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PubMed1992

The healing of segmental bone defects, induced by recombinant human bone morphogenetic protein (rhBMP-2). A radiographic, histological, and biomechanical study in rats.

Subcutaneous implants of a recombinant human form of the bone-inducing protein rhBMP-2 (recombinant human bone morphogenetic protein-2) in rats have resulted in the local induction of endochondral bone formation. To test the osteoinductive activity of rhBMP-2 in an osseous location, we created five-millimeter segmental defects in the femora of forty-five adult male Sprague-Dawley rats. Two doses of lyophilized rhBMP-2 (1.4 or 11.0 micrograms) were implanted in each defect, together with guanidine-hydrochloride extracted demineralized rat-bone matrix as a carrier, and the results were compared with those in rats that had implantation of guanidine-hydrochloride extracted demineralized rat-bone matrix only. The formation and healing of bone were determined by radiographic, histological, and mechanical analysis. Both doses of rhBMP-2 induced formation of endochondral bone in the osseous defects in a dose-related manner. Implantation of 11.0 micrograms of rhBMP-2 yielded significant (p less than 0.05) bone formation, resulting in radiographic, histological, and mechanical evidence of union. Despite new-bone formation in the defects that had received 1.4 micrograms of rhBMP-2, no instances of union were observed.

Animals↗
PubMedDate not supplied

Radioactive isotope labeled diffusible components of a bone morphogenetic substratum.

Bone matrix gelatin labeled with radioactive glucose, cysteine, proline, tyrosine or tryptophan was enclosed in one chamber while an adjoined second chamber was left empty to become filled with interstitial fluid. The paired diffusion chambers were implanted into the anterior abdominal wall of allogeneic rats for 14 days. Release of the matrix gelatin (BMG) from the loaded chamber was followed by a bone formation on the outer membrane of the unloaded chamber. 3H-cysteine labeled components of BMG were disseminated into the interstitial fluids and throughout the host tissues 5 times more rapidly than 3H-proline labeled BMG. The relative rates of loss of radioactivity from the residue was cysteine greater than tryptophan greater than tyrosine greater than proline. Electron microscopic autoradiography revealed random dissemination of collagenous and non-collagenous derivatives of BMG. 3H-glucose distribution was coordinated with ruthenium red staining coarse granules and may have originated from BMG. A component of interstitial fluid staining positively with Coomassie brilliant blue and PAS methods was identified by SDS polyacrylamide gel electrophoresis of interstitial fluid aspirated from empty chambers attached to chambers loaded with bone matrix gelatin. The character of the bone morphogenetic property in bone gelatin has not yet been defined in physico-chemical terms but present evidence points to the view that it is associated with a protein molecule.

Animals↗
PubMed2002

[Experimental fusion of the sheep cervical spine. Part II: Effect of growth factors and carrier systems on interbody fusion].

INTRODUCTION: A sheep cervical spine interbody fusion model was used to determine the effect of different carriers and growth factors on interbody bone matrix formation. The purpose of this study was to compare the efficacy and safety of combined IGF-I and TGF-beta1 application with BMP-2 application in spinal fusion. Additionally, a new poly (D, L-lactide) carrier system was compared to a collagen sponge carrier. METHOD: Forty sheep underwent C3/4 discectomy and fusion: group 1: titanium cage ( n=8), group 2: titanium cage coated with a PDLLA carrier (n=8), group 3: titanium cage coated with a PDLLA carrier including BMP-2 ( n=8), group 4: titanium cage with a collagen carrier including BMP-2 ( n=8), and group 5: titanium cage coated with a PDLLA carrier including IGF-I and TGF-beta1 ( n=8). Blood samples, body weight, and temperature were analyzed. Radiographic scans were performed pre- and postoperatively and after 1, 2, 4, 8, and 12 weeks, respectively. At the same time points, disc space height (DSH) and intervertebral angle (IVA) were measured. After 12 weeks the animals were killed and fusion sites were evaluated using functional radiographic views in flexion and extension. Quantitative computed tomographic scans (QCT) were performed to assess bone mineral density (BMD), bone mineral content (BMC), and bony callus volume (BCV). Biomechanical testing was carried out in flexion, extension, axial rotation, and lateral bending. Range of motion (ROM), neutral zone (NZ), and elastic zone (EZ) were determined. Histomorphological and histomorphometrical analyses were performed and polychrome sequential labeling was used to determine the time frame of new bone formation. RESULTS: In comparison to the non-coated cages, all PDLLA-coated cages showed significantly higher values for BMD of the callus and bone volume/total volume ratio. In comparison to the cage groups (groups 1 and 2), the cage plus BMP-2 (groups 3 and 4) and the cage plus IGF-I and TGF-beta1 group (group 5) demonstrated a significantly higher fusion rate in radiographic findings, a higher biomechanical stability, an advanced interbody fusion in histomorphometric analysis, and an accelerated interbody fusion on fluorochrome sequence labeling. BMP-2 application by the PDLLA carrier system (group 3) demonstrated significantly higher bony callus volume than BMP-2 application by a collagen sponge carrier (group 4). The BMP-2 group (group 3) showed significantly lower residual motion on functional radiographic evaluation and higher intervertebral bone matrix formation on fluorochrome sequence labeling at 9 weeks in comparison to the IGF-I/TGF-beta1 group (group 5). In contrast, the IGF-I/TGF-beta1 group (group 5) showed a significantly higher bone mineral density of the callus than the BMP-2 group (group 3). CONCLUSION: PDLLA coating of cervical spine interbody fusion cages as a delivery system for growth factors was effective and safe. In comparison to the collagen sponge carrier, the new PDLLA carrier system was able to improve results of interbody bone matrix formation. Both growth factors (BMP-2 and combined IGF-I and TGF-beta1) significantly accelerated results of interbody fusion. Based on these preliminary results, the combined IGF-I/TGF-beta1 application yields results equivalent to BMP-2 application at an early time in anterior sheep cervical spine fusion.

Animals↗
PubMed2002

Osteoblastic response to the defective matrix in the osteogenesis imperfecta murine (oim) mouse.

This work examines the cellular pathophysiology associated with the weakened bone matrix found in a murine model of osteogenesis imperfecta murine (oim). Histomorphometric analysis of oim/oim bone showed significantly diminished bone mass, and the osteoblast and osteoclast histomorphometric parameters were increased in the oim/oim mice, compared with wild-type (+/+) mice. To assess osteoblast activity, a rat Col1a1 promoter linked to the chloramphenicol acetyltransferase reporter transgene was bred into the oim model. At 8 d and 1 month of age, no difference in transgene activity between oim and control mice was observed. However, at 3 months of age, chloramphenicol acetyl transferase activity was elevated in oim/oim;Tg/Tg, compared with +/+;Tg/Tg and oim/+;Tg/Tg. High levels of urinary pyridinoline crosslinks in the oim/oim;Tg/Tg mice were present at all ages, reflecting continuing high bone resorption. Our data portray a state of ineffective osteogenesis in which the mutant mouse never accumulates a normal quantity of bone matrix. However, it is only after the completion of the rapid growth phase that the high activity of the oim/oim osteoblast can compensate for the high rate of bone resorption. This relationship between bone formation and resorption may explain why the severity of osteogenesis imperfecta decreases after puberty is completed. The ability to quantify high bone turnover and advantages of using a transgene that reflects osteoblast lineage activity make this a useful model for studying interventions designed to improve the bone strength in osteogenesis imperfecta.

Amino Acids↗
PubMed1997

Lipids closely associated with bone morphogenetic protein (BMP)--and induced heterotopic bone formation. With preliminary observations of deficiencies in lipid and osteoinduction in lathyrism in rats.

An extensive literature on bone morphogenetic protein (BMP) induced generation and regeneration shows general agreement about one observation. The incidence and quantity of bone were greatest when BMP was delivered with a carrier of various biologic and non biologic polymers. In the present research, neutral lipids either endogenous in demineralized bone matrix (DBM) or exogenous in orign were employed as a delivery system for induced heterotopic bone formation in the rectus muscle in rats. Total neutral lipids including cholesterol were measured by correlated gravimetric and Sudan Black B dye binding methods. The heterotopic bone was measured by computer assisted radiomorphometric and histologic methods. Bone formation was measured by total calcium, DNA-P, and alkaline phosphatase activity. Composites of BMP and neutral lipids, separable from phospholipids by extraction with absolute acetone, were consistently osteoinductive. A significant quantity of the total bone lipid was closely associated with and extractable from the bone matrix non-collagenous protein fraction which had high levels of BMP activity. Lathyritic matrix was very low both in dye binding and osteoinductive activity. These observations suggest the possibility that lipids may serve as a BMP carrier in the process of induced bone development.

Alkaline Phosphatase↗
PubMed1988

Skeletal tissue and transforming growth factor beta.

Normal skeletal growth results from a balance between the processes of bone matrix synthesis and resorption. These activities are regulated by both systemic and local factors. Bone turnover is dynamic, and skeletal growth must be maintained throughout life. Although many growth promoters are associated with bone matrix, it is enriched particularly with transforming growth factor beta (TGF-beta) activity. Experimental evidence indicates that TGF-beta regulates replication and differentiation of mesenchymal precursor cells, chondrocytes, osteoblasts, and osteoclasts. Recent studies further suggest that TGF-beta activity in skeletal tissue may be controlled at multiple levels by other local and systemic agents. Consequently, the intricate mechanisms by which TGF-beta regulates bone formation are likely to be fundamental to understanding the processes of skeletal growth during development, maintenance of bone mass in adult life, and healing subsequent to bone fracture.

Alkaline Phosphatase↗
PubMed2006

The influence of processes for the purification of human bone allografts on the matrix surface and cytocompatibility.

Different industrial processes exist to purify allogenic bone, providing safe and cleaned blocks for bone allografting. However, they often make use of chemical reagents that can be aggressive for the bone matrix. Bone samples were processed with several soaking techniques used in industry: NaHCO3, H2O2, NaOH and H2O2+NaOH combined; the consequences on the bone matrix and cytocompoatibility were evaluated on femoral heads from osteoarthritic patients. Alterations of matrix were searched by histochemistry, atomic force microscopy (AFM), scanning electron microscopy (SEM) and transmission electron microscopy (TEM). Cytocompatibility was evaluated by coculturing human osteoblast-like cells (SaOS-2) on bone slices. Collagen fibers were dramatically altered at the surface of bone treated with H2O2, NaOH (and their association), but not with NaHCO3. A marked reduction in the number of hydroxyapatite crystals was observed on the trabecular surfaces by TEM and morphological changes were evidenced in SEM and AFM. Argyrophilic proteins of the bone matrix were removed by H2O2 and NaOH (and their association), but not by NaHCO3. As a consequence, attachment, spreading, proliferation and alkaline phosphatase activity of SaOS-2 were reduced by H2O2 and NaOH treatments. Strong oxidizing reagents altered matrix integrity by modifying collagenous and non-collagenous proteins. Whether these changes have clinical consequences on the bone bonding and osseointegration in human necessitate further investigations.

Bone Transplantation↗
PubMed2003

Measurement of gene expression following cryogenic mu-CT scanning of human iliac crest biopsies.

An important consideration in interpreting indices of gene expression in human bone is relating mRNA levels to functional endpoints such as bone architecture. In the present study, a method was developed for quantitative measurement of gene expression and bone morphology in the same specimen. Three-dimensional images of iliac crest bone biopsies from healthy premenopausal women were obtained using a novel high resolution cryogenic mu-CT scanner. RNA was isolated from the biopsies and mRNA levels were measured for genes related to bone metabolism. The gene expression profile and variability of expression within iliac crest biopsies of women was similar to human osteoblastic cell lines and rat long bones. mRNA for alkaline phosphatase, bone matrix proteins, and selected cytokines and cytokine receptors were consistently detected in biopsies. As previously shown in rat bone, there was a tight correlation between mRNA levels for type 1 collagen and osteonectin, a weaker correlation between type 1 collagen and osteocalcin and no correlation between bone matrix proteins and alkaline phosphatase. The relative abundance of the mRNA for the three most prevalent transforming growth factor-beta (TGF-beta) isoforms in bone (TGF-beta(1)>> TGF-beta(3)> TGF-beta(2)) was the same as the known abundance of the corresponding TGF-beta peptides in bone matrix. The results demonstrate the feasibility of analyzing the three-dimensional architecture of a bone biopsy using cryogenic mu-CT imaging and then measuring expression of genes related to bone cell function within the same specimen following RNA extraction and analysis.

Journal Article↗
PubMed1997

Neutral lipids facilitate transfer of bone morphogenetic proteins and other noncollagenous proteins.

In the process of separation of bone morphogenetic proteins from bone matrix, lipids were found in unexpected amounts closely associated with noncollagenous proteins soluble in guanidine hydrochloride. Lipids representing 33.7-49.9% by weight were recovered with various solvents. Composites of noncollagenous proteins and lipids soluble in either chloroform- methanol or acetone implanted in the hindquarter muscles of mice induced the formation of large deposits of heterotopic bone. The protein-lipid aggregates formed microspherules which were stained by Sudan Black B. Implants of bone morphogenetic proteins and noncollagenous proteins-lipid microspherules stained with Sudan Black B induced bone development in the same manner as unstained delipidized bone morphogenetic proteins associated with noncollagenous proteins. Lipid-free osteocalcein, osteonectin, albumin and other bone matrix proteins did not induce bone formation or bind Sudan Black B. The more highly purified the noncollagenous proteins, with or without activity of bone morphogenetic proteins, the lower the level of binding with Sudan Black B. Acetone-soluble bone matrix lipids consisted chiefly of triglycerides, cholesterol and saturated short chain fatty acids, and included little or no phospholipids or monounsaturated fatty acids. Composites of recombinant bone morphogenetic proteins-2 and acetone-soluble lipids induced larger deposits of bone than implants of recombinant bone morphogenetic proteins-2 without acetone-soluble lipids. The hypothesis that an association of bone lipids with protein facilitates the local transport of bone morphogenetic proteins warrants further investigation.

Animals↗
PubMed1994

Bone-related matrix proteins expression in vitro and in vivo by marrow stromal cell line.

MBA-1, a bone marrow stroma-derived cell line, was transplanted in an ectopic site and formed endochondral bone. The ossicle developed through stages of cell proliferation, differentiated into a zone of hypertrophy and formed a chondroid-like area which further developed to primary mineralized bone. We explored the expression of various matrix proteins by MBA-1 cells in vitro and in the ossicle formed in vivo. MBA-1 cells constitutively expressed mRNAs encoding for collagen I, non-collagenous proteins and alkaline phosphatase. RNA extracted from the ossicle formed by these cells was expressed in a different pattern. The in vivo maturation of MBA-1 cells was accompanied by low expression of mRNA for procollagen alpha 2(I) and a marked increase in osteonectin and osteopontin mRNA levels. Thus, the ability to follow expression of these genes through bone formation in vivo has been demonstrated.

Actins↗
PubMed1995

Effect of particulate porous hydroxyapatite on osteoinduction of demineralized bone autografts in experimental reconstruction of the rat mandible.

In an experimental model in the rat, a nonhealing bone defect was created in the left ascending mandibular ramus to test the effect of particulate porous hydroxyapatite (HA) on osteoinduction of demineralized bone autografts. The bone fragment removed was demineralized in HCl and used as an autograft for mandibular reconstruction. Granules of HA were added to the lingual and vestibular surfaces of the graft. The effect of this material was evaluated by determining the number of mesenchymal cells induced in the biomaterial and the central and peripheral zones of the bone graft, at 2-and 6-week intervals. The results show that the sites containing HA showed inhibition of osteoinduction by the bone matrix. In all groups, a proliferative gradient from the peripheral zone toward the center of the bone was observed. Similarly, the HA experienced a greater cellular increase in the regions in contact with the demineralized bone matrix.

Animals↗
PubMed2005

Osteocyte lacunae tissue strain in cortical bone.

Current theories suggest that bone modeling and remodeling are controlled at the cellular level through signals mediated by osteocytes. However, the specific signals to which bone cells respond are still unknown. Two primary theories are: (1) osteocytes are stimulated via the mechanical deformation of the perilacunar bone matrix and (2) osteocytes are stimulated via fluid flow generated shear stresses acting on osteocyte cell processes within canaliculi. Recently, much focus has been placed on fluid flow theories since in vitro experiments have shown that bone cells are more responsive to analytically estimated levels of fluid shear stress than to direct mechanical stretching using macroscopic strain levels measured on bone in vivo. However, due to the complex microstructural organization of bone, local perilacunar bone tissue strains potentially acting on osteocytes cannot be reliably estimated from macroscopic bone strain measurements. Thus, the objective of this study was to quantify local perilacunar bone matrix strains due to macroscopically applied bone strains similar in magnitude to those that occur in vivo. Using a digital image correlation strain measurement technique, experimentally measured bone matrix strains around osteocyte lacunae resulting from macroscopic strains of approximately 2000 microstrain are significantly greater than macroscopic strain on average and can reach peak levels of over 30,000 microstrain locally. Average strain concentration factors ranged from 1.1 to 3.8, which is consistent with analytical and numerical estimates. This information should lead to a better understanding of how bone cells are affected by whole bone functional loading.

Animals↗
PubMed1951

The role of alkaline phosphatase in osteogenesis.

The role of alkaline phosphatase in osteogenesis has been investigated by histochemical techniques with particular attention to its relationship to phosphate metabolism and matrix elaboration. The upper tibial epiphysis mainly, and other epiphyses as well of growing rabbits, and the costochondral junctions of newborn human beings were studied, as were bone grafts in growing rabbits. The findings in the newborn human beings were identical with those in the rabbits. Phosphatase activity and free phosphate localization do not universally coincide. The enzyme appears to be intimately related to preosseous cellular metabolism and to the elaboration of a bone matrix that is chemically calcifiable. It remains possible, however, that phosphatase may be in some way involved in making inorganic salts available to the calcifiable matrix. If this function does exist it is a secondary one, since the elaboration of bone matrix, which is always associated with phosphatase activity, can and does occur in the absence of calcification. Calcification may occur later, in the absence of the enzyme. There is evidence to suggest that cartilage matrix is utilized in the formation of bone matrix. Phosphatase is physiologically active only in the presence of living cells. Where it is demonstrable in the absence of living cells, as in the cartilage remnants of the metaphysis, it appears to be physiologically inactive. Since phosphatase is temporarily inactivated in weakly acid media, and readily reactivated by alkaline solutions it is possible that the enzyme might survive in a physiologically inactive state in weakly acid tissues, and yet remain capable of histochemical demonstration in vitro in an alkaline medium. Phosphatase is not related to the disappearance of chondroitin sulfate.

Alkaline Phosphatase↗
PubMed1992

Localization of malachite green positive lipids in the matrix of bone nodule formed in vitro.

An electron histochemical study was carried out on bone nodules formed in vitro in collagenase-released calvarial cells in order to visualize the lipid components of the extracellular matrix (EM). The malachite green aldehyde fixative technique, which allows both preservation and staining of some phospholipids of the extracellular matrix, was used. Controls were performed on sections demineralized, and then submitted to lipid extraction with a chloroformmethanol mixture (2/1 v/v) and to glycosaminoglycans digestion with 0.5% bovine testicular hyaluronidase to verify specificity for lipid staining. This allowed us to visualize the lipids (1) in the osteoid as granules associated to ribbon-like structures connected to the collagen fibers, (2) as electrondense deposits seen as dots on the outer surface membrane of the matrix vesicles, and (3) in the mineralized matrix as roundish patches formed of needle-shaped materials and at the mineralization front as individual ones. This study demonstrated that at the EM level, the lipids are present in the osteoid at locations very similar to what have been observed for the glycosaminoglycans, and in the mineralized matrix as components of the crystal ghosts.

Animals↗
PubMed1989

Study of the osteoconductive properties of bioactive glass fibers.

Bioactive glass fibers have been prepared and implanted in cortical defect and in muscle. The fibers can act as a substrate for bone apposition, when implanted in a cortical defect, and become incorporated in the new bone matrix. The same results were obtained when fibers were implanted in a muscle pouch together with bone marrow cells. An intense inflammatory reaction was observed when bioactive glass fibers were implanted in muscle; the reaction was milder when fibers were implanted in bone or in muscle together with bone marrow cells. This fact supports the hypothesis that osteogenic cells adhere in an early phase to the substrate and prevent recognition of the foreign material by inflammatory cells. This appears to be a fundamental condition for direct bone matrix apposition on the surface of fibers.

Animals↗
PubMed1997

Comparative evaluation of markers of bone resorption in patients with breast cancer-induced osteolysis before and after bisphosphonate therapy.

The understanding of the pathophysiology and the monitoring of metastatic bone disease remains unsatisfactory. We compared several new markers of bone turnover in normocalcaemic patients with breast cancer-induced osteolysis before and after a single infusion of the bisphosphonate pamidronate. We studied 19 ambulatory patients with advanced breast cancer and extensive bone metastases who did not receive any systemic antineoplastic therapy. Pamidronate was administered at doses of 30, 60, 90 or 120 mg and the patients were followed weekly during a mean of 8 (range 4-10) weeks. Compared with healthy premenopausal women, the percentage of elevated values at baseline was 47% for fasting urinary calcium (uCa), 74% for hydroxyproline, 83% for CrossLaps (a new marker of type I collagen degradation) and 100% for the collagen cross-links (measured by high performance liquid chromatography), namely pyridinoline (Pyr) and deoxyPyr (D-Pyr). Pretreatment levels of uCa did not correlate significantly with any of the four markers of bone matrix resorption, whereas the correlations between these four markers were generally significant (r(s)=0.43-0.71). Alkaline phosphatase correlated significantly with markers of bone matrix resorption (r(s)=0.54-0.74). All parameters, except phosphaturia (uPi) and the bone formation markers (osteocalcin and alkaline phosphatase), fell significantly after pamidronate therapy, up to day 42 for hydroxyproline, D-Pyr and CrossLaps and day 56 for uCa. This longer lasting effect was probably due to the parathyroid hormone (PTH) surge following the decrease in serum calcium, implying that the decrease in uCa can overestimate the effects of bisphophonates on bone resorption. The decrease in bone turnover parameters was most marked for CrossLaps, indicating the potential of this new marker for monitoring therapy. Sequential determinations of markers of bone matrix resorption should be useful in delineating the optimal therapeutic schemes of bisphosphonates and for evaluating treatment effects on bone in cancer patients.

Adult↗
PubMed1985

The vitamin K-dependent bone protein is accumulated within cultured osteosarcoma cells in the presence of the vitamin K antagonist warfarin.

Osteosarcoma cells grown in normal culture medium secrete bone gamma-carboxyglutamic acid protein (BGP, osteocalcin) which is identical with BGP purified from the bone matrix. Two tests indicate that the secreted medium protein contains the full complement of three gamma-carboxyglutamate residues present on BGP purified from the bone matrix. First, the secreted protein from ROS 17/2 and bone matrix BGP have identical isoelectric points (pI = 4.0). Second, they have identical hydroxyapatite binding behavior. If warfarin is added to the culture medium, the secreted protein has a higher isoelectric point (pI = 4.6) and a lower affinity for hydroxyapatite characteristic of thermally decarboxylated or non-gamma-carboxylated BGP. The observed shift in isoelectric point of secreted BGP after warfarin treatment from pH 4.0 to 4.6 is also reflected in the presence of pI = 4.1 and pI = 4.6 species intracellularly. These isoelectric species correspond to fully carboxylated BGP and noncarboxylated BGP, which are in the process of secretion. Addition of 10 micrograms/ml of warfarin causes a specific 47% reduction in secretion rate of BGP, while at the same time, the intracellular BGP concentration increases 3-fold. These phenomena appear related to the interruption by warfarin of the normal sequence of processing of precursor BGP proteins, as a new, immunoreactive species with a higher isoelectric pH not present in control cells appears to be responsible for the increased intracellular antigen within warfarin-treated cells. Our results show that vitamin K-dependent processing is important for normal secretion of BGP from the cell.

Animals↗