Enhancement of osteogenesis in vitro and in vivo by a novel osteoblast differentiation promoting compound, TAK-778.
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TAK-778 [(2R,4S)-(-)-N-(4-diethoxyphosphorylmethylphenyl)-1,2,4, 5-tetrahydro-4-methyl-7, 8-methylenedioxy-5-oxo-3-benzothiepin-2-carboxyamide; mw 505.53], a novel osteoblast differentiation promoting compound, was characterized in vitro and in vivo models. TAK-778 at doses of 10(-6) M and higher promoted potently bone-like nodule formation in the presence of dexamethasone in rat bone marrow stromal cell culture. This was accompanied by increases in cellular alkaline phosphatase activity, soluble collagen release, and osteocalcin secretion. Under the culture conditions, TAK-778 also stimulated the secretion of transforming growth factor-beta and insulin-like growth factor-I, indicating that TAK-778 may exert regulatory effects on osteoblast differentiation via autocrine/paracrine mechanisms. Furthermore, the in vivo osteogenic potential of TAK-778 was studied in bony defect and osteotomy animal models, using sustained release microcapsules consisted of a biodegradable polymer, poly (dl-lactic/glycolic) acid (PLGA). Single local injection of TAK-778/PLGA-microcapsules (PLGA-MC) (0.2-5 mg/site) to rat skull defects resulted in a dose-dependent increase in new bone area within the defects after 4 weeks. When the pellet containing TAK-778/PLGA-MC (4 mg/pellet) was packed into place to fill the tibial segmental defect in rabbit, this pellet induced osseous union within 2 months, whereas the placebo pellet did not. In addition, single local application of TAK-778/PLGA-MC (10 mg/site) to rabbit tibial osteotomy site enhanced callus formation accompanied by an increase in breaking force after 30 days. These results reveal for the first time that a nonendogenous chemical compound promotes potently osteogenesis in vitro and enhances new bone formation during skeletal regeneration and bone repair in vivo and should be useful for the stimulation of fracture healing. (+info)
Acceleration of increase in bone mineral content by low-intensity ultrasound energy in leg lengthening.
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The effect of ultrasound energy on bone has been studied for a long time. In particular, multiple effects of low-intensity ultrasound energy have recently been demonstrated experimentally, such as increases in bending strength of fracture callus, acceleration of soft callus formation and endochondral ossification of the callus at the fracture site, stimulation of aggrecan gene expression, or modulation of TGF-beta synthesis and increase of calcium uptake. Clinically, prospective, randomized, and double-blind trials showed the efficacy of low-intensity ultrasound beam stimulation in the acceleration of fracture healing, with a significant decrease in the time to healing. On the other hand, callotasis, a popular method for bone lengthening, requires much time for new bone formation, and an external fixator must be remain on the patient for a long period. This is one of the major problems of the callotasis technique. If ultrasound energy stimulation could accelerate the rate of callus formation in callotasis, the external fixator could be removed earlier, the treatment period could be shortened, and the patient could return to daily activities more quickly. We report on the use low-intensity ultrasound beam stimulation during leg lengthening with the callotasis method in which callus formation was poor. (+info)
Bone morphogenetic proteins in human bone regeneration.
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Recently, the first clinical reports on bone regeneration by two recombinant human bone morphogenetic proteins (rhBMPs), BMP-2 and BMP-7 (also named osteogenic protein-1, OP-1) have been published (1-4). Although both BMPs were able to support bone regeneration, a significant variation in individual response was observed with both proteins. Animal studies and laboratory experiments reveal a number of conditions that influence the osteoinductivity of BMP, such as BMP concentration, carrier properties and influence of local and systemic growth factors and hormones. In this paper, these studies and the clinical reports are reviewed, and the conditions that modulate the BMP-dependent osteoinduction are discussed. The information may provide clues as to how the performance of recombinant human BMP as bone-graft substitute in humans can be improved. (+info)
Bone marrow stromal cells: characterization and clinical application.
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The bone marrow stroma consists of a heterogeneous population of cells that provide the structural and physiological support for hematopoietic cells. Additionally, the bone marrow stroma contains cells with a stem-cell-like character that allows them to differentiate into bone, cartilage, adipocytes, and hematopoietic supporting tissues. Several experimental approaches have been used to characterize the development and functional nature of these cells in vivo and their differentiating potential in vitro. In vivo, presumptive osteogenic precursors have been identified by morphologic and immunohistochemical methods. In culture, the stromal cells can be separated from hematopoietic cells by their differential adhesion to tissue culture plastic and their prolonged proliferative potential. In cultures generated from single-cell suspensions of marrow, bone marrow stromal cells grow in colonies, each derived from a single precursor cell termed the colony-forming unit-fibroblast. Culture methods have been developed to expand marrow stromal cells derived from human, mouse, and other species. Under appropriate conditions, these cells are capable of forming new bone after in vivo transplantation. Various methods of cultivation and transplantation conditions have been studied and found to have substantial influence on the transplantation outcome. The finding that bone marrow stromal cells can be manipulated in vitro and subsequently form bone in vivo provides a powerful new model system for studying the basic biology of bone and for generating models for therapeutic strategies aimed at regenerating skeletal elements. (+info)
Bone wound healing after maxillary molar extraction in ovariectomized aged rats: quantitative backscattered electron image analysis.
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The processes of bone wound healing after maxillary molar extraction in ovariectomized aged rats were examined by means of quantitative backscattered electron image analysis and energy-dispersive X-ray microanalysis. Six-month-old female rats were either sham-operated or underwent bilateral ovariectomy (OVX), and 60 days postoperatively, the maxillary first molars were extracted. On post-extraction days 7, 30, and 60, the dissected and resin-embedded maxillae were micromilled in the transverse direction through the extracted alveolar sockets, and new bone formation on the buccal maxillary bone surface and within the extracted alveolar sockets was examined. In both sham-operated control and OVX rats, new bone formation was recognized on the buccal bone surface, as well as within the extracted sockets, and increased daily through to day 60. In comparison to sham-operated controls, new bone formation in OVX rats was significantly decreased both on the buccal bone surface and within the extracted sockets. Our results suggest that bone wound healing by new bone formation after maxillary molar extraction is significantly decreased in OVX-induced osteoporosis. (+info)
Healing of erosions in rheumatoid arthritis.
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Reports on healing of erosions in rheumatoid arthritis are rare. However, it is expected that repair of erosions should be seen more often during the period of extensive use of disease modifying antirheumatic drugs, especially in patients who experience sustained remission. Two such cases are described. (+info)
A modular femoral implant for uncemented stem revision in THR.
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We present the early results of 142 uncemented femoral stem revisions using the modular MRP-Titan system. There were 70 cases with marked preoperative femoral bone defects (Paprosky type 2C and type 3); and bone grafts were used in 31 cases. At a mean follow-up of 2.3 years five cases were re-revised due to dislocation and two due to aseptic loosening. The mean Harris hip score improved from 37.4 preoperatively to 92.4. In 122 cases progressive bone regeneration on X-ray was seen; and no further osteolysis was observed. (+info)
The Wagner revision prosthesis consistently restores femoral bone structure.
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The short-term results are reported for 43 hip revision operations with the long-stemmed Wagner prosthesis. The patients were followed-up for an average of 25 months. The Charnley scores were; pain 5.2, movement 4.0 and walking 4.0. All patients except one showed abundant new bone formation. The stem subsided more than 20 mm in 5 patients and in 22 the subsidence was less than 5 mm. The major complication was dislocation, which occurred in 9 patients; 8 of these were reoperated and from then on remained stable. (+info)