No abstract

This study investigated the actions of fibroblast growth factor (FGF)-18, a novel member of the FGF family, on osteoblasts, chondrocytes, and osteoclasts and compared them with those of FGF-2 and FGF-10. FGF-18 stimulated the proliferation of cultured mouse primary osteoblasts, osteoblastic MC3T3-E1 cells, primary chondrocytes, and prechondrocytic ATDC5 cells, although it inhibited the differentiation and matrix synthesis of these cells. FGF-18 up-regulated the phosphorylation of extracellular signal-regulated kinase in both osteoblasts and chondrocytes and up-regulated the phosphorylation of p38 mitogen-activated protein kinase only in chondrocytes. FGF-18 mitogenic actions were blocked by a specific inhibitor of extracellular signal-regulated kinase in both osteoblasts and chondrocytes and by a specific inhibitor of p38 mitogen-activated protein kinase in chondrocytes. With regard to the action of FGF-18 on bone resorption, FGF-18 not only induced osteoclast formation through receptor activator of nuclear factor-B ligand and cyclooxygenase-2 but also stimulated osteoclast function to form resorbed pits on a dentine slice in the mouse coculture system. All these effects of FGF-18 bore a close resemblance to those of FGF-2, whereas FGF-10 affects none of these cells. FGF-18 may therefore compensate for the action of FGF-2 on bone and cartilage.Fibroblast growth factors (FGFs) 1 are potent mitogens for a wide variety of cells of mesenchymal and neuroectodermal origin (1). FGFs also play a role in the differentiation of a variety of cells and are involved in morphogenesis, angiogenesis, and development. The FGF family now consists of 23 members, FGF-1 to FGF-23, and there are 4 structurally related highaffinity receptors (FGFR1 to FGFR4) belonging to receptor tyrosine kinases that have an intrinsic protein tyrosine kinase activity and elicit tyrosine autophosphorylation of the receptor (1, 2). Recent reports showing that mutations of FGFRs cause several genetic diseases with severe impairment of bone and cartilage formation, such as achondroplasia (3, 4) and thanatophoric dysplasia type II (5), indicate the essential role of FGF signalings on bone and cartilage metabolism.Among FGFs, FGF-2 is well known as a potent regulator of functions of bone and cartilage cells. It is produced by cells of osteoblastic lineage, accumulated in bone matrix, and acts as an autocrine/paracrine factor for bone cells (6 -8). 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 (9 -11). In addition, the Fgf-2-deficient mouse exhibits decreased bone mass and bone formation, although these changes were rather moderate (12). Paradoxically, FGF-2 is also known as a potent stimulator of bone resorption (13-17) and is involved in joint destruction of rheumatoid arthritis patients (18). The stimulatory effect of FGF-2 on osteoclast formation is mediated by the induction of cyclooxygenase-2, a main regulatory enzyme for prostagland...

Ideally, artificial bones should be dimensionally compatible with deformities, and be biodegradable and osteoconductive; however, there are no artificial bones developed to date that satisfy these requirements. We fabricated novel custom-made artificial bones from alpha-tricalcium phosphate powder using an inkjet printer and implanted them in ten patients with maxillofacial deformities. The artificial bones had dimensional compatibility in all the patients. The operation time was reduced due to minimal need for size adjustment and fixing manipulation. The postsurgical computed tomography analysis detected partial union between the artificial bones and host bone tissues. There were no serious adverse reactions. These findings provide support for further clinical studies of the inkjet-printed custom-made artificial bones.

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...

We tested the hypothesis that induction of cyclo-oxygenase (COX) 2 mediates some effects of bone morphogenetic protein (BMP) 2 on bone. BMP-2 induced COX-2 mRNA and prostaglandin (PG) production in cultured osteoblasts. BMP-2 increased luciferase activity in calvarial osteoblasts from mice transgenic for a COX-2 promoter-luciferase reporter construct (