemble to make up the gap junction hemichannel on the plasma membrane of one cell, which docks with a hemichannel on an adjacent cell to form an aqueous gap junction channel. The resultant gap junctions provide direct conduits for the passage of ions and other low molecular weight molecules, including second messengers, among cells.The gap junction protein connexin43 (Cx43) is abundantly expressed in both osteoblasts and osteocytes, where it has been hypothesized to transmit hormonal signals, mechanical load, and growth factor cues among cells in order to coordinate the synthesis of new bone (reviewed in Stains and Civitelli, 2005a;Jiang et al., 2007). Genetic ablation of gja1, the gene encoding Cx43, in mice leads to a severe delay in the ossification of both intramembranous and endochondral derived skeletal elements during embryonic development (Lecanda et al., 2000). The bones of these animals are remarkably brittle, and the osteoblasts isolated from the Cx43 null animals are dysfunctional, with reduced osteogenic and mineralizing capacity (Lecanda et al., 2000). These Cx43-deficient mice die at birth because of a defect in cardiac f...

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Effects of basic fibroblast growth factor (bFGF) on bone formation in growing rats

Cited by 132 publications

References 25 publications

Selected Extraskeletal Effects of Systemic Treatment with Basic Fibroblast Growth Factor in Ovariectomized Rats

Selected Extraskeletal Effects of Systemic Treatment with Basic Fibroblast Growth Factor in Ovariectomized Rats

Local application of basic fibroblast growth factor increases the risk of local infection after trauma: An in-vitro and in-vivo study in rats

Connexin43 Potentiates Osteoblast Responsiveness to Fibroblast Growth Factor 2 via a Protein Kinase C-Delta/Runx2–dependent Mechanism

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