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At least 1,207 records · Page 67Linked to original sources
PubMed2002

Interleukin-11 as a stimulatory factor for bone formation prevents bone loss with advancing age in mice.

Cytokines in interleukin (IL)-11 subfamily participate in the regulation of bone cell proliferation and differentiation. We report here positive effects of IL-11 on osteoblasts and bone formation. Overexpression of human IL-11 gene in transgenic mice resulted in the stimulation of bone formation to increase cortical thickness and strength of long bones, and in the prevention of cortical bone loss with advancing age. Bone resorption and osteoclastogenesis were not affected in IL-11 transgenic mice. In experiments in vitro, IL-11 stimulated transcription of the target gene for bone morphogenetic protein (BMP) via STAT3, leading to osteoblastic differentiation in the presence of BMP-2, but inhibited adipogenesis in bone marrow stromal cells. These results indicate that IL-11 is a stimulatory factor for osteoblastogenesis and bone formation to conserve cortical bone, possibly by enhancing BMP actions in bone. IL-11 may be a new therapeutic target for senile osteoporosis.

Aging↗
PubMed2004

Bone morphogenetic protein type IA receptor signaling regulates postnatal osteoblast function and bone remodeling.

Bone morphogenetic proteins (BMPs) function during various aspects of embryonic development including skeletogenesis. However, their biological functions after birth are less understood. To investigate the role of BMPs during bone remodeling, we generated a postnatal osteoblast-specific disruption of Bmpr1a that encodes the type IA receptor for BMPs in mice. Mutant mice were smaller than controls up to 6 months after birth. Irregular calcification and low bone mass were observed, but there were normal numbers of osteoblasts. The ability of the mutant osteoblasts to form mineralized nodules in culture was severely reduced. Interestingly, bone mass was increased in aged mutant mice due to reduced bone resorption evidenced by reduced bone turnover. The mutant mice lost more bone after ovariectomy likely resulting from decreased osteoblast function which could not overcome ovariectomy-induced bone resorption. In organ culture of bones from aged mice, ablation of the Bmpr1a gene by adenoviral Cre recombinase abolished the stimulatory effects of BMP4 on the expression of lysosomal enzymes essential for osteoclastic bone resorption. These results demonstrate essential and age-dependent roles for BMP signaling mediated by BMPRIA (a type IA receptor for BMP) in osteoblasts for bone remodeling.

Alkaline Phosphatase↗
PubMed2004

Amylin inhibits bone resorption while the calcitonin receptor controls bone formation in vivo.

Amylin is a member of the calcitonin family of hormones cosecreted with insulin by pancreatic beta cells. Cell culture assays suggest that amylin could affect bone formation and bone resorption, this latter function after its binding to the calcitonin receptor (CALCR). Here we show that Amylin inactivation leads to a low bone mass due to an increase in bone resorption, whereas bone formation is unaffected. In vitro, amylin inhibits fusion of mononucleated osteoclast precursors into multinucleated osteoclasts in an ERK1/2-dependent manner. Although Amylin +/- mice like Amylin-deficient mice display a low bone mass phenotype and increased bone resorption, Calcr +/- mice display a high bone mass due to an increase in bone formation. Moreover, compound heterozygote mice for Calcr and Amylin inactivation displayed bone abnormalities observed in both Calcr +/- and Amylin +/- mice, thereby ruling out that amylin uses CALCR to inhibit osteoclastogenesis in vivo. Thus, amylin is a physiological regulator of bone resorption that acts through an unidentified receptor.

Amyloid↗
PubMed2002

Demineralized bone matrix and native bone morphogenetic protein in orthopaedic surgery.

The recognition that demineralized bone matrix could induce bone formation when placed in mammalian skeletal muscle led to preclinical studies of crude native insoluble bone morphogenetic protein and noncollagenous protein, followed by the clinical application of demineralized bone matrix, chemosterilized autolyzed antigen-extracted allogenic bone, and autolyzed antigen-extracted allogenic bone matrix gelatin. Cultural norms and regulatory agencies influence the availability of different demineralized bone matrix preparations in different parts of the world, but there is continued interest in the biologic structure of native insoluble bone morphogenetic protein and noncollagenous protein aggregates and the applied science of osteoinduction and osteoconduction in reconstructive orthopaedic surgery. Demineralized bone matrix is not widely available in Asia, but tissue processing facilities in the United States distribute demineralized bone matrix materials with different carriers, handling properties, and possibly osteoinductive potential. The purpose of the current study was to review the development and use of various preparations of demineralized bone matrix materials.

Animals↗
PubMed2001

Prefabricated vascularized bone flap: a tissue transformation technique for bone reconstruction.

In this study, an attempt was made to transform a muscle vascularized pedicle raised on host vessels into a vascularized bone flap, using recombinant human bone morphogenetic protein 2 (rhBMP-2). The purpose of this study was to produce new bone vascularized in nature to increase the survival rate of the subsequently grafted bone and to fabricate the newly formed bone into the desired shape. Silicone molds in the shape of a rat mandible were used to deliver rat bone matrix impregnated with or without rhBMP-2. A muscle pedicle the same size as the mold was raised on the saphenous vessels in the rat thigh and then sandwiched in the center of the silicone molds. The molds were sliced in half and each section was filled with rat bone matrix that was impregnated either with 25 microg of rhBMP-2 for the experimental group or with diluting material alone for the control group. The sandwiched flaps were then secured by tying them to the adjacent muscles and were harvested at 2 and 4 weeks after surgery. Three and six rats were used in the control and experimental groups at each time point, respectively. Bone formation was assessed in the ex vivo specimens by macroscopic, radiologic, and histologic evaluation. Macroscopically, the continuation of the vascular pedicle was clearly visible for both the control and experimental muscle flaps. However, no evidence of muscle-tissue transformation was observed in the control flaps, whereas all the flaps treated with rhBMP-2 produced new bone that replicated the shape of the mold exactly and had saphenous vessels supplying the newly formed bone. This study demonstrates that this experimental model has the potential to be therapeutically applied for effective bone reconstruction.

Animals↗
PubMedDate not supplied

Age-related bone loss: old bone, new facts.

The human skeleton serves several functions for the body: support, locomotion, protection of vital organs, and housing of bone marrow. Bone remodeling is the result of the interactions of multiple elements, including osteoblasts, osteoclasts, hormones, growth factors, and cytokines, the end result being the maintenance of the bone architecture and to maintain systemic calcium homeostasis. In early life, a careful balance exists between bone formation by osteoblasts and bone resorption by osteoclasts. With aging, the process of coupled bone formation is affected by the reduction of osteoblast differentiation, activity, and life span which is further potentiated in the perimenopausal years with hormone deprivation and increased osteoclast activity. Age-related bone loss is thus not only a consequence of hormone deprivation, but also the result of changes in bone formation and cell-cell interactions with a unique pathophysiology. In this review, we describe the cellular and metabolic changes associated with aging bone and present recent evidence regarding cell differentiation within the bone marrow. We also consider the mechanism of programmed cell death, apoptosis, as being an important determinant of aging in bone as well as describe possible future interventions to prolong the life span of osteoblasts.

Adipocytes↗
PubMed2000

Critical ages and stages of puberty in the accumulation of spinal and femoral bone mass: the validity of bone mass measurements.

In growing children, lumbar and femoral areal bone mineral density (aBMD), as measured by dual-energy X-ray absorptiometry (DXA), is influenced by skeletal growth and bone size. Correction of lumbar bone mineral density (BMD) for bone volume (volumetric BMD [vBMD]), by the use of mathematical extrapolations, reduces the confounding effect of bone size, but vBMD remains dependent on age and bone size during growth. Femoral (neck and mid-shaft) vBMD, assessed by DXA, is independent of age prior to puberty, but a slight increase occurs in late puberty and after menarche. Femoral (mid-shaft) cortical bone density and radial cortical and trabecular bone densities, assessed by quantitative computed tomography (QCT), show no peak during childhood or adolescence. Bone strength index, calculated by peripheral QCT, increases with age and correlates with handgrip strength, bone cross-sectional area and cortical area. Puberty is one of the main factors that influences lumbar bone mineral content and aBMD accumulation, but a high incidence of fractures occurs during this period of life, which may be associated with a reduced aBMD.

Absorptiometry, Photon↗
PubMed1985

An in vitro assay of bone development using fetal long bones of mice: morphological studies.

The purpose of this study was to examine the morphological changes in an in vitro system in which the two elements of bone modelling, formation and resorption, could be studied simultaneously. Pregnant mice were killed on days 15, 16 and 17 of gestation, the fetuses were removed and the radii and ulnae dissected free of soft tissue. The bones were cultured for 6 days in media (BGJ) supplemented with 20% fetal calf serum and 150 micrograms/ml vitamin C. Growth and mineralization were estimated by measuring the total length of the bone, and diaphysis, and by light and transmission electron microscopy (TEM). The results of this study indicate that there is a continuous measurable increase in the total length of fetal mouse long bones over the 6 days of culture. These bones show a continuous growth of periosteal bone, with mesenchymal tissue penetrating into the diaphyseal shaft, and development of bone marrow like tissue. TEM examination showed differentiation of mesenchymal cells to osteoblasts, formation of new bone matrix and bone mineralization similar to that found in developmentally matched controls. In the cartilagenous epiphyses, however, many hydroxyapatite crystals were not associated with matrix vesicles. In addition, some of the chondrocytes of the hypertrophic zone appeared to be dedifferentiating into mesenchymal cells with osteoblast-like features. In spite of the lack of osteoclasts in the 15- and 16-day explants, osteoclasts appeared in the diaphysis after 2 and 4 days in culture. Our results suggest that this system can serve as a good model for the study of bone formation and resorption as they occur, simultaneously, during bone modelling.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1983

Increase in serum bone gamma-carboxyglutamic acid protein with aging in women. Implications for the mechanism of age-related bone loss.

Because it is unclear whether age-related bone loss results from increased bone resorption, decreased bone formation or both, we measured the serum level of bone Gla-protein (BGP), a specific marker for bone turnover, in 174 women, ages 30 to 94 yr. Serum BGP increased linearly with aging (r = 0.44, P less than 0.001) from 4.4 +/- 0.4 (mean +/- SE) in the 4th decade to 8.9 +/- 0.9 ng/ml in the 10th decade. This increase correlated inversely (P less than 0.001) with concomitant decreases in bone mineral density at the lumbar spine, midradius, and distal radius. Using partial correlation coefficients, serum BGP still correlated positively with age (r = 0.31, P less than 0.001) after creatinine clearance was fixed but not with creatinine clearance (r = -0.04, NS) when age was fixed. Urinary hydroxyproline (r = 0.29, P less than 0.001), an index of bone resorption, and serum alkaline phosphatase (r = 0.31, P less than 0.001), an index of bone formation, also increased with age and these increases correlated with increases in serum BGP (r = 0.39, P less than 0.001 and r = 0.43, P less than 0.001, respectively). Serum immunoreactive parathyroid hormone concentrations (r = 0.39, P less than 0.001) and urinary cyclic AMP excretion (r = 0.38, P less than 0.001) increased, suggesting that PTH secretion increased with age; these increases correlated significantly with increases in serum BGP. A subgroup of 32 women who were found to have vertebral fractures, hip fractures, or both had significantly higher values for serum BGP than the remainder. These data suggest that overall bone turnover increases in women with aging and, especially considering the concomitant decrease in skeletal mass, do not support the view that age-related bone loss results primarily from decreased bone formation.

1-Carboxyglutamic Acid↗
PubMed2004

Decreased bone turnover and deterioration of bone structure in two cases of pycnodysostosis.

Pycnodysostosis is an uncommon human genetic disorder characterized by osteosclerosis of the skeleton, short stature, and bone fragility. The disease results from mutations in the cathepsin K gene, a lysosomal cysteine protease highly expressed in osteoclasts and crucial for the degradation of organic matrix from mineralized bone. Recently, interest has focused on a pharmaceutical inhibition of cathepsin K to prevent bone loss. However, little is known about the cellular activity or material quality of bone in pycnodysostosis. In the present study, transiliac bone biopsies from two affected individuals, aged 5 and 21 yr, were investigated using light microscopy, quantitative backscattered electron imaging, and small angle x-ray scattering. Results were compared with published age-matched reference data. The mutations in the cathepsin K gene of both patients were identified, including one novel defect. Both individuals had severe osteosclerosis, and their biopsies displayed multinucleated osteoclasts apposed to areas of demineralized matrix as well as bone-lining cells adjacent to this undigested collagen left over by osteoclasts. The homogeneity of the mineralized matrix was markedly disturbed due to large inclusions of mineralized cartilage residues. Histomorphometric evaluation showed a quantitative decrease in static parameters of bone formation. In contrast and despite deficient cathepsin K activity, osteoclastic parameters were close to normal range. At the nanostructural level, there was a marked increase in the mean thickness of the mineral particles, reflecting decreased bone remodeling. Examination of the trabecular structure revealed that the lamellae were highly disordered, which was also apparent from a poor alignment of mineral crystals oriented along the longitudinal axis of collagen fibrils. Taken together, these results strongly suggest that functional cathepsin K is important for balanced bone turnover, and enzyme deficiency results in a profound deterioration of bone quality with respect to trabecular architecture and lamellar arrangement, which is presumably the reason for bone fragility in pycnodysostosis.

Adult↗
PubMed2006

Childhood fractures are associated with decreased bone mass gain during puberty: an early marker of persistent bone fragility?

UNLABELLED: Whether peak bone mass is low among children with fractures remains uncertain. In a cohort of 125 girls followed over 8.5 years, 42 subjects reported 58 fractures. Among those, BMC gain at multiple sites and vertebral bone size at pubertal maturity were significantly decreased. Hence, childhood fractures may be markers of low peak bone mass acquisition and persistent skeletal fragility. INTRODUCTION: Fractures in childhood may result from a deficit in bone mass accrual during rapid longitudinal growth. Whether low bone mass persists beyond this period however remains unknown. MATERIALS AND METHODS: BMC at the spine, radius, hip, and femur diaphysis was prospectively measured over 8.5 years in 125 girls using DXA. Differences in bone mass and size between girls with and without fractures were analyzed using nonparametric tests. The contribution of genetic factors was evaluated by mother-daughter correlations and that of calcium intake by Cox proportional hazard models. RESULTS: Fifty-eight fractures occurred in 42 among 125 girls (cumulative incidence, 46.4%), one-half of all fractures affecting the forearm and wrist. Girls with and without fractures had similar age, height, weight. and calcium intake at all time-points. Before and during early puberty, BMC and width of the radius diaphysis was lower in the fracture compared with no-fracture group (p < 0.05), whereas aBMD and BMAD were similar in the two groups. At pubertal maturity (Tanner's stage 5, mean age +/- SD, 16.4 +/- 0.5 years), BMC at the ultradistal radius (UD Rad.), femur trochanter, and lumbar spine (LS), and LS projected bone area were all significantly lower in girls with fractures. Throughout puberty, BMC gain at these sites was also decreased in the fracture group (LS, -8.0%, p = 0.015; UD Rad., -12.0%, p = 0.004; trochanter, -8.4%, p = 0.05 versus no fractures). BMC was highly correlated between prepuberty and pubertal maturity (R = 0.54-0.81) and between mature daughters and their mothers (R = 0.32-0.46). Calcium intake was not related to fracture risk. CONCLUSIONS: Girls with fractures have decreased bone mass gain in the axial and appendicular skeleton and reduced vertebral bone size when reaching pubertal maturity. Taken together with the evidence of tracking and heritability for BMC, these observations indicate that childhood fractures may be markers for low peak bone mass and persistent bone fragility.

Aging↗
PubMed2002

Leptin directly regulates bone cell function in vitro and reduces bone fragility in vivo.

Fat mass is an important determinant of bone density, but the mechanism of this relationship is uncertain. Leptin, as a circulating peptide of adipocyte origin, is a potential contributor to this relationship. Recently it was shown that intracerebroventricular administration of leptin is associated with bone loss, suggesting that obesity should be associated with low bone mass, the opposite of what is actually found. Since leptin originates in the periphery, an examination of its direct effects on bone is necessary to address this major discrepancy. Leptin (>10(-11) m) increased proliferation of isolated fetal rat osteoblasts comparably with IGF-I, and these cells expressed the signalling form of the leptin receptor. In mouse bone marrow cultures, leptin (>or=10(-11) m) inhibited osteoclastogenesis, but it had no effect on bone resorption in two assays of mature osteoclasts. Systemic administration of leptin to adult male mice (20 injections of 43 micro g/day over 4 weeks) reduced bone fragility (increased work to fracture by 27% and displacement to fracture by 21%, P<0.001). Changes in tibial histomorphometry were not statistically significant apart from an increase in growth plate thickness in animals receiving leptin. Leptin stimulated proliferation of isolated chondrocytes, and these cells also expressed the signalling form of the leptin receptor. It is concluded that the direct bone effects of leptin tend to reduce bone fragility and could contribute to the high bone mass and low fracture rates of obesity. When administered systemically, the direct actions of leptin outweigh its centrally mediated effects on bone, the latter possibly being mediated by leptin's regulation of insulin sensitivity.

Animals↗
PubMed1999

The effects of alendronate on bone turnover and bone quality.

During Phase III clinical trials with alendronate, biochemical and histological studies assessed bone turnover and bone quality in patients treated for 3 years. Patients were randomised in double-blind fashion to receive placebo, alendronate 5 or 10 mg/day for 3 years or 20 mg/day for 2 years followed by 5 mg/day for 1 year. All patients also received 500 mg/day of calcium carbonate. Decreases in bone resorption with alendronate preceded decreases in bone formation. After approximately 6 months of continuous treatment, a new steady state of bone turnover was attained, leading to the increase in bone density. No subsequent decrease in the rate of bone turnover or of frozen bone was noted. Alendronate treatment did not impair bone mineralisation, induce the formation of woven bone or have any other adverse effects on bone quality.

Alendronate↗
PubMed2006

Physiological bases of bone regeneration I. Histology and physiology of bone tissue.

Bone is the only body tissue capable of regeneration, allowing the restitutio ad integrum following trauma. In the event of a fracture or bone graft, new bone is formed, which following the remodeling process is identical to the pre-existing. Bone is a dynamic tissue in constant formation and resorption. This balanced phenomena, known as the remodeling process, allows the renovation of 5-15% of the total bone mass per year under normal conditions. Bone remodeling consists of the resorption of a certain amount of bone by osteoclasts, likewise the formation of osteoid matrix by osteoblasts, and its subsequent mineralization. This phenomenon occurs in small areas of the cortical bone or the trabecular surface, called Basic Multicellular Units (BMU). Treatment in Traumatology, Orthopedics, Implantology, and Maxillofacial and Oral Surgery, is based on the biologic principals of bone regeneration, in which cells, extracellular matrix, and osteoinductive signals are involved. The aim of this paper is to provide an up date on current knowledge on the biochemical and physiological mechanisms of bone regeneration, paying particular attention to the role played by the cells and proteins of the bone matrix.

Bone Matrix↗
PubMed2006

Characteristic features of disseminated carcinomatosis of the bone marrow due to gastric cancer: the pathogenesis of bone destruction.

Disseminated carcinimatosis of the bone marrow is accompanied by solid tumors, and gastric cancer accounts for the majority. The prognosis of this condition is poor, however, the pathogenesis for wide-spread bone lesions has yet to be elucidated. In 9 patients with gastric cancer demonstrating disseminated carcinomatosis of the bone marrow, the characteristic clinicopathological features were examined. Immunohistochemistry for receptor activator of NF-kappaB ligand (RANKL) and parathyroid hormone-related protein was also performed on gastric cancer tissue and bone marrow specimens to identify the factors responsible for the occurrence of bone lesions in patients presenting with this condition. The characteristic features of disseminated carcinomatosis of the bone marrow due to gastric cancer include a yonger patient age, an elevation of serum alkaline phosphatase and/or lactate dehydrogenase levels, wide-spread bone metastases with osteolytic bone destruction, a low incidence of hypercalcemia and a histological gastric cancer type of either signet ring cell carcinoma or poorly diffentiated adenocarcinoma. The expression of RANKL, which is one of the master regulators of osteoclastic bone resorption in bone metastasis, was also found in gastric cancer cells obtained from such patients. The RANKL expressed in gastric cancer may therefore play a critical role in the promotion of osteoclast formation, which has been suggested to be involved in the pathogenesis of bone lesions.

Adult↗
PubMed1987

Bridging large defects in bone by demineralized bone matrix in the form of a powder. A radiographic, histological, and radioisotope-uptake study in rats.

Demineralized bone powder was used as an osteoinductive substance to bridge very large defects (more than 50 per cent of the total length of the bone) in one radius of each of thirty-three rats. An identical defect was produced in the contralateral radius of each animal for use as a control. The defect on the control side was left unbridged or was bridged by large chips of autologous bone or an autologous inlay graft. All rats showed formation of new bone throughout the length of the radial defect only on the side in which the demineralized bone powder had been implanted. The control side, in which an autologous graft in the form of chips or inlay had been implanted, showed resorption of the graft. The maximum rate of formation of bone occurred fifteen to twenty-one days after implantation of the demineralized bone powder. At thirty-five days, the experimental defect was fully bridged, forming solid bone, in 71 per cent of the rats, and the remaining 29 per cent showed bridging of 95.8 per cent of the length of the defect, with union on one side. Analysis of the sequential radiographs, technetium-99m scans, and histological findings showed that the formation of bone and bridging of the defect were superior on the side in which the demineralized bone powder had been implanted compared with the side in which pieces of autologous bone or an autologous inlay graft had been used.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMedDate not supplied

Experimental spinal fusion with decalcified bone matrix and deep-frozen allogeneic bone in rabbits.

The effects of allogeneic decalcified bone matrix (DBM) on the formation of bone between the spinous processes of the rabbit vertebrae was compared with the effects of allogenic deep-frozen cortical bone (AFB). Autologous cancellous bone (ACB) chips were used for a control substance. Healing was estimated by gross anatomical roentgenologic and microscopic methods one, two, four and six months after the operation. The ACB and DBM transplants gave comparable results. A stable bony bridge was formed at one month, and this was seen to strengthen during the follow-up time. Both transplanting materials were accepted by the host without foreign body reactions. Inflammatory cell accumulations and sequesterated particles were not seen in any of the specimens with ACB and DBM transplants. The DBM induced new bone formation and the transplanted material was resorbed within two months after the operation. The AFB transplants did not induce the new bone formation, but the implanted fragments in contact with the host bone were surrounded by the callus, which produced a bony bridge but only as late as four months after the operation. After six months, the bridging was incomplete and sequestered bone particles were still seen in some of the specimens. The AFB transplants were slowly resorbed and accumulations of inflammatory cells were present at least six months postoperation. The results indicate that in rabbits, decalcified bone matrix is a better substitute for autologous bone than the allogeneic deep-frozen cortical bone.

Animals↗
PubMed1995

The mechanism of bone induction and bone healing by human osteosarcoma cell extracts.

Saos-2 cultured human osteosarcoma cells contain an extractable bone inducing agent that can induce heterotopic bone in the muscle of Nu/Nu mice. A semipurified GuHCl extract of Saos-2 cells also can promote healing and complete bony union in otherwise non-healing surgically induced defects of rat femur. Northern blot analyses indicate expression of mRNAs for bone morphogenetic proteins (BMP)-1, 2, 3, 4, 6 and transforming growth factor beta (TGF beta) in Saos-2 cells, and BMP-2, 3, 4, 5, 7 and TGF beta in nonosteoinductive U20S human osteosarcoma cells. Saos-2 cells exceeded U20S cells in expression levels of BMP-1, 3, 4 and TGF beta, whereas U20S cells expressed higher levels of BMP-2, 6 and also expressed trace amounts of BMP-5 and 7 not seen in Saos-2 cells. The authors hypothesize that Saos-2 cells contain an optimal admixture of known bone growth factors plus possible other unknown components that, acting alone or in combination with bone morphogenetic protein and/or TGF beta, can induce bone. Although bone inducing agent-induced heterotopic bones have half lives of only a few weeks, the reparative bone induced by bone inducing agent in femoral defects gives every indication of being permanent and self-sustaining. This suggests a fundamental difference between heterotopic and orthotopic osteoprogenitor cells with those involved in orthotopic bone repair more closely resembling the committed or determined osteoprogenitor cells of marrow as described by Friedenstein.

Animals↗