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PubMed1996

Paget's disease is associated with changes in the immunohistochemical distribution of noncollagenous matrix proteins in bone.

Paget's disease of bone is characterized histologically by abnormal architecture of bone matrix. Extensive areas of woven bone and numerous scalloped cement lines occur as a result of increased irregular remodeling. Noncollagenous proteins (NCP) play an important role in the organization and mineralization of bone matrix and promote distinct cell-matrix interactions necessary for normal remodeling. To gain insight into the pathological changes in the biochemical composition of Pagetic bone, the distribution of NCPs in the calcified matrix of bone from patients with known Paget's disease was compared to that of bone from normal healthy volunteers. Undecalcified plastic-embedded sections of bone were stained immunohistochemically using antibodies generated against several NCPs. In Pagetic and normal bone a similar distribution of osteopontin was observed at cement (reversal) lines, whereas significant differences were observed in the distribution of osteopontin in the matrix immediately adjacent to Haversian canals, where initial osteoclast recruitment and attachment occur. The differences in osteopontin distribution appeared to be related to the state and severity of the disease. Site-specific differences in the distribution of osteonectin, osteocalcin, and decorin were also observed between normal bone and cortical and periosteal de novo Pagetic bone, whereas the distribution of other matrix proteins, such as biglycan, was unchanged. We conclude that these site-specific changes in the biochemical distribution of NCPs in Pagetic bone probably reflect abnormal production and/or incorporation during bone remodeling and may lead to disorganized matrix assembly and mineralization as well as have profound effects on bone cell functions.

Adult↗
PubMed1988

Platelet-derived growth factor enhances demineralized bone matrix-induced cartilage and bone formation.

Subcutaneous implantation of demineralized bone matrix induces the local formation of cartilage and bone. In this study we have investigated the influence of adding various growth factors to the implant. Cartilage formation was monitored by measuring collagen II mRNA levels, and bone formation in the implant was assessed from alkaline phosphatase activity and calcium content. Supplements of the platelet-derived growth factor to implants in older rats increased and production of mRNA for collagen II, alkaline phosphatase activity, and the calcium content of the implant, whereas the other growth factors tested were without effect. The data suggest that under some conditions bone induction is submaximal and can be increased by local supplement of platelet-derived growth factor (PDGF). The present observations may have important therapeutic implications in the treatment of nonunions of fractures and impaired bone formation in the aged.

Animals↗
PubMed1995

Endogenous lipids in matrix-induced bone morphogenesis.

Demineralized matrix was delipidized with chloroform methanol before and after demineralization and implanted in muscle of allogeneic rats. Because lipids are difficult to separate completely from bone collagen, another preparation was gelatinized and delipidized with either chloroform methanol or acetone or both. Bone matrix demineralized without delipidization induced formation of a spherical-shaped deposit of new bone, which was remodeled to form a shell of cortical bone and central pool of normal hematopoietic bone marrow. When the bone was delipidized, only 20% to 25% was resorbed and replaced by new bone; unresorbed matrix failed to recalcify. Gelatinized bone matrix delipidized before implantation was even less well resorbed or replaced by new bone, but 12% to 44% of the matrix residue recalcified. The new deposits of bone were colonized by blood-borne bone marrow-derived stem cells and developed central pools of normal hematopoietic bone marrow. Recalcified residual matrix did not develop bone marrow. Additional investigations are required to determine whether the host bed adipocytes provide the phospholipids for recalcification of bone matrix. There was no preliminary recalcification in matrix-induced bone development, even though the 2 processes may occur simultaneously under specified experimental and pathologic conditions. Additional investigations are in progress to determine whether certain acetone soluble lipids may form the endogenous delivery system for bone morphogenetic protein and induced bone development.

Adipocytes↗
PubMed1991

The matrix of endochondral bone differs from the matrix of intramembranous bone.

Osseous tissue develops via two distinctly different processes: endochondral (EC) ossification and intramembranous (IM) ossification. The present study tests the hypothesis that each type of osseous tissue contains unique inducing factors for the promotion of cartilage and bone development. Previous work suggests that subcutaneous implants of demineralized EC and IM bone matrices both induce endochondral ossification. Thus, it concludes that the bone growth promotion properties of the respective matrices are very similar. As it was unclear to us why EC and IM bone powders should possess identical osteoinductive properties, we attempted to reproduce these results. We implanted EC (femoral) demineralized bone matrix (DBM), IM (frontal) DBM, or a mixture of the two into the ventral thoracic subcutaneous tissue of 12 to 15-week-old male Sprague Dawley rats. Morphological and radiolabeling techniques in this study demonstrated that implants of EC bone matrix induce bone formation via EC ossification in contrast to implants of IM bone matrix which do not induce EC ossification. Our findings suggest that the matrix of EC bone differs qualitatively from the matrix of IM bone due to their respective abilities to induce cartilage and/or bone formation. These observations differ from those previously reported possibly because our IM DBM preparations were not contaminated with tissues of endochondral origin. In current clinical practice, EC DBM allografts are often used to induce new bone formation in defects involving both IM and EC bone. We conclude that there may be clinical settings in which it would be more appropriate to replace bone originally formed via IM ossification with IM DBM rather than EC DBM.

Animals↗
PubMed2006

[Effects of salidroside on bone marrow matrix metalloproteinases of bone marrow depressed anemic mice].

To examine the effect of salidroside on the expression and activities of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) in bone marrow (BM) of BM depressed anemic mice by immunohistochemistry and gelatin zymography respectively, and to explore its roles in hematopoietic regulation. Immunohistochemistry showed that the expression of MMP-2 and MMP-9 of bone marrow cells (BMCs) was found in each group. Compared with control group, the expression of MMP-2 and MMP-9 was obviously increased in the model group, low-dose, middle-dose and high-dose salidroside. At day 4 after treatment of radiation and chemotherapy, the peak of the expression of MMP-2 and MMP-9 was found in middle-dose salidroside . At day 8 after treatment of radiation and chemotherapy, the peak of the expression of MMP-2 and MMP-9 was found in low-dose and middle-dose salidroside respectively. Gelatin zymography revealed that 66 kD proMMP-2, 62 kD MMP-2, 86 kD MMP-9 and 94 kD proMMP-9 were detected in control group, and the activity of MMP-9 was stronger among them. After treatment of radiation and chemotherapy, the activity of gelatinases of hemopoietic microenviroment (HM) was obviously decreased, but low-dose, middle-dose and high-dose salidroside could significantly increase the activities of proMMP-9 and MMP-9, attenuate the activity of proMMP-2. These results suggest that salidroside could promote the recovery of hematopoietic function of BM depressed anemic mice by increasing the expression and activity of MMPs, releasing the cytokines from ECM or cell membrane, repairing impaired microvessels of HM and promotion proliferation, migration and differentiation of HSCs.

Anemia, Aplastic↗
PubMed2006

Bioactive glass nanofiber-collagen nanocomposite as a novel bone regeneration matrix.

Nanoscale organized organic-inorganic nanocomposite systems have great potential in the development of biomaterials with advanced properties. Herein, we developed a novel nanocomposite biomaterial consisting of bioactive glass nanofiber (BGNF) and collagen reconstituted fibrous matrix for bone regenerative medicine. A sol-gel derived glass with a bioactive composition (58SiO(2). 38CaO.4P(2)O(5)) was electrospun to a nanoscale fiber with an average diameter of approximately 320 nm. The BGNF was subsequently hybridized with type I collagen, which is the main organic constituent of bone matrix. The BGNF and self-assembled collagen sol were combined in aqueous solution, and then crosslinked to produce a BGNF-collagen nanocomposite, in the form of either a thin membrane or a macroporous scaffold, by adopting appropriate processing conditions. The BGNF was observed to be distributed uniformly within the collagen reconstituted nanofibrous matrix. The nanocomposite matrices induced rapid formation of bone-like apatite minerals on their surfaces when incubated in a simulated body fluid, exhibiting excellent bioactivity in vitro. Osteoblastic cells showed favorable growth on the BGNF-collagen nanocomposite. In particular, the alkaline phosphatase activity of the cells on the nanocomposite was significantly higher than that on the collagen. This novel BGNF-collagen nanocomposite is believed to have significant potential in bone regeneration and tissue engineering applications.

Biocompatible Materials↗
PubMed1978

Experimental myositis ossificans: cartilage and bone formation in muscle in response to a diffusible bone matrix-derived morphogen.

Bone matrix gelatin, prepared by chemical extraction of soluble noncollagenous proteins, was half digested with a chromatographically purified collagenase. The residue was placed on one side and autologous muscle on the other side of cellulose acetate membranes in diffusion chambers and tissue cultures. In this avascular system, the muscle septa connective tissue proliferated and differentiated into cartilage. Muscle tissue cultured in media conditioned with matrix residues and then transferred into a vascularized muscle pouch differentiated into cartilage and bone. These observations form the basis for a working hypothesis that myositis ossificans is a response of new populations of proliferating intramuscular connective tissue cells to a bone matrix-derived diffusible molecule.

Animals↗
PubMed1984

Extracellular matrix proteins involved in bone induction are vitamin D dependent.

Subcutaneous implantation of demineralized diaphyseal bone matrix into allogeneic rats results in local formation of cartilage and bone. However, implantation of demineralized bone matrix obtained from rachitic rats did not induce bone. Rachitic bone matrix was therefore dissociatively extracted with 4 M guanidine HCl and then reconstituted with an inactive collagenous residue of control as carrier. Such reconstituted materials also lacked bone inductive potential. On the other hand, reconstitution of guanidine HCl extracts of control bone matrix with inactive vitamin D deficient matrix did result in bone induction. Partial purification (fractions containing proteins (less than 50,000 daltons) of the guanidine HCl extract from rachitic rats on Sepharose CL-6B followed by reconstitution with inactive collagenous residues resulted in a weak (25% of control) inductive response. These observations imply that bone inductive proteins are vitamin D dependent and are reduced in matrix obtained from rachitic rats.

Animals↗
PubMed1998

Initiation of fracture repair by bone morphogenetic proteins.

The potential for regeneration and repair of bone is well known. This article conveys the current progress in the realm of bone morphogenetic proteins and their potential for initiating fracture repair cascade. Demineralized bone matrix induces bone formation and has served as a model for the bone repair cascade. A family of bone morphogenetic proteins has been identified, isolated, and cloned from the demineralized bone matrix. Bone morphogenetic proteins are pleiotropic regulators of chemotaxis, mitosis, and differentiation. The bone morphogenetic protein receptors, Types I and II, bind bone morphogenetic proteins and act in collaboration to transduce the phosphorylation of Smad 1 and Smad 5, which enter the nucleus in partnership with Smad 4 to initiate bone morphogenetic protein responses including fracture healing. The accumulated information on bone morphogenetic proteins may aid in accelerating fracture repair and the potential use of bone morphogenetic protein antibodies to inhibit heterotopic bone formation and fibrodysplasia ossificans progressiva.

Antibodies↗
PubMed1984

In vitro transformation of mesenchymal cells derived from embryonic muscle into cartilage in response to extracellular matrix components of bone.

Subcutaneous implantation of demineralized diaphyseal bone matrix into rats induces cartilage and bone formation in vivo. When minced skeletal muscle is cultured on hemicylinders of demineralized bone in vitro, mesenchymal cells are transformed into chondrocytes. In the present investigation, the potential of extracellular matrix components of bone to trigger cartilage differentiation in vitro was examined. Extraction of bone hemicylinders with 6 M guanidine X HCl resulted in the absence of chondrogenesis in vitro and endochondral bone formation in vivo. Biologically inactive hemicylinders of bone were then reconstituted with the guanidine extract and also with partially purified components extracted from bone matrix and bioassayed. Reconstitution completely restored the ability to elicit chondrogenesis in vitro and endochondral bone differentiation in vivo. Reconstitution of the whole guanidine extract on Millipore filters coated with gels of tendon collagen (type I) and subsequent culture with minced skeletal muscle also resulted in cartilage induction in vitro. These observations show that the extracellular matrix of bone is a repository of factors that govern local cartilage and bone differentiation.

Animals↗
PubMed1984

Importance of geometry of the extracellular matrix in endochondral bone differentiation.

Subcutaneous implantation of coarse powders (74-420 micron) of demineralized diaphyseal bone matrix resulted in the local differentiation of endochondral bone. However, implantation of matrix with particle size of 44-74 micron (Fine matrix) did not induce bone. We have recently reported that the dissociative extraction of coarse matrix with 4 M guanidine HCl resulted in a complete loss of the ability of matrix to induce endochondral bone; the total loss of biological activity could be restored by reconstitution of extracted soluble components with inactive residue. To determine the possible biochemical potential of fine matrix to induce bone, the matrix was extracted in 4 M guanidine HCl and the extract was reconstituted with biologically inactive 4 M guanidine HCl-treated coarse bone matrix residue. There was a complete restoration of the biological activity by the extract of fine matrix upon reconstitution with extracted coarse matrix. Polyacrylamide gel electrophoresis of the extract of fine matrix revealed similar protein profiles as seen for the extract of coarse matrix. Gel filtration of the 4 M guanidine HCl extract of fine powder on Sepharose CL-6B and the subsequent reconstitution of various column fractions with inactive coarse residue showed that fractions with proteins of 20,000-50,000 mol wt induced new bone formation. These observations demonstrate that although fine bone matrix contains, osteoinductive proteins, matrix geometry (size) is a critical factor in triggering the biochemical cascade of endochondral bone differentiation. Mixing of coarse matrix with Fine results in partial response and it was confined to areas in contact with coarse particles. The results imply a role for geometry of extracellular bone matrix in anchorage-dependent proliferation and differentiation of cells.

Alkaline Phosphatase↗
PubMed1981

Dissociative extraction and reconstitution of extracellular matrix components involved in local bone differentiation.

Subcutaneous implantation of demineralized diaphyseal bone matrix in allogeneic rats results in the local induction of endochondral bone differentiation. We have explored the potential of three dissociative extractants, 4 M guanidine hydrochloride (Gdn . HCl), 8 M urea/1 M NaCl, and 1% NaDodSO4 at pH 7.4, containing protease inhibitors to solubilize putative inductive molecules in the bone matrix. Extraction of bone matrix with any one of these extracts resulted in the loss of the bone inductive property. The solubilized extracts were then reconstituted with the residue by dialysis against water. The various reconstituted matrices were bioassayed for bone inductive potential by quantitation of alkaline phosphatase activity and 45Ca incorporation on day 12 after implantation. There was complete recovery of biological activity after reconstitution of the residues with each of the three extracts. Polyacrylamide gel electrophoresis of the extracts revealed similar protein profiles. Gel filtration of the 4 M Gdn. HCl extract on Sepharose CL-4B showed a heterogeneous broad peak. When fractions of that peak containing proteins less than 50,000 daltons were reconstituted with inactive 4 M Gdn . HCl-treated bone matrix and then implanted, new bone was induced. These observations demonstrate the dissociative extraction and successful biological reconstitution of bone inductive macromolecules in demineralized bone matrix.

Alkaline Phosphatase↗
PubMed1990

Influence of whole body irradiation and local shielding on matrix-induced endochondral bone differentiation.

Subcutaneous implantation of demineralized bone matrix into allogeneic rats induces endochondral bone formation. We have investigated the effects of irradiation on the sequelae of the interaction of collagenous matrix and mesenchymal cells and on cartilage and bone differentiation. Rats were irradiated in a vertical direction with a midline dose of 850 rad. Radiation entered the rats ventrally while a small area of the upper thorax was locally shielded. After irradiation, bone matrix was implanted in shielded and nonshielded sites, and the implants were studied at various stages. On day 3, [3H]thymidine incorporation, an index of cell proliferation, was inhibited by 70% in the nonshielded sites compared to nonirradiated control rats. The degree of inhibition (35%) was less pronounced in shielded sites. Furthermore, there was recovery of cell proliferation in the shielded sites as opposed to the nonshielded contralateral site. A similar pattern was observed on day 7 as assessed by 35SO4 incorporation into proteoglycans during chondrogenesis. Bone formation and mineralization were quantified on day 11 by alkaline phosphatase activity and 45Ca incorporation. In nonshielded sites, there was a 73% inhibition of alkaline phosphatase activity. In conclusion, radiation impaired progenitor cell proliferation which resulted in decreased cartilage and bone differentiation. These findings imply that local mesenchymal cells proliferate and differentiate into bone in response to implanted collagenous matrix.

Animals↗
PubMed2000

Characterization of demineralized bone matrix-induced osteogenesis in rat calvarial bone defects: III. Gene and protein expression.

Our previous studies of rat cranial defect repairs after the implantation of demineralized bone matrix (DBM) have demonstrated that healing occurs initially and principally by the direct induction and proliferation of osteoblasts derived principally from resident mesenchymal stem cells of the dura, and to a lesser extent by resident mesenchymal stem cells of the connective tissues beneath the skin flap. A small amount of cartilage is also synthesized after the direct process of ossification occurs. To further confirm the molecular phenotypes of the repair cells in rat cranial defects, the present study evaluated mRNA expression and synthesis of collagens I, II, and X and osteocalcin in the DBM-induced repair tissue by Northern blot analyses, autoradiography after in vivo (3)H-proline labeling of collagen, and immunohistochemistry. The results demonstrated that osteocalcin mRNA appeared in small amounts by day 4 and continued to increase over the experimental period. Much lesser quantities of collagen types II and X mRNAs appeared by day 6 and day 8, respectively. Collagen type I mRNA was present at all times examined but its expression significantly increased by day 5. Autoradiographic and immunohistochemical studies showed that type II collagen was not detected whereas type I collagen was synthesized on days 3-5. The data provide definitive molecular evidence confirming that the initial and by far the major pathway of cranial defects repair induced by implantation of DBM is by the direct induction of resident mesenchymal stem cells to osteoblasts and the direct formation of bone, which is spatially and temporarily distinct from the later formation of cartilage.

Animals↗
PubMed1996

Bone cell matrix promotes the adhesion of human prostatic carcinoma cells via the alpha 2 beta 1 integrin.

Prostatic carcinoma cells have a propensity to metastasize to bone, and we propose that this phenomenon may be promoted by the adhesion of metastatic cells to bone matrix. Bone matrix is produced by osteoblasts, and we have developed an in vitro model of bone matrix by isolating the substratum deposited by human osteoblast-like U2OS cells. The collagenous nature of this matrix was demonstrated by the incorporation of [3H]proline and its subsequent release by purified collagenase. Both U2OS matrix and purified type I collagen stimulated the adhesion of human PC-3 prostatic carcinoma cells. Human laminin supported adhesion to a much lesser extent, and PC-3 cells did not adhere to fibronectin. Adhesion of PC-3 cells to U2OS matrix closely resembled adhesion to purified type I collagen with respect to (a) inhibition by a collagen-derived peptide and by antibodies raised against alpha 2 or beta 1 integrin collagen receptor subunits; (b) lack of inhibition by RGD (Arg-Gly-Asp) peptides; (c) stimulation by Mn2+ and Mg2+ ions but not by Ca2+ ion; and (d) stimulation by the phorbol ester PMA (phorbol 12-myristate 13-acetate). This adhesion was also stimulated (2.3-fold) by transforming growth factor beta (TGF-beta), which is a major bone-derived growth factor. We conclude that human osteoblast-like matrix is an adhesive substrate for PC-3 prostate carcinoma cells. This adhesion appears to be mediated by the interaction of alpha 2 beta 1 integrin on PC-3 cells with matrix-derived collagen. The stimulation of this adhesion by TGF-beta suggests that the co-expression of TGF-beta and type I collagen in bone may synergistically facilitate the adhesion of metastatic cells to bone matrix proteins and thereby increase their localization in the skeleton.

Amino Acid Sequence↗
PubMedDate not supplied

Human metastatic prostate PC3 cell lines degrade bone using matrix metalloproteinases.

Bone metastases are often associated with osteolysis and subsequent pathological fractures. To determine if metastatic human cancer cells can directly degrade non-mineralized and mineralized bone, we used prostate PC3 adenocarcinoma cell lines, which were originally established from skeletal metastases. We show that PC3 cells and their conditioned medium degraded non-mineralized, osteoid-like radiolabelled extracellular matrices from human Saos2 and U2OS osteoblast-like cells. These cells also directly degraded mineralized bone by inducing (45)Ca release from rat fetal calvariae and forming resorption pits on bone slices, an effect increased by transforming growth factor-beta(1). A role for matrix metalloproteinases in degradation was shown by: (1) stimulation by the phorbol ester TPA of PC3-induced matrix degradation and release of matrix metalloproteinase activity; (2) abrogation of matrix degradation by 1,10-phenanthroline, a metalloproteinase inhibitor, and (3) degradation of purified type I collagen by PC3 cells and their conditioned medium. We demonstrate that human prostate cancer cells can directly degrade bone-related matrices and that matrix metalloproteinases have a role in this process.

Adenocarcinoma↗
PubMed1995

Calcitonin down-regulates immediate cell signals induced in human osteoclast-like cells by the bone sialoprotein-IIA fragment through a postintegrin receptor mechanism.

Calcitonin (CT) is a peptide hormone that interacts with the cAMP-and phospholipase C-associated CT receptor subtypes. We investigated whether CT modulates the interaction of human tumoral osteoclast-like (GCT23) cells with a protein of the bone matrix, bone sialoprotein-II (BSP-II). Single GCT23 cells loaded with the intracellular Ca2+ indicator fura-2 were treated with the maximal active dose (300 micrograms/ml) of the 18-mer Arg-Gly-Asp (RGD)-containing BSP-IIA fragment, and the cytosolic free Ca2+ concentration ([Ca2+]i) was measured by dual wavelength microfluorometry. BSP-IIA stimulated an elevation in [Ca2+]i, consisting mainly of a peak, followed by a rapid return toward baseline. Pretreatment with CT induced a modest elevation of [Ca2+]i. However, CT significantly inhibited the response to BSP-IIA in a dose-dependent manner. Maximal inhibition (90% vs. untreated) was observed in the micromolar range. The intracellular mechanisms leading to this effect were investigated by pretreatment of GCT23 cells with the cAMP permeant analog, (Bu2)cAMP, and the protein kinase-C-activating agent, 12-O-tetradecanoylphorbol 13-acetate. Similar to CT, both agents inhibited the response to 300 micrograms/ml BSP-IIA. The effect induced by CT was specific, because an increase in the extracellular Ca2+ concentration, which is also known to inhibit bone resorption, failed to modify the ability of BSP-IIA to alter [Ca2+]i in GCT23 cells. To investigate whether the CT-induced alteration of BSP-IIA-dependent cell signals was due to a modification in the synthesis of cell surface receptors (integrins) for the extracellular matrix macromolecules, 1-h CT-treated [35S]methionine metabolically labeled GCT23 cell lysates were immunoprecipitated with anti-alpha 3-, -alpha v-, -beta 1-, and -beta 3-integrin subunit antibodies. Autoradiography demonstrated that 10(-7)-10(-6) M CT did not alter new synthesis of the alpha v beta 3 and the alpha 3 beta 1 receptors. Similarly, CT did not affect surface expression of these receptors, assessed by enzyme-linked immunosorbent assay. Finally, no alteration of the adhesion rate and spreading of GCT23 cells onto BSP-IIA-coated substrates was observed. This indicates that CT-induced down-regulation of immediate cell signals prompted by BSP-IIA in GCT23 cells is a postintegrin receptor event.

Animals↗
PubMed1985

Bone matrix-directed chondrogenesis of muscle in vitro.

Bone matrix is the largely collagenous residue of demineralized bone. Experimental data demonstrate that a substance, which is acid-stable during demineralization, occurs as a part of bone matrix, and that it is capable of stimulating the redifferentiation of skeletal muscle into cartilage. Reproducibility of redifferentiation is high and all cells derived from embryonic mesoderm appear competent to yield cartilage. This effect is highly significant to the developmental biology of musculoskeletal tissues, as muscle and cartilage arise from a similar embryonic origin. With regard to the embryonic limb as a model system, it appears that both muscle and cartilage progenitor cells do not have rigidly-defined developmental programs, and that this is a result of their origin from a common pool of embryonic mesoderm. This pool originates as embryonic mesenchyme long before any evidence of limb development can be detected. It is proposed that the active component of bone matrix, termed "bone morphogenetic protein (BMP)," acts upon a tissue whose developmental program is not stabilized, or has been experimentally destabilized (by injury), to augment and sustain syntheses of cartilage extracellular matrix. The use of bone matrix, and active substances derived from it, suggests that differentiation is not irreversible. Hard tissue growth and repair may occur via recruitment of competent responding cells from a variety of nonchondrogenic sources, provided that the extracellular milieu (i.e., presence of BMP) is supportive.

Animals↗