Osteogenic Protein 1

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T. K. Sampath - One of the best experts on this subject based on the ideXlab platform.

  • opposite effects of Osteogenic Protein and transforming growth factor β on chondrogenesis in cultured long bone rudiments
    Journal of Bone and Mineral Research, 2009
    Co-Authors: S. C. Dieudonne, C M Semeins, S W Goei, Slobodan Vukicevic, T. K. Sampath, Klein J Nulend, M N Helder, E H Burger
    Abstract:

    Osteogenic Protein-1 (OP-1, also called BMP-7) is a bone morphogenetic member of the TGF-β superfamily. In the present study, we examined the effect of recombinant human OP-1 on cartilage and bone formation in organ cultures of metatarsal long bones of mouse embryos and compared the OP-1 effects with those of human TGF-β1 and porcine TGF-β1 and β2. Cartilage formation was determined by measurement of longitudinal growth of whole bone rudiments during culture and by the incorporation of 35SO4 into glycosaminoglycans. Mineralization was monitored by 45Ca incorporation in the acid-soluble fraction and by measuring the length of the calcifying center of the rudiment. Toluidine blue-stained histologic sections were used for quantitative histomorphometric analysis. We found that OP-1 stimulated cartilage growth as determined by sulfate incorporation and that it increased remarkably the width of the long bones ends compared with controls. This effect was partly caused by differentiation of perichondrial cells into chondrocytes, resulting in increased appositional growth. In contrast to OP-1, TGF-β1 and β2 inhibited cartilage growth and reduced the length of whole bone rudiments compared with controls. In the ossifying center of the bone rudiments, both OP-1 and TGF-β inhibited cartilage hypertrophy, growth of the bone collar, and matrix mineralization. These data demonstrate that OP-1 and TGF-β exhibit opposite effects on cartilage growth but similar effects on osteogenesis in embryonic mouse long bone cultures. Since both OP-1 and TGF-β have been demonstrated in embryonic cartilage and bone, these results suggest that they act as autocrine or paracrine regulators of embryonic bone development.

  • stimulation of proteoglycan synthesis in explants of porcine articular cartilage by recombinant Osteogenic Protein 1 bone morphogenetic Protein 7
    Journal of Bone and Joint Surgery American Volume, 1997
    Co-Authors: Steven A Lietman, T. K. Sampath, Masaki Yanagishita, Hari A Reddi
    Abstract:

    Osteogenic Protein-1 (also known as bone morphogenetic Protein-7) is a member of the bone morphogenetic Protein family. Bone morphogenetic Proteins and related members of the TGF-β (transforming growth factor-β) superfamily are involved in the development and repair of bone. Recombinant bone morphogenetic Proteins induce the formation of new cartilage and bone at heterotopic sites. We investigated the influence of recombinant Osteogenic Protein-1 (at doses of three, ten, thirty, or 100 nanograms per milliliter) on the synthesis and release of proteoglycans and the maintenance of a steady-state concentration of proteoglycans in explants of porcine articular cartilage that were maintained in chemically defined serum-free medium. We found a dose-dependent stimulation of proteoglycan synthesis and a concurrent decrease in the rate of release of proteoglycans from the explants. The size of the proteoglycan monomers and the composition of the glycosaminoglycan chains in the untreated articular cartilage were similar to those in the articular cartilage treated with Osteogenic Protein-1. The capacity of the newly synthesized proteoglycan monomers to form aggregates with exogenous hyaluronic acid was found to be similar to that of proteoglycans in bovine nasal cartilage. Our results demonstrated that Osteogenic Protein-1 stimulated the synthesis of proteoglycans and diminished the release of proteoglycans from explants of porcine articular cartilage. CLINICAL RELEVANCE: The maintenance and repair of articular cartilage is a formidable challenge in clinical orthopaedics. The stimulation of proteoglycan synthesis by Osteogenic Protein-1 (bone morphogenetic Protein-7) in explants of cartilage maintained in chemically defined serum-free medium implies that recombinant Osteogenic Protein-1 may play a role in the maintenance of a steady-state concentration of proteoglycans in articular cartilage, a desirable prerequisite for optimum repair of cartilage. Osteogenic Protein-1 can initiate the formation of cartilage from mesenchymal cells. Once new cartilage has formed at the site of repair, Osteogenic Protein-1 also may maintain the synthesis of proteoglycans.

  • expression and localization of bone morphogenetic Proteins bmps and bmp receptors in ossification of the ligamentum flavum
    Bone, 1997
    Co-Authors: Kyouji Hayashi, T Nagamine, Nobuo Origuchi, Y Ishidou, Takeshi Imamura, K Yonemori, Shingo Maeda, Mitsuyasu Kato, Hiroki Yoshida, T. K. Sampath
    Abstract:

    To clarify the pathogenesis of ossification of the ligamentum flavum (OLF), we examined the expression and localization of bone morphogenetic Proteins (BMPs) and their receptors (BMPRs) in the ligamentum flavum of the patients with OLF by immunohistochemical staining and compared them with staining patterns in control patients. The BMPRs appeared extensively in mature and immature chondrocytes around the calcified zone and in spindle-shaped cells and round cells in the remote part from ossified foci in examined tissue of OLF. The ligands for BMPRs, BMP-2/-4 and Osteogenic Protein-1 (OP-1)/BMP-7, colocalized in OLF patients. In the control cases, expression of BMPs and BMPRs was observed around the calcified zone at the insertion of the ligamentum flavum to the bone, and limited expression was found in the smaller range. Thus, the expression profile of BMPs and BMPRs in OLF patients was entirely different from the control patients, suggesting that BMPs may be involved in promoting endochondral ossification at ectopic ossification sites in OLF, and that ossification activity is continuous in these patients.

  • role of bmp 2 and op 1 bmp 7 in programmed cell death and skeletogenesis during chick limb development
    Development, 1997
    Co-Authors: D Macias, T. K. Sampath, Y Ganan, M E Piedra, J M Hurle
    Abstract:

    Bone Morphogenetic Protein 2 (BMP-2) and Osteogenic Protein 1 (OP-1, also termed BMP-7) are members of the transforming growth factor beta superfamily. In the present study, we have analyzed the effects of administering them locally at different stages and locations of the chick limb bud using heparin beads as carriers. Our results show that these BMPs are potent apoptotic signals for the undifferentiated limb mesoderm but not for the ectoderm or the differentiating chondrogenic cells. In addition, they promote intense radial growth of the differentiating cartilages and disturb the formation of joints accompanied by alterations in the pattern of Indian hedgehog and ck-erg expression. Interestingly, the effects of these two BMPs on joint formation were found to be different. While the predominant effect of BMP-2 is alteration in joint shape, OP-1 is a potent inhibitory factor for joint formation. In situ hybridizations to check whether this finding was indicative of specific roles for these BMPs in the formation of joints revealed a distinct and complementary pattern of expression of these genes during the formation of the skeleton of the digits. While Op-1 exhibited an intense expression in the perichondrium of the developing cartilages with characteristic interruptions in the zones of joint formation, Bmp-2 expression was a positive marker for the articular interspaces. These data suggest that, in addition to the proposed role for BMP-2 and OP-1 in the establishment of the anteroposterior axis of the limb, they may also play direct roles in limb morphogenesis: (i) in regulating the amount and spatial distribution of the undifferentiated prechondrogenic mesenchyme and (ii) in controlling the location of the joints and the diaphyses of the cartilaginous primordia of the long bones once the chondrogenic aggregates are established.

  • subcloning of three osteoblastic cell lines with distinct differentiation phenotypes from the mouse osteoblastic cell line ks 4
    Bone, 1996
    Co-Authors: Takeyoshi Yamashita, T. K. Sampath, H Ishii, K Shimoda, T Katagiri, M Wada, T Osawa, Tatsuo Suda
    Abstract:

    Abstract Three distinct osteoblastic cell lines (KS418, KS460, and KS483) were subcloned from the mouse osteoblastic KS-4 cells, which possessed the abilities not only to differentiate into mature osteoblasts, but also to support osteoclast differentiation in coculture with spleen cells. The order of the magnitude of the basal alkaline phosphatase (ALP) activity was KS483 > KS418 > KS460. KS483 cells were also more differentiated than KS418 and KS460 in terms of ALP activity and osteocalcin production, when cultured in growth medium containing 10% fetal bovine serum. In long-term culture, KS418 and KS483 apparently differentiated into mature osteoblasts and formed calcified nodules without addition of β-glycerophosphate. Electron microscopic analysis demonstrated that calcification occurring in the nodules was initiated in the matrix vesicles as observed in bone formation in vivo. Nodule formation and mineral deposition occurred simultaneously in the presence of β-glycerophosphate, but the former always preceded the latter without addition of β-glycerophosphate. In contrast, KS460 cells did not show time-dependent increases of ALP activity, type I collagen expression and osteocalcin production, which were induced by treatment with recombinant Osteogenic Protein-1 (OP-1). The three cell lines similarly supported osteoclast differentiation in coculture with spleen cells in response to 1,25-dihydroxyvitamin D 3 . These results indicate that the three cell lines subcloned from the original KS-4 cells represent phenotypically distinct osteoblasts during osteoblast differentiation, but are equipped similarly with the capacity to support osteoclast differentiation. The subcloned cells of the KS-4 series may provide useful systems in which to study osteoblast differentiation and function.

David C. Rueger - One of the best experts on this subject based on the ideXlab platform.

  • RESEARCH ARTICLE Open Access Regulation of chondrocyte gene expression by Osteogenic Protein-1
    2013
    Co-Authors: Susan Chubinskaya, David C. Rueger, Lori Otten, Stephan Soeder, Jeffrey A Borgia, Thomas Aigner, Richard F Loeser
    Abstract:

    Introduction: The objective of this study was to investigate which genes are regulated by Osteogenic Protein-1 (OP-1) in human articular chondrocytes using Affimetrix gene array, in order to understand the role of OP-1 in cartilage homeostasis. Methods: Chondrocytes enzymatically isolated from 12 normal ankle cartilage samples were cultured in high-density monolayers and either transfected with OP-1 antisense oligonucleotide in the presence of lipofectin or treated wit

  • synergistic effect of igf 1 and op 1 on matrix formation by normal and oa chondrocytes cultured in alginate beads
    Osteoarthritis and Cartilage, 2007
    Co-Authors: Susan Chubinskaya, David C. Rueger, Thomas Aigner, C Pacione, Arnavaz A Hakimiyan, Adam B Yanke, L Rappoport, Richard F Loeser
    Abstract:

    Summary Objective Growth factor therapy may be useful for stimulation of cartilage matrix synthesis and repair. Thus, the purpose of our study was to further understand the effect of combined insulin-like growth factor-1 (IGF-1) and Osteogenic Protein-1 (OP-1) treatment on the matrix synthesized by human adult normal and osteoarthritic (OA) chondrocytes. Design Chondrocytes were isolated post-mortem from articular cartilage from tali of normal human donors and femoral condyles of OA patients undergoing knee replacement surgery. Cells were cultured in alginate beads for 21 days in four experimental groups: (1) "mini-ITS" control; (2) 100ng/ml IGF-1; (3) 100ng/ml OP-1; (4) IGF-1+OP-1, each at 100ng/ml. Beads were processed for histological (Safranin O and fast green), morphometrical and immunohistochemical (aggrecan, decorin, type I, II, VI, and X collagens, and fibronectin accumulation) analyses. Results Histology showed that IGF-1 alone did not induce substantial matrix production. OP-1 alone caused a considerable matrix formation, but the highest matrix accumulation by normal and OA chondrocytes was found when OP-1 and IGF-1 were added together. Morphometrical analysis indicated larger matrices produced by OA chondrocytes than by normal cells under the combined treatment. All tested matrix Proteins were more abundant in the combination group. Type X collagen was detected only under the combined OP-1 and IGF-1 treatment and was present at very low levels. Type I collagen was found only in OA chondrocytes. Conclusions The results obtained in the current study suggest that combined therapy with IGF-1 and OP-1 may have a greater potential in treating cartilage defects seen in OA than use of either growth factor alone.

  • Osteogenic Protein 1 in synovial fluid from patients with rheumatoid arthritis or osteoarthritis relationship with disease and levels of hyaluronan and antigenic keratan sulfate
    Arthritis Research & Therapy, 2006
    Co-Authors: Susan Chubinskaya, Eugene J M A Thonar, David C. Rueger, Lori Otten, Benjamin S Frank, Margaret Michalska, Bhavna Kumar, Charis Merrihew, Mary Ellen Lenz, Joel A Block
    Abstract:

    The measurement of body fluid levels of biochemical markers in joint tissues has begun to provide clinically useful information. Synovial fluid (SF) plays an important role in articular joint lubrication, nutrition, and metabolism of cartilage and other connective tissues within the joint. The purpose of our study was to identify and characterize Osteogenic Protein 1 (OP-1) in SF from patients with rheumatoid arthritis (RA) or with osteoarthritis (OA) and to correlate levels of OP-1 with those of hyaluronan (HA) and antigenic keratan sulfate (AgKS). SF was aspirated from the knees of patients with either RA or OA and from the knees of asymptomatic organ donors with no documented history of joint disease. The presence of detectable OP-1 in SF was demonstrated by western blots with specific anti-pro-OP-1 and anti-mature OP-1 antibodies. Measurement of levels of OP-1, HA and AgKS was performed using ELISAs. OP-1 was identified in human SF in two forms, pro-OP-1 and active (mature) OP-1 – mature OP-1 being detected only in SF from OA patients and RA patients. Levels of OP-1 and HA were higher in RA patients than in OA patients and asymptomatic donors, while the level of AgKS was highest in SF from asymptomatic donors. Statistically significant differences were found between SF levels of OP-1 in RA and OA patients and between SF levels of AgKS among the three groups tested. The SF content of OP-1 tended to correlate positively with HA levels, but negatively with AgKS concentrations. In conclusion, the results of this study suggest that measurement of OP-1 in joint fluid may have value in the clinical evaluation of joint disease processes.

  • repair of articular cartilage defects with Osteogenic Protein 1 bmp 7 in dogs
    Journal of Bone and Joint Surgery American Volume, 2003
    Co-Authors: Stephen D Cook, Samantha L Salkeld, Laura P Patron, David C. Rueger
    Abstract:

    Background: Articular cartilage injury has a poor prognosis for repair. Mesenchymal cells, when exposed to Osteogenic Proteins and other cytokines, can differentiate into cells that behave phenotypically as chondrocytes. In this study, we examined the ability of recombinant human Osteogenic Protein-1 (rhOP-1 or rhBMP-7) to elicit the repair of osteochondral defects in dogs. Methods: Bilateral osteochondral defects that were 5 mm in diameter by 6 mm deep were surgically created in the medial femoral condyles of sixty-five adult dogs. rhOP-1-treated (100 mg of a 3.5-mg rhOP-1/g bovine bone-derived Type-I collagen device) and control defects (untreated or treated with 100 mg bovine bone-derived collagen implants) were evaluated grossly and histologically at six, twelve, sixteen, twenty-six, and fifty-two weeks postoperatively. The influence of protected initial weight-bearing and surgical placement of periosteal flaps was also evaluated. Results: Gross and histologic grading of the defect repair indicated improvement in the rhOP-1-treated defects compared with that in the controls. Grossly, the repair tissue in the rhOP-1-treated defects was continuous with the adjacent intact cartilage and appeared translucent. By comparison, the repair tissue in the control defects was discontinuous and opaque or inhomogeneous in nature. Histologically, maturing cartilage similar in appearance to the intact articular cartilage was present in the rhOP-1-treated defects. Cartilage at the defect interface was minimally degraded. The control defects were filled primarily with fibrous tissue and fibrocartilage. Significant differences based upon treatment type were observed at twelve weeks, sixteen weeks, and for all time-periods combined (p = 0.0385, p = 0.0070, and p = 0.0026, respectively). Conclusion: rhOP-1 (rhBMP-7) induced hyaline cartilage-like repair of full-thickness osteochondral defects in a dog model. Differences in cartilage repair were maintained at fifty-two weeks postoperatively with no significant degradation of the rhOP-1-induced repair tissue. Clinical Relevance: The dog osteochondral defect model is a challenging one that reflects the difficulties of eliciting articular cartilage repair that are seen in the clinical setting. The results of this study indicate that rhOP-1 may improve the repair of articular cartilage, and they demonstrate the importance of further investigation to characterize the effects of growth factors on the cartilage repair process.

  • a comparative dose response study of cartilage derived morphogenetic Protein cdmp 1 2 and 3 for tendon healing in rats
    Journal of Orthopaedic Research, 2003
    Co-Authors: Carina Forslund, David C. Rueger, Per Aspenberg
    Abstract:

    Abstract Cartilage-derived morphogenetic Proteins (CDMPs), belonging to the bone morphogenetic Protein (BMP) family, are known to be cartilage and bone inducers as well as to induce tendon and ligament-like tissue. In this study we investigated the influence of CDMP-1, -2 or -3 at four different doses (0, 0.4, 2 and 10 μg) on tendon healing in a rat model, as well as differences in osteogenesis between the different CDMPs and doses. In 110 rats, a 3 mm segment of the Achilles tendon was removed via a 2 mm skin incision. CDMP-1, -2 or -3 was injected into the defect 6 h postoperative. The rats were killed 8 days after operation. The tendon regenerates were tested biomechanically. There was a significant dose-related increase in strength and stiffness with all three CDMPs, but no difference between the CDMPs was found. Another 50 rats were used to compare the highest dose of the CDMPs with controls and Osteogenic Protein 1 (OP-1), as regards cartilage or bone formation after 4 weeks. Cartilage occurred in all groups, including the controls. Some specimens in all groups contained bone, except the controls. No difference between the CDMPs could be demonstrated. The CDMP-1, CDMP-3 and OP-1 groups contained significantly more calcium than controls. Only the CDMP-2 group and the controls contained significantly less calcium than the OP-1 group. In conclusion, the three CDMPs appeared similar as regards improvement of tendon repair and Osteogenicity in this setting.

Ugo Ripamonti - One of the best experts on this subject based on the ideXlab platform.

  • biological aspects of periodontal tissue regeneration cementogenesis and the induction of sharpey s fibres
    journal of the South African Dental Association, 2013
    Co-Authors: Ansuyah Magan, Ugo Ripamonti
    Abstract:

    The realm of periodontal tissue regeneration has a plethora of unanswered questions and challenges due to the complexity of restoring mineralised and fibrous connective tissues ultimately to be covered by epithelium in a very specific spatial organisation. Wound healing of the periodontium follows a highly ordered sequence of events that guides cellular morphology, differentiation, migration and proliferation and comprises a series of cellular, extracellular and molecular reciprocal interactions. The prerequisite for regeneration of any structure is the trio of a soluble molecular signal, a scaffold and responding stem cells. Striated muscle represents an abundant source of easily accessible tissue that contains several perivascular, pericytic and myoblastic cell niches capable of differentiating and inducing selected tissue phenotypes and morphogenesis. Morcellated autogenous rectus abdominis muscle combined with 75µg of hTGF-β3 in Matrigel® matrix implanted into non-human primate class II and III furcation defects induced greater alveolar bone formation and cementogenesis when compared to furcation defects without the addition of morcellated autogenous bone. In situ hybridisation and immunohistochemistry during embryonic development and tooth morphogenesis have shown synchronous but spatially different bone morphogenetic Proteins (BMPs) expression during tissue induction and morphogenesis. Preclinical studies in the non-human primate Papio ursinus have shown a seemingly specific cementogenic function of Osteogenic Protein-1 (OP-1, also known as BMP-7) when treating Class II furcation defects of Papio ursinus. In context, hOP-1 is preferentially cementogenic when implanted into non-human primate class II and III furcation defects whilst hBMP-2 is highly Osteogenic but not cementogenic when in contact with dentine extracellular matrix. Importantly, naturally-derived highly purified BMPs/OPs, recombinant hOP-1 and hTGF-β3 when implanted into non-human primates Class II and III furcation defects induce cementogenesis with morphologically and functionally oriented periodontal ligament fibres coursing within a newly formed highly vascular periodontal ligament space with Sharpey's fibres generated within the newly secreted cementoid matrix. The grand challenge of molecular and therapeutic implications is the biological significance of apparent redundancy. The presence of several homologous but molecularly different isoforms all endowed with the striking capacity of inducing "bone formation by autoinduction" indicates that there is a structure/activity profile amongst soluble Osteogenic molecular signals; this suggests a therapeutic significance in clinical contexts. The structure/activity profile finely tunes the vast pleiotropic activities of the soluble molecular signals in mineralised and non-mineralised tissues profoundly modulating epithelial/mesenchymal tissue interactions. Significant advances in regenerative tissue engineering may be expected if ongoing research is tailored to provide further mechanistic and morphological insights into the relevance of the apparent redundancy and the structure/activity profile of the recombinant human Osteogenic Proteins. The presence of the structure/activity profile together with the biological significance of apparent redundancy will necessitate re-shaping and re-engineering developing newly devised targeted therapeutics for periodontal tissue engineering.

  • bone morphogenetic Proteins cementogenesis myoblastic stem cells and the induction of periodontal tissue regeneration
    Cytokine & Growth Factor Reviews, 2009
    Co-Authors: Ugo Ripamonti, Jeanclaude Petit
    Abstract:

    Abstract ‘ Bone : Formation by autoinduction ', initiates by invocation of soluble molecular signals which, when combined to insoluble signals or substrata trigger the ripple-like cascade of bone differentiation by induction. The Osteogenic Proteins of the transforming growth factor-β (TGF-β) superfamily, the bone morphogenetic/Osteogenic Proteins (BMPs/OPs), and uniquely in the non-human primate Papio ursinus also the three mammalian TGF-β isoforms, induce endochondral bone formation as recapitulation of embryonic development. The pleiotropic activities of the BMPs/OPs are vast and include the induction of periodontal tissue regeneration. Implantation of naturally derived highly purified Osteogenic fractions after sequential adsorption/affinity and gel filtration chromatography in mandibular Class II furcation defects of P. ursinus induces cementogenesis as highly cellular collagenic cementoid attached to the exposed dentine with foci of nascent mineralization with inserted de novo generated Sharpey's fibres. Recombinant human Osteogenic Protein-1 (hOP-1) when implanted in Class II furcation defects of P. ursinus with surgically exposed dentine matrix preferentially initiates the induction of cementogenesis; on the other hand, hBMP-2 preferentially induces alveolar bone regeneration with mineralized bone covered by prominent osteoid seams. Long-term studies with gamma-irradiated 0.5 and 2.5mg hOP-1 per gram of xenogeneic bovine collagenous matrix induce the restitutio ad integrum of the periodontal tissues in furcation defects exposed by chronic periodontitis in P. ursinus . A challenging question for tissue engineering and regenerative medicine is whether the presence of molecularly different Osteogenic Proteins of the TGF-β superfamily has a therapeutic significance. Mechanistically, the specificity of hOP-1 primarily initiating cementogenesis in periodontal defects is regulated by both the dentine extracellular matrix upon which responding cells attach and differentiate, and the structure/activity profile of the implanted hOP-1; the limited induction of cementogenesis by hBMP-2 in furcation defects of non-human primate and canine models is consistent with the reported data that hBMP-2 inhibits differentiation and mineralization of cementoblasts in vitro aside the specific structure/activity profile of the implanted hBMP-2 Protein. The induction of periodontal tissue regeneration develops as a mosaic structure in which the Osteogenic Proteins of the TGF-β superfamily singly, synergistically and synchronously initiate and maintain tissue induction and morphogenesis as a recapitulation of embryonic development.

  • cementogenesis and the induction of periodontal tissue regeneration by the Osteogenic Proteins of the transforming growth factor β superfamily
    Journal of Periodontal Research, 2009
    Co-Authors: Ugo Ripamonti, Jeanclaude Petit, June Teare
    Abstract:

    : The antiquity and severity of periodontal diseases are demonstrated by the hard evidence of alveolar bone loss in gnathic remains of the Pliocene/Pleistocene deposits of the Bloubank Valley at Sterkfontein, Swartkrans and Kromdrai in South Africa. Extant Homo has characterized and cloned a superfamily of Proteins which include the bone morphogenetic Proteins that regulate tooth morphogenesis at different stages of development as temporally and spatially connected events. The induction of cementogenesis, periodontal ligament and alveolar bone regeneration are regulated by the co-ordinated expression of bone morphogenetic Proteins. Naturally derived and recombinant human bone morphogenetic Proteins induce periodontal tissue regeneration in mammals. Morphological analyses on undecalcified sections cut at 3-6 mum on a series of mandibular molar Class II and III furcation defects induced in the non-human primate Papio ursinus show the induction of cementogenesis. Sharpey's fibers nucleate as a series of composite collagen bundles within the cementoid matrix in close relation to embedded cementocytes. Osteogenic Protein-1 and bone morphogenetic Protein-2 possess a structure-activity profile, as shown by the morphology of tissue regeneration, preferentially cementogenic and Osteogenic, respectively. In Papio ursinus, transforming growth factor-beta(3) also induces cementogenesis, with Sharpey's fibers inserting into newly formed alveolar bone. Capillary sprouting and invasion determine the sequential insertion and alignment of individual collagenic bundles. The addition of responding stem cells prepared by finely mincing fragments of autogenous rectus abdominis muscle significantly enhances the induction of periodontal tissue regeneration when combined with transforming growth factor-beta(3) implanted in Class II and III furcation defects of Papio ursinus.

  • bone induction by recombinant human Osteogenic Protein 1 hop 1 bmp 7 in the primate papio ursinus with expression of mrna of gene products of the tgf β superfamily
    Journal of Cellular and Molecular Medicine, 2005
    Co-Authors: Ugo Ripamonti
    Abstract:

    : Predictable bone induction in clinical contexts requires information on the expression and cross regulation of gene products of the transforming growth factor-beta (TGF-beta) superfamily elicited by single applications of each recombinant human bone morphogenetic/Osteogenic Proteins (BMPs/OPs). Using the calvarium and the rectus abdominis muscle of adult baboons Papio ursinus as a model for tissue induction and morphogenesis, this study investigated the induction of bone morphogenesis by gamma-irradiated hOP-1 delivered by gamma-irradiated bovine insoluble collagenous bone matrix, the hOP-1 Osteogenic device, for bone induction in heterotopic and orthotopic sites of the primate Papio ursinus and the expression patterns of OP-1, collagen type IV, BMP-3 and TGFbeta1mRNAs elicited by increasing single applications of doses of the hOP-1 Osteogenic devices (0.1, 0.5 and 2.5 mg hOP-1/g of matrix) applied heterotopically in the rectus abdominis muscle and orthotopically in 48 calvarial defects of 12 adult baboons. Histology and histomorphometry on serial undecalcified sections prepared from the specimens harvested on day 15, 30 and 90 showed that all the doses of the hOP-1 Osteogenic device induced bone formation culminating in complete calvarial regeneration by day 90. Type IV collagen mRNA expression, a marker of angiogenesis, was strongly expressed in both heterotopic and orthotopic tissues. High levels of expression of OP-1 mRNA demonstrated autoinduction of OP-1 mRNAs. Expression levels of BMP-3 mRNA varied from tissues induced in heterotopic vs. orthotopic sites with high expression in rapidly forming heterotopic ossicles together with high expression of type IV collagen mRNA. The temporal and spatial expressions of TGF-beta1 mRNAindicate a specific temporal transcriptional window during which expression of TGF-beta1 is mandatory for successful and optimal osteogenesis. The induction of bone by hOP-1 in Papio ursinus develops as a mosaic structure with distinct spatial and temporal patterns of gene expression of members of the TGF-beta superfamily that singly, synergistically and synchronously initiate and maintain tissue induction and morphogenesis.

  • Osteogenic Protein 1 a bone morphogenetic Protein induces angiogenesis in the chick chorioallantoic membrane and synergizes with basic fibroblast growth factor and transforming growth factor β1
    Anatomical Record-advances in Integrative Anatomy and Evolutionary Biology, 2000
    Co-Authors: Lentsha Nathaniel Ramoshebi, Ugo Ripamonti
    Abstract:

    Capillary invasion is a vital regulatory signal during bone morphogenesis that is influenced by angiogenic molecules such as fibroblast growth factor (FGF) and some members of the transforming growth factor-β (TGF-β) superfamily, including TGF-βs themselves. Bone morphogenetic Proteins (BMPs), which are members of the TGF-β superfamily, have previously not been shown to possess direct angiogenic properties. Osteogenic Protein-1 (OP-1; BMP-7) is a potent regulator of cartilage and bone differentiation in vivo. The Osteogenic and angiogenic properties of OP-1 at both ortho- and heterotopic sites in adult chacma baboons (Papio ursinus) are enhanced synergistically by the simultaneous application of relatively low doses of TGF-β1. The single application of relatively high doses of TGF-β1 (20 ng), and bFGF (500 ng) or relatively low (100 ng) and high (1,000 ng) doses of OP-1 in the chick chorioallantoic membrane (CAM) assay elicited a prominent and (for OP-1) dose-dependent angiogenic response. The binary application of a relatively low dose of OP-1 (100 ng) with a relatively low dose of bFGF (100 ng) or with a relatively low (5 ng) or high (20 ng) dose of TGF-β1 resulted in a synergistic enhancement of the angiogenic response. The angiogenic effect of the relatively low doses of the combined morphogens was distinctly more pronounced than that of the single application of the relatively high doses of the respective factors. The present findings suggest that these morphogens may be deployed in binary combination in order to accentuate experimental angiogenesis. The cooperative interaction of the different morphogens in the CAM assay may provide important biological clues towards the control of clinical angiogenesis. Anat Rec 259:97-107, 2000. © 2000 Wiley-Liss, Inc.

E H Burger - One of the best experts on this subject based on the ideXlab platform.

  • opposite effects of Osteogenic Protein and transforming growth factor β on chondrogenesis in cultured long bone rudiments
    Journal of Bone and Mineral Research, 2009
    Co-Authors: S. C. Dieudonne, C M Semeins, S W Goei, Slobodan Vukicevic, T. K. Sampath, Klein J Nulend, M N Helder, E H Burger
    Abstract:

    Osteogenic Protein-1 (OP-1, also called BMP-7) is a bone morphogenetic member of the TGF-β superfamily. In the present study, we examined the effect of recombinant human OP-1 on cartilage and bone formation in organ cultures of metatarsal long bones of mouse embryos and compared the OP-1 effects with those of human TGF-β1 and porcine TGF-β1 and β2. Cartilage formation was determined by measurement of longitudinal growth of whole bone rudiments during culture and by the incorporation of 35SO4 into glycosaminoglycans. Mineralization was monitored by 45Ca incorporation in the acid-soluble fraction and by measuring the length of the calcifying center of the rudiment. Toluidine blue-stained histologic sections were used for quantitative histomorphometric analysis. We found that OP-1 stimulated cartilage growth as determined by sulfate incorporation and that it increased remarkably the width of the long bones ends compared with controls. This effect was partly caused by differentiation of perichondrial cells into chondrocytes, resulting in increased appositional growth. In contrast to OP-1, TGF-β1 and β2 inhibited cartilage growth and reduced the length of whole bone rudiments compared with controls. In the ossifying center of the bone rudiments, both OP-1 and TGF-β inhibited cartilage hypertrophy, growth of the bone collar, and matrix mineralization. These data demonstrate that OP-1 and TGF-β exhibit opposite effects on cartilage growth but similar effects on osteogenesis in embryonic mouse long bone cultures. Since both OP-1 and TGF-β have been demonstrated in embryonic cartilage and bone, these results suggest that they act as autocrine or paracrine regulators of embryonic bone development.

  • Bone morphogenetic Proteins in human bone regeneration
    Eur J Endocrinol, 2000
    Co-Authors: E H Groeneveld, E H Burger
    Abstract:

    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.

  • histomorphometrical analysis of bone formed in human maxillary sinus floor elevations grafted with op 1 device demineralized bone matrix or autogenous bone comparison with non grafted sites in a series of case reports
    Clinical Oral Implants Research, 1999
    Co-Authors: Erika H J Groeneveld, P Holzmann, Chris Ten M Bruggenkate, J P A Van Den Bergh, D B Tuinzing, E H Burger
    Abstract:

    Bone morphogenetic Proteins have proven to be effective bone inductors in animals and are therefore promising as inductors of bone formation in humans. In the present study we investigated the tissue formed after grafting Osteogenic Protein 1 on a collagen carrier (OP-1-device) in the human sinus floor elevation procedure. Three patients were grafted with OP-1 device. For comparison 3 groups of 3 patients were included in the study receiving respectively, autogenous bone, human freeze-dried demineralized bone matrix (DBM) or no graft. This last group had a sufficient alveolar bone height for dental implantation. Six months after grafting, at the time of implantation, biopsies were taken from the grafted area and/or the future dental positions. Undecalcified sections were used for histological and histomorphometrical analysis. All grafted sinuses showed an increased osteoid percentage when compared to non-grafted sinuses. Autogenous bone grafts all showed lamellar bone formation. In the DBM grafts mostly woven bone had been formed, predominantly by what appeared to be osteo-conduction. The OP-1 device gave rise to bone formation in 2 of the 3 patients. After 6 months implants could only be placed in 1 out of the 3 patients treated with OP-1 device. This patient showed mature lamellar bone formation, comparable to autogenous bone grafts. In the second patient all bone found was woven and the presence of a high osteoid percentage and large osteocyte lacunae indicated that this was recently-formed bone. Remnants of the collagen carrier were rare and new bone was never found against them, suggesting that this bone was formed by osteo-induction. In the third patient no new bone had been formed. The device had been encapsulated with fibrous tissue and inflammatory reaction was present. We conclude that in the human sinus floor elevation OP-1 has potential bone inductive capacity, but that results in the 3 patients tested with the current OP-1 device are inconsistent.

  • Osteogenic Protein op 1 bmp 7 stimulates cartilage differentiation of human and goat perichondrium tissue in vitro
    Journal of Biomedical Materials Research, 1998
    Co-Authors: Jenneke Kleinnulend, R T Louwerse, Ide C. Heyligers, C M Semeins, S W Goei, Paul I J M Wuisman, E H Burger
    Abstract:

    The objective of this study was to examine in vitro the influence of recombinant human Osteogenic Protein-1 [rhOP-1, or bone morphogenetic Protein-7 (BMP-7)] on cartilage formation by human and goat perichondrium tissue containing progenitor cells with chondrogenic potential. Fragments of outer ear perichondrium tissue were embedded in clotting autologous blood to which rhOP-1 had been added or not added (controls), and the resulting explant was cultured for 3 weeks without further addition of rhOP-1. Cartilage formation was monitored biochemically by measuring [35S]-sulphate incorporation into proteoglycans and histologically by monitoring the presence of metachromatic matrix with cells in nests. The presence of rhOP-1 in the explant at the beginning of culture stimulated [35S]-sulphate incorporation into proteoglycans in a dose-dependent manner after 3 weeks of culture. Maximal stimulation was reached at 40 μg/mL (human explants: +148%; goat explants: +116%). Histology revealed that explants treated with 20–200 μg/mL of rhOP-1, but not untreated control explants, contained areas of metachromatic-staining matrix with chondrocytes in cell nests. It was concluded that rhOP-1 stimulates differentiation of cartilage from perichondrium tissue. The direct actions of rhOP-1 on perichondrium cells in the stimulation of chondrocytic differentiation and production of cartilage matrix in vitro provides a cellular mechanism for the induction of cartilage formation by rhOP-1 in vivo. Thus rhOP-1 may promote early steps in the cascade of events leading to cartilage formation and could prove to be an interesting factor in the regeneration of cartilage in articular cartilage defects. © 1998 John Wiley & Sons, Inc. J Biomed Mater Res, 40, 614–620, 1998.

  • stimulation of cartilage differentiation by Osteogenic Protein 1 in cultures of human perichondrium
    Tissue Engineering, 1998
    Co-Authors: Jenneke Kleinnulend, H A H Winters, Marcel E. Ooms, J W Mulder, C M Semeins, S W Goei, E H Burger
    Abstract:

    Exposure of progenitor cells with chondrogenic potential to recombinant human Osteogenic Protein-1 [rhOP-1, or bone morphogenetic Protein-7 (BMP-7] may be of therapeutic interest in the regeneratio...

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  • aging and oxidative stress reduce the response of human articular chondrocytes to insulin like growth factor 1 and Osteogenic Protein 1
    Arthritis & Rheumatism, 2014
    Co-Authors: Richard F Loeser, Uma Gandhi, David L Long, Susan Chubinskaya
    Abstract:

    Objective To determine the effects of aging and oxidative stress on the response of human articular chondrocytes to insulin-like growth factor 1 (IGF-1) and Osteogenic Protein 1 (OP-1). Methods Chondrocytes isolated from normal articular cartilage obtained from tissue donors were cultured in alginate beads or monolayer. Cells were stimulated with 50–100 ng/ml of IGF-1, OP-1, or both. Oxidative stress was induced using tert-butyl hydroperoxide. Sulfate incorporation was used to measure proteoglycan synthesis, and immunoblotting of cell lysates was performed to analyze cell signaling. Confocal microscopy was performed to measure nuclear translocation of Smad4. Results Chondrocytes isolated from the articular cartilage of tissue donors ranging in age from 24 years to 81 years demonstrated an age-related decline in proteoglycan synthesis stimulated by IGF-1 and IGF-1 plus OP-1. Induction of oxidative stress inhibited both IGF-1– and OP-1–stimulated proteoglycan synthesis. Signaling studies showed that oxidative stress inhibited IGF-1–stimulated Akt phosphorylation while increasing phosphorylation of ERK, and that these effects were greater in cells from older donors. Oxidative stress also increased p38 phosphorylation, which resulted in phosphorylation of Smad1 at the Ser206 inhibitory site and reduced nuclear accumulation of Smad1. Oxidative stress also modestly reduced OP-1–stimulated nuclear translocation of Smad4. Conclusion These results demonstrate an age-related reduction in the response of human chondrocytes to IGF-1 and OP-1, which are 2 important anabolic factors in cartilage, and suggest that oxidative stress may be a contributing factor by altering IGF-1 and OP-1 signaling.

  • RESEARCH ARTICLE Open Access Regulation of chondrocyte gene expression by Osteogenic Protein-1
    2013
    Co-Authors: Susan Chubinskaya, David C. Rueger, Lori Otten, Stephan Soeder, Jeffrey A Borgia, Thomas Aigner, Richard F Loeser
    Abstract:

    Introduction: The objective of this study was to investigate which genes are regulated by Osteogenic Protein-1 (OP-1) in human articular chondrocytes using Affimetrix gene array, in order to understand the role of OP-1 in cartilage homeostasis. Methods: Chondrocytes enzymatically isolated from 12 normal ankle cartilage samples were cultured in high-density monolayers and either transfected with OP-1 antisense oligonucleotide in the presence of lipofectin or treated wit

  • synergistic effect of igf 1 and op 1 on matrix formation by normal and oa chondrocytes cultured in alginate beads
    Osteoarthritis and Cartilage, 2007
    Co-Authors: Susan Chubinskaya, David C. Rueger, Thomas Aigner, C Pacione, Arnavaz A Hakimiyan, Adam B Yanke, L Rappoport, Richard F Loeser
    Abstract:

    Summary Objective Growth factor therapy may be useful for stimulation of cartilage matrix synthesis and repair. Thus, the purpose of our study was to further understand the effect of combined insulin-like growth factor-1 (IGF-1) and Osteogenic Protein-1 (OP-1) treatment on the matrix synthesized by human adult normal and osteoarthritic (OA) chondrocytes. Design Chondrocytes were isolated post-mortem from articular cartilage from tali of normal human donors and femoral condyles of OA patients undergoing knee replacement surgery. Cells were cultured in alginate beads for 21 days in four experimental groups: (1) "mini-ITS" control; (2) 100ng/ml IGF-1; (3) 100ng/ml OP-1; (4) IGF-1+OP-1, each at 100ng/ml. Beads were processed for histological (Safranin O and fast green), morphometrical and immunohistochemical (aggrecan, decorin, type I, II, VI, and X collagens, and fibronectin accumulation) analyses. Results Histology showed that IGF-1 alone did not induce substantial matrix production. OP-1 alone caused a considerable matrix formation, but the highest matrix accumulation by normal and OA chondrocytes was found when OP-1 and IGF-1 were added together. Morphometrical analysis indicated larger matrices produced by OA chondrocytes than by normal cells under the combined treatment. All tested matrix Proteins were more abundant in the combination group. Type X collagen was detected only under the combined OP-1 and IGF-1 treatment and was present at very low levels. Type I collagen was found only in OA chondrocytes. Conclusions The results obtained in the current study suggest that combined therapy with IGF-1 and OP-1 may have a greater potential in treating cartilage defects seen in OA than use of either growth factor alone.

  • nanomechanical properties of individual chondrocytes and their developing growth factor stimulated pericellular matrix
    Journal of Biomechanics, 2007
    Co-Authors: Hanhwa Hung, Susan Chubinskaya, Alexander Sprunt, Christine Ortiz, A Grodzinsky
    Abstract:

    The nanomechanical properties of individual cartilage cells (chondrocytes) and their aggrecan and collagen-rich pericellular matrix (PCM) were measured via atomic force microscope nanoindentation using probe tips of two length scales (nanosized and micron-sized). The properties of cells freshly isolated from cartilage tissue (devoid of PCM) were compared to cells that were cultured for selected times (up to 28 days) in 3-D alginate gels which enabled PCM assembly and accumulation. Cells were immobilized and kept viable in pyramidal wells microfabricated into an array on silicon chips. Hertzian contact mechanics and finite element analyses were employed to estimate apparent moduli from the force versus depth curves. The effects of culture conditions on the resulting PCM properties were studied by comparing 10% fetal bovine serum to medium containing a combination of insulin growth factor-1 (IGF-1)+Osteogenic Protein-1 (OP-1). While both systems showed increases in stiffness with time in culture between days 7 and 28, the IGF-1+OP-1 combination resulted in a higher stiffness for the cell-PCM composite by day 28 and a higher apparent modulus of the PCM which is compared to the FBS cultured cells. These studies give insight into the temporal evolution of the nanomechanical properties of the pericellar matrix relevant to the biomechanics and mechanobiology of tissue-engineered constructs for cartilage repair.

  • Osteogenic Protein 1 in synovial fluid from patients with rheumatoid arthritis or osteoarthritis relationship with disease and levels of hyaluronan and antigenic keratan sulfate
    Arthritis Research & Therapy, 2006
    Co-Authors: Susan Chubinskaya, Eugene J M A Thonar, David C. Rueger, Lori Otten, Benjamin S Frank, Margaret Michalska, Bhavna Kumar, Charis Merrihew, Mary Ellen Lenz, Joel A Block
    Abstract:

    The measurement of body fluid levels of biochemical markers in joint tissues has begun to provide clinically useful information. Synovial fluid (SF) plays an important role in articular joint lubrication, nutrition, and metabolism of cartilage and other connective tissues within the joint. The purpose of our study was to identify and characterize Osteogenic Protein 1 (OP-1) in SF from patients with rheumatoid arthritis (RA) or with osteoarthritis (OA) and to correlate levels of OP-1 with those of hyaluronan (HA) and antigenic keratan sulfate (AgKS). SF was aspirated from the knees of patients with either RA or OA and from the knees of asymptomatic organ donors with no documented history of joint disease. The presence of detectable OP-1 in SF was demonstrated by western blots with specific anti-pro-OP-1 and anti-mature OP-1 antibodies. Measurement of levels of OP-1, HA and AgKS was performed using ELISAs. OP-1 was identified in human SF in two forms, pro-OP-1 and active (mature) OP-1 – mature OP-1 being detected only in SF from OA patients and RA patients. Levels of OP-1 and HA were higher in RA patients than in OA patients and asymptomatic donors, while the level of AgKS was highest in SF from asymptomatic donors. Statistically significant differences were found between SF levels of OP-1 in RA and OA patients and between SF levels of AgKS among the three groups tested. The SF content of OP-1 tended to correlate positively with HA levels, but negatively with AgKS concentrations. In conclusion, the results of this study suggest that measurement of OP-1 in joint fluid may have value in the clinical evaluation of joint disease processes.

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