We previously reported that fibroblast growth factor-2 (FGF-2) acts not only on osteoblasts to stimulate osteoclastic bone resorption indirectly but also on mature osteoclasts directly. In this study, we investigated the mechanism of this direct action of FGF-2 on mature osteoclasts using mouse and rabbit osteoclast culture systems. FGF-2 stimulated pit formation resorbed by isolated rabbit osteoclasts moderately from low concentrations (>10 ؊12 M), whereas at high concentrations (>10 ؊9 M) it showed stimulation on pit formation resorbed by unfractionated bone cells very potently. FGF-2 (>10؊12 M) also increased cathepsin K and MMP-9 mRNA levels in mouse and rabbit osteoclasts. Among FGF receptors (FGFR1 to 4) only FGFR1 was detected on isolated mouse osteoclasts, whereas all FGFRs were identified on mouse osteoblasts. FGF-2 (>10 ؊12 M) upregulated the phosphorylation of cellular proteins, including p42/p44 mitogen-activated protein (MAP) kinase, and increased the kinase activity of immunoprecipitated FGFR1 in mouse osteoclasts. The stimulation of FGF-2 on mouse and rabbit osteoclast functions was abrogated by PD-98059, a specific inhibitor of p42/p44 MAP kinase. These results strongly suggest that FGF-2 acts directly on mature osteoclasts through activation of FGFR1 and p42/p44 MAP kinase, causing the stimulation of bone resorption at physiological or pathological concentrations.Among many growth factors regulating bone metabolism, fibroblast growth factor-2 (FGF-2 or basic FGF) 1 is recognized as a potent mitogen for a variety of mesenchymal cells (1). Several genetic diseases with severe impairment of bone and cartilage formation, such as achondroplasia (2-4) and thanatophoric dysplasia type II (5), have recently been shown to be caused by mutations of FGF receptors (FGFRs). In bone tissues, FGF-2 is produced by cells of osteoblastic lineage, is accumulated in bone matrix, and acts as an autocrine/paracrine factor for bone cells (6 -10). We and others have reported that the exogenous application of FGF-2 has stimulatory effects on bone formation in several in vivo models as a pharmacological action of FGF-2 (11-17). On the other hand, in vitro studies revealed that high concentrations of FGF-2 (10 Ϫ9 -10 Ϫ8 M) stimulated osteoclastogenesis in bone marrow culture (18) and bone resorption in bone organ cultures (19,20). This stimulatory effect of FGF-2 on bone resorption is known to be mediated at least in part by cyclooxygenase-2 (COX-2) induction and prostaglandin production (18,20), which cause the expression of osteoclast differentiation factor (RANKL/ODF), a key membrane-associated molecule that regulates osteoclast differentiation, in osteoblastic cells (21). Other than this indirect action through the mediation of osteoblasts, we recently reported that FGF-2 acts directly on mature osteoclasts to stimulate bone resorption (22).There are four structurally related high affinity receptors (FGFR1 to 4) belonging to receptor tyrosine kinases (RTKs) that have an intrinsic protein-tyrosine kinase activity and e...
Milk has more beneficial effects on bone health than other food sources. Recent in vitro and in vivo studies have shown that milk whey protein, especially its basic protein fraction (milk basic protein, MBP), contains several components capable of promoting bone formation and inhibiting bone resorption. The object of this study was to examine the effect of MBP on the bone metabolism of healthy menopausal women. Thirty-two healthy menopausal women were randomly assigned to treatment with either placebo or MBP (40 mg per day) for 6 months. The bone mineral density (BMD) of the lumbar vertebrae L2-L4 of each subject was measured by dual-energy X-ray absorptiometry (DXA) at 0 and 6 months of treatment. Serum and urine indices of bone metabolism were measured at 0, 3 and 6 months. Twenty-seven subjects who completed the study in accordance with the protocol were included in the analysis. The mean rate of gain of lumbar BMD in the MBP group (1.21%) was significantly higher than in the placebo group (-0.66%, P=0.046). When compared with the placebo group, urinary cross-linked N-telopeptides of type-I collagen (NTx) were significantly decreased in the MBP group at 6 months, but no significant difference in serum osteocalcin was observed between the two groups. The urinary NTx excretion was found to be related to serum osteocalcin in the MBP group at 3 and 6 months, indicating that MBP maintained the balance of bone remodeling. These results suggested that MBP supplementation was effective in preventing bone loss in menopausal women and that this improvement in BMD may be primarily mediated through the inhibition of bone resorption while maintaining the balance of bone remodeling by MBP supplementation.
The safety and efficacy of raloxifene, a selective estrogen receptor modulator (SERM), has been studied extensively in large, global clinical trials. However, the effect of raloxifene on bone mineral density (BMD) and on biochemical markers of bone turnover in Japanese postmenopausal women with osteoporosis has not been rigorously evaluated. This study was designed to assess the safety and efficacy of raloxifene in Japanese postmenopausal women with osteoporosis following 1 year of therapy. Participants in this multicenter trial were randomly assigned to receive placebo, raloxifene 60 mg/day (RLX60), or raloxifene 120 mg/day (RLX120). Lumbar spine BMD was measured at baseline, 24, 40, and 52 weeks, and biochemical markers of bone turnover were assessed at baseline, 12, 24, and 52 weeks. Serum lipids were assessed at baseline, 12, 24, 40, and 52 weeks, and breast examinations and transvaginal ultrasound of the endometrium were performed at enrollment and 52 weeks. Compared with baseline, women taking RLX60 had significant increases in lumbar spine (L2-L4) BMD at 24 weeks (+3.3%, p<0.001) through 52 weeks (+3.5%, p<0.001) of therapy, and similar results were observed in the RLX120 group. Markers of bone turnover and total cholesterol and LDL-C were significantly reduced, and no significant treatment-group difference was observed for patients reporting at least one adverse event following randomization. In addition, there were no reported venous thromboembolic events (VTE) in any treatment group. The results of this study demonstrate that raloxifene is associated with early increases in lumbar spine BMD, has favorable effects on biochemical markers of bone turnover and lipid profile, and is well tolerated in postmenopausal Japanese women.
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