18 results on '"Luyten, Frank P."'
Search Results
2. Combinatorial Analysis of Growth Factors Reveals the Contribution of Bone Morphogenetic Proteins to Chondrogenic Differentiation of Human Periosteal Cells.
- Author
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Mendes LF, Tam WL, Chai YC, Geris L, Luyten FP, and Roberts SJ
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- Adolescent, Animals, Cells, Cultured, Chondrocytes drug effects, Chondrocytes metabolism, Chondrogenesis drug effects, Female, Humans, Male, Mesenchymal Stem Cells cytology, Mesenchymal Stem Cells drug effects, Mesenchymal Stem Cells metabolism, Mice, Mice, Nude, Periosteum drug effects, Periosteum metabolism, Tissue Donors, Bone Morphogenetic Proteins metabolism, Cell Differentiation drug effects, Chondrocytes cytology, Chondrogenesis physiology, Intercellular Signaling Peptides and Proteins pharmacology, Periosteum cytology, Tissue Engineering methods
- Abstract
Successful application of cell-based strategies in cartilage and bone tissue engineering has been hampered by the lack of robust protocols to efficiently differentiate mesenchymal stem cells into the chondrogenic lineage. The development of chemically defined culture media supplemented with growth factors (GFs) has been proposed as a way to overcome this limitation. In this work, we applied a fractional design of experiment (DoE) strategy to screen the effect of multiple GFs (BMP2, BMP6, GDF5, TGF-β1, and FGF2) on chondrogenic differentiation of human periosteum-derived mesenchymal stem cells (hPDCs) in vitro. In a micromass culture (μMass) system, BMP2 had a positive effect on glycosaminoglycan deposition at day 7 (p < 0.001), which in combination with BMP6 synergistically enhanced cartilage-like tissue formation that displayed in vitro mineralization capacity at day 14 (p < 0.001). Gene expression of μMasses cultured for 7 days with a medium formulation supplemented with 100 ng/mL of BMP2 and BMP6 and a low concentration of GDF5, TGF-β1, and FGF2 showed increased expression of Sox9 (1.7-fold) and the matrix molecules aggrecan (7-fold increase) and COL2A1 (40-fold increase) compared to nonstimulated control μMasses. The DoE analysis indicated that in GF combinations, BMP2 was the strongest effector for chondrogenic differentiation of hPDCs. When transplanted ectopically in nude mice, the in vitro-differentiated μMasses showed maintenance of the cartilaginous phenotype after 4 weeks in vivo. This study indicates the power of using the DoE approach for the creation of new medium formulations for skeletal tissue engineering approaches.
- Published
- 2016
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3. Bone morphogenetic protein signaling and arthritis.
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Lories RJ and Luyten FP
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- Animals, Arthritis genetics, Arthritis physiopathology, Bone Morphogenetic Proteins genetics, Bone Morphogenetic Proteins metabolism, Cartilage physiopathology, Humans, Inflammation physiopathology, Joints physiology, Joints physiopathology, Models, Biological, Signal Transduction genetics, Arthritis etiology, Bone Morphogenetic Proteins physiology, Signal Transduction physiology
- Abstract
Chronic joint diseases have a major impact on society as patients suffer from pain and disability. The spectrum of arthritic disorders is wide including autoimmune and autoinflammatory diseases such as rheumatoid arthritis, ankylosing spondylitis and related spondyloarthritides but also the more prevalent osteoarthritic diseases. The latter appear to be mainly the consequence of injury, strain and aging in a predisposing genetic background. The therapeutic options for chronic inflammatory and immune joint diseases have greatly increased over the last decade by the use of targeted anti-cytokine or anti-immune cell drugs. However, such a shift towards successful treatment has not been achieved for osteoarthritis. In addition, control of inflammation does not equal cure of the disease as relapse occurs as soon as the treatment is interrupted, and only limited tissue repair has been observed. Bone morphogenetic proteins are potent regulators of cell proliferation, differentiation and apoptosis and they have come into the spotlight in arthritis research. Here, we summarize the recent data on the role of bone morphogenetic proteins in joint protection and repair and but also their potential disease promoting or controlling roles. These data are presented in the context of a systems biology view of joint diseases based on their histomorphological phenotype rather than on existing clinical classifications.
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- 2009
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4. Xenopus SMOC-1 Inhibits bone morphogenetic protein signaling downstream of receptor binding and is essential for postgastrulation development in Xenopus.
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Thomas JT, Canelos P, Luyten FP, and Moos M Jr
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- Animals, Humans, Ligands, Mice, Models, Biological, Oligonucleotides, Antisense chemistry, Osteonectin biosynthesis, Osteonectin metabolism, Phosphorylation, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, Xenopus, Xenopus Proteins biosynthesis, Xenopus laevis, Zebrafish, Bone Morphogenetic Proteins metabolism, Gene Expression Regulation, Developmental, Osteonectin physiology, Xenopus Proteins physiology
- Abstract
The bone morphogenetic protein (BMP) family of signaling molecules and their antagonists are involved in patterning of the body axis and numerous aspects of organogenesis. Classical biochemical purification and protein sequencing of highly purified fractions containing potent bone forming activity from bovine cartilage identified several BMPs together with a number of other proteins. One such protein was SMOC-2 (secreted modular calcium-binding protein-2), classified as belonging to the BM-40 family of modular extracellular proteins. Data regarding the biological function of SMOC-2 and closely related SMOC-1 remain limited, and their expression or function during embryological development is unknown. We therefore isolated the Xenopus ortholog of human SMOC-1 (XSMOC-1) and explored its function in Xenopus embryos. In gain-of-function assays, XSMOC-1 acted similarly to a BMP antagonist. However, in contrast to known extracellular ligand-binding BMP antagonists, such as noggin, SMOC antagonizes BMP activity in the presence of a constitutively active BMP receptor, indicating a mechanism of action downstream of the receptor. We provide several lines of evidence to suggest that SMOC acts downstream of the BMP receptor via MAPK-mediated phosphorylation of the Smad linker region. Loss-of-function studies, using antisense morpholino oligonucleotides, revealed XSMOC-1 to be essential for postgastrulation development. The catastrophic developmental failure observed following XSMOC knockdown resembles that observed following simultaneous depletion of three ligand-binding BMP antagonists described in prior studies. These findings provide a direct link between the extracellular matrix-associated protein SMOC and a signaling pathway of general importance in anatomic patterning and cell or tissue fate specification.
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- 2009
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5. Dynamic activation of bone morphogenetic protein signaling in collagen-induced arthritis supports their role in joint homeostasis and disease.
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Daans M, Lories RJ, and Luyten FP
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- Animals, Arthritis, Experimental pathology, Arthritis, Rheumatoid pathology, Blotting, Western, Cartilage metabolism, Humans, Immunohistochemistry, Joints pathology, Male, Mice, RNA, Messenger analysis, Reverse Transcriptase Polymerase Chain Reaction, Smad Proteins metabolism, Synovial Membrane metabolism, Arthritis, Experimental metabolism, Arthritis, Rheumatoid metabolism, Bone Morphogenetic Proteins metabolism, Homeostasis physiology, Joints metabolism, Signal Transduction physiology
- Abstract
Introduction: Rheumatoid arthritis is a chronic systemic autoimmune disease affecting peripheral joints and leading to loss of joint function. The severity and outcome of disease are dependent on the balance between inflammatory/destructive and homeostatic or repair pathways. Increasing evidence suggests a role for bone morphogenetic protein (BMP) signaling in joint homeostasis and disease., Methods: Activation of BMP signaling in collagen-induced arthritis as a model of rheumatoid arthritis was studied by immunohistochemistry and Western blot for phosphorylated SMAD1/5 at different time points. Expression of different BMP ligands and noggin, a BMP antagonist, was determined on synovium and cartilage extracts of arthritic knees, at different time points, with quantitative polymerase chain reaction. At the protein level, BMP2 and BMP7 were studied with immunohistochemistry. Finally, the effect of anti-tumor necrosis factor-alpha (TNFalpha) treatment on the expression of BMP2, BMP7, and growth and differentiation factor-5 (GDF5) in synovium and cartilage of arthritic knees was investigated., Results: A time-dependent activation of the BMP signaling pathway in collagen-induced arthritis was demonstrated with a dynamic and characteristic expression pattern of different BMP subfamily members in synovium and cartilage of arthritic knees. As severity increases, the activation of BMP signaling becomes more prominent in the invasive pannus tissue. BMP2 is present in cartilage and the hyperplastic lining layer. BMP7 is found in the sublining zone and inflammatory infiltrate. Treatment with etanercept slowed down progression of disease, but no change in expression of GDF5, BMP2, and BMP7 in synovium was found; in the cartilage, however, blocking of TNFalpha increased the expression of BMP7., Conclusions: BMP signaling is dynamically activated in collagen-induced arthritis and is partly TNFalpha-independent. TNFalpha blocking increased the expression of BMP7 in the articular cartilage, possibly enhancing anabolic mechanisms. Different types of source and target cells are recognized. These data further support a role for BMP signaling in arthritis.
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- 2008
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6. Bone morphogenetic proteins in destructive and remodeling arthritis.
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Lories RJ and Luyten FP
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- Animals, Bone Remodeling physiology, Cartilage metabolism, Cartilage pathology, Humans, Arthritis metabolism, Arthritis pathology, Bone Morphogenetic Proteins metabolism, Joints metabolism, Joints pathology
- Abstract
Joint destruction and tissue responses determine the outcome of chronic arthritis. Joint inflammation and damage are often the dominant clinical presentation. However, in some arthritic diseases, in particular the spondyloarthritides, joint remodeling is a prominent feature, with new cartilage and bone formation leading to ankylosis and contributing to loss of function. A role for bone morphogenetic proteins in joint remodeling has been demonstrated in the formation of both enthesophytes and osteophytes. Data from genetic models support a role for bone morphogenetic protein signaling in cartilage homeostasis. Finally, this signaling pathway is likely to play a steering role in the synovium.
- Published
- 2007
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7. Noggin haploinsufficiency differentially affects tissue responses in destructive and remodeling arthritis.
- Author
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Lories RJ, Daans M, Derese I, Matthys P, Kasran A, Tylzanowski P, Ceuppens JL, and Luyten FP
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- Animals, Arthritis, Experimental chemically induced, Cartilage, Articular pathology, Disease Progression, Gene Transfer Techniques, Homeostasis physiology, Mice, Mice, Inbred C57BL, Mice, Inbred DBA, Osteogenesis physiology, Serum Albumin, Bovine pharmacology, Signal Transduction physiology, Arthritis, Experimental physiopathology, Bone Morphogenetic Proteins physiology, Carrier Proteins genetics, Carrier Proteins physiology
- Abstract
Objective: The balance between destruction and homeostatic or reparative responses determines the outcome of arthritis. Increasing evidence suggests a role for signaling pathways, essential for development and growth, in the maintenance of tissue homeostasis and attempts at repair. Inappropriate activation of such pathways may also have a role in disease progression. We undertook this study to determine the effect of shifting the balance in bone morphogenetic protein (BMP) signaling in different mouse models of arthritis., Methods: Endogenous levels of noggin, a BMP antagonist, were reduced using heterozygous noggin(+/LacZ) mice in a model of inflammation-driven destruction (methylated bovine serum albumin [mBSA]-induced monarthritis), a model of systemic autoimmune arthritis (collagen-induced arthritis [CIA]), and a model of joint ankylosis (spontaneous arthritis in DBA/1 mice). In addition, we studied BMP inactivation by adenoviral noggin overexpression in destructive arthritis. Cartilage damage and activation of BMP signaling were studied by digital image analysis using Safranin O sulfated glycosaminoglycan staining and immunohistochemistry for phosphorylated Smads (Smads 1, 5, and 8), respectively., Results: Noggin haploinsufficiency provided protection for articular cartilage against destruction in mBSA-induced arthritis. Antagonist overexpression rendered cartilage more vulnerable in this model. Noggin gene transfer in knees affected by CIA also enhanced cartilage damage. Haploinsufficiency did not affect CIA, but noggin(+/LacZ) mice had an increased number of CD4-positive cells with normal immune responses. In noggin(+/LacZ) DBA/1 mice with spontaneous arthritis, we observed delayed progression from cartilage to bone formation., Conclusion: Tight spatiotemporal control of BMP signaling appears to be critical in the response of joint tissues in models of arthritis.
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- 2006
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8. Bone morphogenetic protein signaling in joint homeostasis and disease.
- Author
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Lories RJ and Luyten FP
- Subjects
- Animals, Arthritis, Rheumatoid physiopathology, Bone Remodeling, Homeostasis, Humans, Osteoarthritis physiopathology, Signal Transduction, Spondylarthritis physiopathology, Bone Morphogenetic Proteins metabolism, Joints physiology, Joints physiopathology
- Abstract
Despite advances in therapies that target inflammation and tissue destruction in chronic arthritis, stimulation of tissue repair and restoration of joint function, the ultimate goal of treatment, is far from achieved. We introduce a new paradigm that may help to improve our understanding and management of chronic arthritis. The presence or absence of tissue responses distinguishes destructive arthritis, steady-state arthritis and remodeling arthritis. Increasing evidence suggests that reactivation of embryonic molecular pathways is an important mechanism to stimulate postnatal tissue repair. Bone Morphogenetic Proteins (BMPs) have critical roles in skeletal development and joint morphogenesis, but also in postnatal joint homeostasis and joint tissue remodeling. Therefore, modulation of BMP signaling may be an attractive therapeutic target in chronic arthritis to restore homeostasis and function of synovial joints.
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- 2005
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9. Modulation of bone morphogenetic protein signaling inhibits the onset and progression of ankylosing enthesitis.
- Author
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Lories RJ, Derese I, and Luyten FP
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- Animals, Bone and Bones embryology, Bone and Bones pathology, Carrier Proteins genetics, Cell Proliferation, Disease Models, Animal, Humans, Mice, Mice, Inbred DBA, Spondylitis, Ankylosing pathology, Spondylitis, Ankylosing therapy, Bone Morphogenetic Proteins antagonists & inhibitors, Bone Morphogenetic Proteins metabolism, Carrier Proteins metabolism, Genetic Therapy, Signal Transduction genetics, Spondylitis, Ankylosing metabolism
- Abstract
Joint ankylosis is a major cause of disability in the human spondyloarthropathies. Here we report that this process partially recapitulates embryonic endochondral bone formation in a spontaneous model of arthritis in DBA/1 mice. Bone morphogenetic protein (BMP) signaling appears to be a key molecular pathway involved in this pathological cascade. Systemic gene transfer of noggin, a BMP antagonist, is effective both as a preventive and a therapeutic strategy in the mouse model, mechanistically interfering with enthesial progenitor cell proliferation in early stages of the disease process. Immunohistochemical staining for phosphorylated smad1/5 in enthesial biopsies of patients with spondyloarthropathy reveals active BMP signaling in similar target cells. Our data suggest that BMP signaling is an attractive therapeutic target for interfering with structural changes in spondyloarthropathy either as an alternative or complementary approach to current antiinflammatory treatments.
- Published
- 2005
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10. Bone morphogenetic proteins 2 and 6, expressed in arthritic synovium, are regulated by proinflammatory cytokines and differentially modulate fibroblast-like synoviocyte apoptosis.
- Author
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Lories RJ, Derese I, Ceuppens JL, and Luyten FP
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- Adult, Aged, Antineoplastic Agents immunology, Antineoplastic Agents pharmacology, Apoptosis drug effects, Arthritis, Rheumatoid immunology, Arthritis, Rheumatoid pathology, Bone Morphogenetic Protein 2, Bone Morphogenetic Protein 6, Bone Morphogenetic Proteins pharmacology, Cell Division drug effects, Cell Division immunology, Cells, Cultured, Female, Fibroblasts pathology, Gene Expression immunology, Humans, Interferon-gamma immunology, Interferon-gamma pharmacology, Interleukin-1 pharmacology, Male, Middle Aged, Nitric Oxide metabolism, Signal Transduction immunology, Synovial Membrane immunology, Synovial Membrane pathology, Tumor Necrosis Factor-alpha immunology, Tumor Necrosis Factor-alpha pharmacology, Up-Regulation immunology, Apoptosis immunology, Arthritis, Rheumatoid physiopathology, Bone Morphogenetic Proteins genetics, Interleukin-1 immunology, Synovial Membrane physiopathology, Transforming Growth Factor beta
- Abstract
Objective: To examine the expression, regulation, and potential roles of bone morphogenetic proteins (BMPs) in arthritic synovium., Methods: Expression of BMPs in arthritic synovium from patients with rheumatoid arthritis (RA) or spondylarthropathy (SpA) and in noninflamed synovium from patients undergoing diagnostic or therapeutic arthroscopies was studied by reverse transcription-polymerase chain reaction (RT-PCR), Western blot, immunohistochemistry, and 2-color immunofluorescence. In vitro regulation of gene expression in fibroblast-like synoviocytes (FLS) was determined by real-time quantitative RT-PCR and immunohistochemistry. We used (3)H-thymidine incorporation after serum deprivation-induced growth arrest to examine effects on FLS proliferation. FLS apoptosis was evaluated by flow cytometry cell cycle analysis. Apoptotic cells in synovial tissue were detected by TUNEL staining., Results: Transcripts of different BMPs, most strikingly BMP-2 and BMP-6, were detected in synovial tissues. By Western blot, BMP-2 and BMP-6 precursor protein was found in RA and SpA synovial tissue extracts, but not in extracts of noninflamed synovial tissue. By immunohistochemistry, BMP-2 and BMP-6 were detected in the hyperplastic lining and the sublining layer of synovium from RA and SpA patients, both in CD90+ cells (FLS) and in some CD68+ cells (macrophages). Proinflammatory cytokines, such as interleukin-1beta and tumor necrosis factor alpha, but not interferon-gamma, enhanced the expression of BMP-2 and BMP-6 transcripts in FLS in vitro. Neither BMP-2 nor BMP-6 affected FLS proliferation. BMP-2 promoted FLS apoptosis, whereas BMP-6 protected against nitric oxide-induced FLS apoptosis. BMP-2-positive apoptotic cells were found in arthritic synovium., Conclusion: BMP-2 and BMP-6 are expressed in arthritic synovium and are strongly up-regulated by proinflammatory cytokines. Although BMP signaling has been proposed to be involved in cartilage and bone repair in arthritis, this pathway may be equally important in modulating FLS cell populations in inflamed synovium.
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- 2003
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11. Activation of cartilage-derived morphogenetic protein-1 in torn rotator cuff.
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Nakase T, Sugamoto K, Miyamoto T, Tsumaki N, Luyten FP, Inui H, Myoui A, Tomita T, and Yoshikawa H
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- Aged, Collagen Type I analysis, Culture Techniques, Female, Growth Differentiation Factor 5, Growth Substances analysis, Humans, Immunohistochemistry, In Situ Hybridization, Male, Middle Aged, Rotator Cuff physiology, Sensitivity and Specificity, Bone Morphogenetic Proteins, Collagen Type I metabolism, Growth Substances metabolism, Regeneration physiology, Rotator Cuff pathology, Rotator Cuff Injuries
- Abstract
Localization and expression of cartilage-derived morphogenetic protein-1 in tissues of torn rotator cuff tendons were examined by in situ hybridization and immunohistochemical analysis. Histologic findings of torn rotator cuff tendons showed that active cells synthesizing the alpha-1 chain of collagen Type I messenger ribonucleic acid were localized predominantly in the torn edge and in the bursa side rather than in the joint side, and scarcely localized in a site distant from the torn edge. Cartilage-derived morphogenetic protein-1 had a similar distribution as the alpha-1 chain of collagen Type I. The current findings provide the first observational evidence that cartilage-derived morphogenetic protein-1 was activated specifically at the site of the torn rotator cuff tendon. The current findings suggest that the cells in the torn rotator cuffs are capable of synthesizing cartilage-derived morphogenetic protein-1, one of the known essential factors for tendon formation.
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- 2002
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12. Toward Advanced Therapy Medicinal Products (ATMPs) Combining Bone Morphogenetic Proteins (BMP) and Cells for Bone Regeneration
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Ji, Wei, Bolander, Johanna, Chai, Yoke Chin, Katagiri, Hiroki, Marechal, Marina, Luyten, Frank P., Parnham, Michael J., Series editor, Schmidtko, Achim, Series editor, Vukicevic, Slobodan, editor, and Sampath, Kuber T., editor
- Published
- 2017
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13. Deciphering the combined effect of bone morphogenetic protein 6 and calcium phosphate on bone formation capacity of periosteum derived cells-based tissue engineering constructs.
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Ji, Wei, Kerckhofs, Greet, Geeroms, Carla, Marechal, Marina, Geris, Liesbet, and Luyten, Frank P.
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BONE morphogenetic proteins ,CALCIUM phosphate ,BONE growth ,TISSUE engineering ,TISSUE scaffolds ,PERIOSTEUM ,PROGENITOR cells ,BONE regeneration - Abstract
Graphical abstract Abstract Cell based combination products with growth factors on optimal carriers represent a promising tissue engineering strategy to treat large bone defects. In this concept, bone morphogenetic protein (BMP) and calcium phosphate (CaP)-based scaffolds can act as potent components of the constructs to steer stem cell specification, differentiation and initiate subsequent in vivo bone formation. However, limited insight into BMP dosage and the cross-talk between BMP and CaP materials, hampers the optimization of in vivo bone formation and subsequent clinical translation. Herein, we combined human periosteum derived progenitor cells with different doses of BMP6 and with three types of clinical grade CaP-scaffolds (ChronOs®, ReproBone™, & CopiOs®). Comprehensive cellular and molecular analysis was performed based on in vitro cell metabolic activity and signaling pathway activation, as well as in vivo ectopic bone forming capacity after 2 weeks and 5 weeks in nude mice. Our data showed that cells seeded on CaP scaffolds with an intermediate Ca
2+ release rate combined with low or medium dosage of BMP6 demonstrated a robust new bone formation after 5 weeks, which was contributed by both donor and host cells. This phenomenon might be due to the delicate balance between Ca2+ and BMP pathways, allowing an appropriate activation of the canonical BMP signaling pathway that is required for in vivo bone formation. For high BMP6 dosage, we found that the BMP6 dosage overrides the effect of the Ca2+ release rate and this appeared to be a dominant factor for ectopic bone formation. Taken together, this study illustrates the importance of matching BMP dosage and CaP properties to allow an appropriate activation of canonical BMP signaling that is crucial for in vivo bone formation. It also provides insightful knowledge with regard to clinical translation of cell-based constructs for bone regeneration. Statement of Significance The combination of bone morphogenetic proteins (BMP) and calcium phosphate (CaP)-based biomaterials with mesenchymal stromal cells represents a promising therapeutic strategy to treat large bone defects, an unmet medical need. However, there is limited insight into the optimization of these combination products, which hampers subsequent successful clinical translation. Our data reveal a delicate balance between Ca2+ and BMP pathways, allowing an appropriate activation of canonical BMP signaling required for in vivo bone formation. Our findings illustrate the importance of matching BMP dosage and CaP properties in the development of cell-based constructs for bone regeneration. [ABSTRACT FROM AUTHOR]- Published
- 2018
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14. Engineering Vascularized Bone: Osteogenic and Proangiogenic Potential of Murine Periosteal Cells.
- Author
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VAN GASTEL, NICK, TORREKENS, SOPHIE, ROBERTS, SCOTT J., MOERMANS, KAREN, SCHROOTEN, JAN, CARMELIET, PETER, LUTTUN, AERNOUT, LUYTEN, FRANK P., and CARMELIET, GEERT
- Subjects
BONE morphogenetic proteins ,PERIOSTEUM ,TREATMENT of fractures ,LABORATORY mice ,HEMATOPOIESIS ,ENDOTHELIAL cells - Abstract
One of the key challenges in bone tissue engineering is the timely formation of blood vessels that promote the survival of the implanted cells in the construct. Fracture healing largely depends on the presence of an intact periosteum but it is still unknown whether periosteumderived cells (PDC) are critical for bone repair only by promoting bone formation or also by inducing neovascularization. We first established a protocol to specifically isolate murine PDC (mPDC) from long bones of adult mice. Mesenchymal stem cells were abundantly present in this cell population as more than 50% of the mPDC expressed mesenchymal markers (CD73, CD90, CD105, and stem cell antigen-1) and the cells exhibited trilineage differentiation potential (chondrogenic, osteogenic, and adipogenic). When transplanted on a collagen-calcium phosphate scaffold in vivo, mPDC attracted numerous blood vessels and formed mature bone which comprises a hematopoiesis-supportive stroma. We explored the proangiogenic properties of mPDC using in vitro culture systems and showed that mPDC promote the survival and proliferation of endothelial cells through the production of vascular endothelial growth factor. Coimplantation with endothelial cells demonstrated that mPDC can enhance vasculogenesis by adapting a pericyte- like phenotype, in addition to their ability to stimulate blood vessel ingrowth from the host. In conclusion, these findings demonstrate that periosteal cells contribute to fracture repair, not only through their strong osteogenic potential but also through their proangiogenic features and thus provide an ideal cell source for bone regeneration therapies. Stem Cells [ABSTRACT FROM AUTHOR]
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- 2012
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15. Bone Morphogenetic Proteins, Carriers, and Animal Models in the Development of Novel Bone Regenerative Therapies.
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Stokovic, Nikola, Ivanjko, Natalia, Maticic, Drazen, Luyten, Frank P., and Vukicevic, Slobodan
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BONE morphogenetic proteins ,BONE growth ,ANIMAL models in research ,RABBITS ,BIOPOLYMERS ,BONE regeneration ,RATS - Abstract
Bone morphogenetic proteins (BMPs) possess a unique ability to induce new bone formation. Numerous preclinical studies have been conducted to develop novel, BMP-based osteoinductive devices for the management of segmental bone defects and posterolateral spinal fusion (PLF). In these studies, BMPs were combined with a broad range of carriers (natural and synthetic polymers, inorganic materials, and their combinations) and tested in various models in mice, rats, rabbits, dogs, sheep, and non-human primates. In this review, we summarized bone regeneration strategies and animal models used for the initial, intermediate, and advanced evaluation of promising therapeutical solutions for new bone formation and repair. Moreover, in this review, we discuss basic aspects to be considered when planning animal experiments, including anatomical characteristics of the species used, appropriate BMP dosing, duration of the observation period, and sample size. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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16. Early BMP, Wnt and Ca2+/PKC pathway activation predicts the bone forming capacity of periosteal cells in combination with calcium phosphates.
- Author
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Bolander, Johanna, Chai, Yoke Chin, Geris, Liesbet, Schrooten, Jan, Lambrechts, Dennis, Roberts, Scott J., and Luyten, Frank P.
- Subjects
- *
BONE morphogenetic proteins , *WNT proteins , *PROTEIN kinase C , *CALCIUM phosphate , *PHOSPHORYLATION - Abstract
The development of osteoinductive calcium phosphate- (CaP) based biomaterials has, and continues to be, a major focus in the field of bone tissue engineering. However, limited insight into the spatiotemporal activation of signalling pathways has hampered the optimisation of in vivo bone formation and subsequent clinical translation. To gain further knowledge regarding the early molecular events governing bone tissue formation, we combined human periosteum derived progenitor cells with three types of clinically used CaP-scaffolds, to obtain constructs with a distinct range of bone forming capacity in vivo . Protein phosphorylation together with gene expression for key ligands and target genes were investigated 24 hours after cell seeding in vitro , and 3 and 12 days post ectopic implantation in nude mice. A computational modelling approach was used to deduce critical factors for bone formation 8 weeks post implantation. The combined Ca 2+ -mediated activation of BMP-, Wnt- and PKC signalling pathways 3 days post implantation were able to discriminate the bone forming from the non-bone forming constructs. Subsequently, a mathematical model able to predict in vivo bone formation with 96% accuracy was developed. This study illustrates the importance of defining and understanding CaP-activated signalling pathways that are required and sufficient for in vivo bone formation. Furthermore, we demonstrate the reliability of mathematical modelling as a tool to analyse and deduce key factors within an empirical data set and highlight its relevance to the translation of regenerative medicine strategies. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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17. Developmental engineering of living implants for deep osteochondral joint surface defects.
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Mendes, Luís F., Bosmans, Kathleen, Van Hoven, Inge, Viseu, Samuel R., Maréchal, Marina, and Luyten, Frank P.
- Subjects
- *
PERIOSTEUM , *SURFACE defects , *ARTICULAR cartilage , *BONE morphogenetic proteins , *ENDOCHONDRAL ossification , *KNEE , *GUIDED tissue regeneration , *SKELETAL maturity - Abstract
The repair of deep osteochondral joint surface defects represents a significant unmet clinical need. Importantly, untreated lesions lead to a high rate of osteoarthritis. The current strategies to repair these defects include osteochondral autograft transplantation or "sandwich" strategies combining bone autografts with autologous chondrocyte implantation, with poorly documented long-term outcomes. In this study, we first investigated the capacity of juvenile osteochondral grafts (OCGs) to repair osteochondral defects in skeletally mature rats. With this regenerative model in view, we produced a new biological, bilayered and scaffold-free Tissue Engineered construct (bTEC) for the repair of a deep osteochondral defect of the rat knee. Cylindrical OCGs were excised from the femoral intercondylar groove of the knee of skeletally immature rats (5 weeks) and transplanted into osteochondral defects created in skeletally mature rats (11 weeks). To create bTECs, micromasses (μMasses) of human periosteum-derived progenitor cells (hPDCs) and human articular chondrocytes (hACs) were produced in vitro using previously optimized chemically defined medium formulations containing growth and differentiation factors including bone morphogenetic proteins. These two μMass types were subsequently implanted as bilayered constructs into osteochondral defects in nude rats. At 4 and 16 weeks after surgery, the knees were collected and processed for subsequent 3D imaging analysis and histological evaluation. Micro-computed tomography (μCT), H&E, and Safranin O staining were used to evaluate the degree and quality of tissue repair. The osteochondral unit of the knee joint in 5 weeks old rats exhibits an immature phenotype, displaying active subchondral bone formation through endochondral ossification and the absence of a tidemark. When transplanted into skeletally mature animals, the immature OCGs resumed their maturation process, i.e. , formed new subchondral bone, established the tidemark, and maintained their Safranin O-positive hyaline cartilage at 16 weeks after transplantation. The bTECs (hPDCs + hACs) could partially recapitulate the biology as seen with the immature OCGs, including the formation of the joint surface architecture with typical zonation, ranging from non-mineralized hyaline cartilage in the superficial layers to a progressively mineralized matrix at the interface with a new subchondral bone plate. Cell-based TE constructs mimicking immature OCGs and displaying a hierarchically organized structure comprising of different tissue forming units seem an attractive strategy to treat deep osteochondral defects of the knee. Unlabelled Image • Immature osteochondral plugs were transplanted into osteochondral knee defects in mature rats. • Immature osteochondral grafts formed a new tidemark, hyaline cartilage, and bone. • Bilayered constructs mimicking the immature osteochondral unit were generated. • Periosteal cell-derived transient cartilage and articular cartilage were used. • Bilayered scaffold-free constructs successfully repaired osteochondral defects. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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18. A cell-based combination product for the repair of large bone defects.
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Lammens, Johan, Maréchal, Marina, Delport, Hendrik, Geris, Liesbet, Oppermann, Hermann, Vukicevic, Slobodan, and Luyten, Frank P.
- Subjects
- *
PERIOSTEUM , *BONES , *BONE morphogenetic proteins , *CERAMIC coating , *STEM cells , *GROWTH factors - Abstract
Regenerative cell-based implants using periosteum-derived stem cells were developed for the treatment of large 3 cm fresh and 4.5 centimeter biological compromised bone gaps in a tibial sheep model and compared with an acellular ceramic-collagen void filler. It was hypothesized that the latter is insufficient to heal large skeletal defects due to reduced endogenous biological potency. To this purpose a comparison was made between the ceramic dicalciumphosphate scaffold (CopiOs®) as such, the same ceramic coated with clinical grade Bone Morphogenetic Protein 2 and 6 (BMP) only or a BMP coated cell-seeded combination product. These implants were evaluated in 2 sheep models, a fresh 3 cm critical size tibial defect and a 4.5 cm biologically exhausted tibial defect. For the groups in which growth factors were applied, BMP-6 was chosen at a dose of 344 μg for 3 cm and 1.500 μg or 3.800 μg for 4.5 cm defects. An additional group in the 4.5 cm defect was tested using BMP-2 in a dose of 1.500 μg. For all the cell based implants autologous periosteum-derived cells were used which were cultured in monolayer during 6 weeks. For the fresh defect 408 million cells and for the biologically exhausted tibial defect 612 million cells were drop-seeded on the BMP coated scaffolds. Bone healing was studied during 16 weeks postimplantation, using standard radiographs. While fresh defects responded to all treatments, regardless the use of cells, the biologically hampered defects responded in half of the cases and only if the BMP-cell combination product was used, supporting the concept that cell-based therapies may become attractive in treating defects with a compromised biological status. • A large animal model for bone defect reconstruction using a cell based implant • It highlights the difference between a fresh bone defect and a compromised environment. • It documents the necessity for cell therapy to heal biological exhausted defects. • A sheep model, mimicking a real clinical condition, illustrates the usefulness of BMP6. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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