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Ellen M Gravallese - One of the best experts on this subject based on the ideXlab platform.
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resolution of inflammation induces osteoblast function and regulates the wnt signaling pathway
Arthritis & Rheumatism, 2012Co-Authors: Melissa M Matzelle, Nicole C Walsh, Catherine A Manning, Keith W Condon, David B Burr, Maxime A Gallant, Gary S Stein, Jane B Lian, Ellen M GravalleseAbstract:Objective Inflammation in the Bone microenvironment stimulates osteoclast differentiation, resulting in uncoupling of resorption and formation. Mechanisms contributing to the inhibition of osteoblast function in inflammatory diseases, however, have not been elucidated. Rheumatoid arthritis (RA) is a prototype of an inflammatory arthritis that results in focal loss of Articular Bone. The paucity of Bone repair in inflammatory diseases such as RA raises compelling questions regarding the impact of inflammation on Bone formation. The aim of this study was to establish the mechanisms by which inflammation regulates osteoblast activity. Methods We characterized an innovative variant of a murine model of arthritis in which inflammation is induced in C57BL/6J mice by transfer of arthritogenic K/BxN serum and allowed to resolve. Results In the setting of resolving inflammation, Bone resorption ceased and appositional osteoblast-mediated Bone formation was induced, resulting in repair of eroded Bone. Resolution of inflammation was accompanied by striking changes in the expression of regulators of the Wnt/β-catenin pathway, which is critical for osteoblast differentiation and function. Down-regulation of the Wnt antagonists secreted frizzled-related protein 1 (sFRP1) and sFRP2 during the resolution phase paralleled induction of the anabolic and pro–matrix mineralization factors Wnt10b and DKK2, demonstrating the role of inflammation in regulating Wnt signaling. Conclusion Repair of Articular Bone erosion occurs in the setting of resolving inflammation, accompanied by alterations in the Wnt signaling pathway. These data imply that in inflammatory diseases that result in persistent Articular Bone loss, strict control of inflammation may not be achieved and may be essential for the generation of an anabolic microenvironment that supports Bone formation and repair.
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Bone damage in rheumatoid arthritis mechanistic insights and approaches to prevention
Rheumatic Diseases Clinics of North America, 2010Co-Authors: Sougata Karmakar, Jonathan Kay, Ellen M GravalleseAbstract:In rheumatoid arthritis, cells within the inflamed synovium and pannus elaborate a variety of cytokines, including TNFα, IL-1, IL-6 and IL-17, that contribute to inflammation, and may directly impact Bone. The RANKL/RANK/OPG pathway plays a critical role in regulating osteoclastogenesis in Articular Bone erosions in RA. Pro-inflammatory cytokines can modulate this pathway, and may also affect the ability of the osteoblast to repair Bone at sites of Articular erosion. In this review, we discuss the current understanding of pathogenic mechanisms of Bone erosion in RA and examine current therapeutic approaches to prevent this damage.
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osteoblast function is compromised at sites of focal Bone erosion in inflammatory arthritis
Journal of Bone and Mineral Research, 2009Co-Authors: Nicole C Walsh, Catherine A Manning, Susan Reinwald, Keith W Condon, Ken Iwata, David B Burr, Ellen M GravalleseAbstract:In rheumatoid arthritis (RA), synovial inflammation results in focal erosion of Articular Bone. Despite treatment attenuating inflammation, repair of erosions with adequate formation of new Bone is uncommon in RA, suggesting that Bone formation may be compromised at these sites. Dynamic Bone histomorphometry was used in a murine model of RA to determine the impact of inflammation on osteoblast function within eroded arthritic Bone. Bone formation rates at Bone surfaces adjacent to inflammation were similar to those observed in nonarthritic Bone; therefore, osteoblast activity is unlikely to compensate for the increased Bone resorption at these sites. Within arthritic Bone, the extent of actively mineralizing surface was reduced at Bone surfaces adjacent to inflammation compared with Bone surfaces adjacent to normal marrow. Consistent with the reduction in mineralized Bone formation, there was a notable paucity of cells expressing the mid- to late stage osteoblast lineage marker alkaline phosphatase, despite a clear presence of cells expressing the early osteoblast lineage marker Runx2. In addition, several members of the Dickkopf and secreted Frizzled-related protein families of Wnt signaling antagonists were upregulated in arthritic synovial tissues, suggesting that inhibition of Wnt signaling could be one mechanism contributing to impaired osteoblast function within arthritic Bone. Together, these data indicate that the presence of inflammation within arthritic Bone impairs osteoblast capacity to form adequate mineralized Bone, thus contributing to the net loss of Bone and failure of Bone repair at sites of focal Bone erosion in RA.
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rankl protein is expressed at the pannus Bone interface at sites of Articular Bone erosion in rheumatoid arthritis
Rheumatology, 2006Co-Authors: Allison R Pettit, Nicole C Walsh, Catherine A Manning, Steven R Goldring, Ellen M GravalleseAbstract:Objectives. Receptor activator of NF-kappa B ligand (RANKL) and osteoprotegerin (OPG) have been demonstrated to be critical regulators of osteoclast generation and activity. In addition, RANKL has been implicated as an important mediator of Bone erosion in rheumatoid arthritis (RA). However, the expression of RANKL and OPG at sites of pannus invasion into Bone has not been examined. The present study was undertaken to further elucidate the contribution of this cytokine system to osteoclastogenesis and subsequent Bone erosion in RA by examining the pattern of protein expression for RANKL, OPG and the receptor activator of NF-kappa B (RANK) in RA at sites of Articular Bone erosion. Methods. Tissues from 20 surgical procedures from 17 patients with RA were collected as discarded materials. Six samples contained only synovium or tenosynovium remote from Bone, four samples contained pannus-Bone interface with adjacent synovium and 10 samples contained both synovium remote from Bone and pannu-Bone interface with adjacent synovium. Immunohistochemistry was used to characterize the cellular pattern of RANKL, RANK and OPG protein expression immediately adjacent to and remote from sites of Bone erosion. Results. Cellular expression of RANKL protein was relatively restricted in the Bone microenvironment; staining was focal and confined largely to sites of osteoclast-mediated erosion at the pannus-Bone interface and at sites of subchondral Bone erosion. RANK-expressing osteoclast precursor cells were also present in these sites. OPG protein expression was observed in numerous cells in synovium remote from Bone but was more limited at sites of Bone erosion, especially in regions associated with RANKL expression. Conclusions. The pattern of RANKL and OPG expression and the presence of RANK-expressing osteoclast precursor cells at sites of Bone erosion in RA contributes to the generation of a local microenvironment that favours osteoclast differentiation and activity. These data provide further evidence implicating RANKL in the pathogenesis of arthritis-induced joint destruction.
Ari Rosling - One of the best experts on this subject based on the ideXlab platform.
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gas foamed poly lactide co glycolide and poly lactide co glycolide with bioactive glass fibres demonstrate insufficient Bone repair in lapine osteochondral defects
Journal of Tissue Engineering and Regenerative Medicine, 2019Co-Authors: Eve Salonius, Virpi Muhonen, Kalle Lehto, Elina Jarvinen, Tuomo Pyhalto, Markus Hannula, Antti S Aula, Peter Uppstu, Annemarie Haaparanta, Ari RoslingAbstract:Deep osteochondral defects may leave voids in the subchondral Bone, increasing the risk of joint structure collapse. To ensure a stable foundation for the cartilage repair, Bone grafts can be used for filling these defects. Poly(lactide-co-glycolide) (PLGA) is a biodegradable material that improves Bone healing and supports Bone matrix deposition. We compared the reparative capacity of two investigative macroporous PLGA-based biomaterials with two commercially available Bone graft substitutes in the bony part of an intra-Articular Bone defect created in the lapine femur. New Zealand white rabbits (n = 40) were randomized into five groups. The defects, 4 mm in diameter and 8 mm deep, were filled with neat PLGA; a composite material combining PLGA and bioactive glass fibres (PLGA-BGf); commercial beta-tricalcium phosphate (β-TCP) granules; or commercial bioactive glass (BG) granules. The fifth group was left untreated for spontaneous repair. After three months, the repair tissue was evaluated with X-ray microtomography and histology. Relative values comparing the operated knee with its contralateral control were calculated. The relative Bone volume fraction (∆BV/TV) was largest in the β-TCP group (p ≤ 0.012), which also showed the most abundant osteoid. BG resulted in improved Bone formation, whereas defects in the PLGA-BGf group were filled with fibrous tissue. Repair with PLGA did not differ from spontaneous repair. The PLGA, PLGA-BGf, and spontaneous groups showed thicker and sparser trabeculae than the commercial controls. We conclude that Bone repair with β-TCP and BG granules was satisfactory, whereas the investigational PLGA-based materials were only as good as or worse than spontaneous repair.
Nicholas A. Athanasou - One of the best experts on this subject based on the ideXlab platform.
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Stimulation of osteoclast formation by inflammatory synovial fluid
Virchows Archiv, 2006Co-Authors: Iannis E. Adamopoulos, Lynett Danks, Ichiro Itonaga, Rachel M. Locklin, Afsie Sabokbar, David J. P. Ferguson, Nicholas A. AthanasouAbstract:Peri-Articular Bone resorption is a feature of arthritis due to crystal deposition and rheumatoid disease. Under these conditions, the synovial fluid contains numerous inflammatory cells that produce cytokines and growth factors which promote osteoclast formation. The aim of this study was to determine whether inflammatory synovial fluid stimulates the formation of osteoclasts. Synovial fluid from rheumatoid arthritis (RA), pyrophosphate arthropathy (PPA) and osteoarthritis (OA) patients was added to cultures ( n =8) of human peripheral blood mononuclear cells (PBMCs) in the presence and absence of macrophage colony-stimulating factor (M-CSF) and the receptor activator of NF-κB ligand (RANKL). Osteoclast formation was assessed by the formation of cells positive for tartrate-resistant acid phosphatase (TRAP) and vitronectin receptor (VNR) and the extent of lacunar resorption. The addition of 10% OA, RA and PPA synovial fluid to PBMC cultures resulted in the formation of numerous multinucleated or mononuclear TRAP^+ and VNR^+ cells which were capable of lacunar resorption. In contrast to PBMC cultures incubated with OA synovial fluid, there was marked stimulation of osteoclast formation and resorption in cultures containing inflammatory RA and PPA synovial fluid which contained high levels of tumour necrosis factor alpha, a factor which is known to stimulate RANKL-induced osteoclast formation.
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Stimulation of osteoclast formation by inflammatory synovial fluid
'Springer Fachmedien Wiesbaden GmbH', 2006Co-Authors: Iannis E. Adamopoulos, Lynett Danks, Ichiro Itonaga, Rachel M. Locklin, Afsie Sabokbar, David J. P. Ferguson, Nicholas A. AthanasouAbstract:Peri-Articular Bone resorption is a feature of arthritis due to crystal deposition and rheumatoid disease. Under these conditions, the synovial fluid contains numerous inflammatory cells that produced cytokines and growth factors which promote osteoclast formation. The aim of the study was to determine whether inflammatory synovial fluid stimulates the formation of osteoclasts. Synovial fluid from rheumatoid arthritis (RA), pyrophosphate arthropathy (PPA) and osteoarthritis (OA) patients was added to cultures (n=8) of human peripheral blood mononuclear cells (PBMCs) in the presence and absence of macrophage colony-stimulating factor (M-CSF) and the receptor activator of NF-KB ligand (RANKL). Osteoclast formation was assessed by the formation of cells positive for tartrare-resistant and phosphatase (TRAP) and vitronectin receptor (VNR) and the extent of lacunar resorption. The addition of 10% OA, RA and PPA synovial fluid to PBMC cultures resulted in the formation of numerous multinicleated or mononuclear TRAP⁺ and VNR⁺ cells which were capable of lacunar resorption. In contrast to PBMC cultures incubated with OA synovial fluid, there was marked stimulation of osteoclast formation and resorption in cultures containing inflammatory RA and PPA synovial fluid which contained high levels of tumour necrosis factor alpha, a factor which is known to stimulate RANKL-induced osteoclast formation
Chingjen Wang - One of the best experts on this subject based on the ideXlab platform.
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total knee arthroplasty for arthritis of the knee with extra Articular deformity
Journal of Bone and Joint Surgery American Volume, 2002Co-Authors: Junwen Wang, Chingjen WangAbstract:Background: Simultaneous corrective osteotomy of angular deformity and total knee arthroplasty has been considered the treatment of choice for patients with arthritis of the knee associated with ipsilateral extra-Articular deformity. However, this procedure is technically demanding, and the functional outcome of the total knee arthroplasty may be jeopardized if the osteotomy fails. This retrospective study was performed to evaluate the clinical results of total knee arthroplasty combined with intra-Articular Bone resection, without osteotomy, in patients with extra-Articular deformity and arthritis of the knee. Methods: Fifteen patients with arthritis of the knee and extra-Articular deformity underwent total knee arthroplasty with Bone resection and soft-tissue balancing. All deformities had resulted from fracture malunion. There were ten uniplanar, three biplanar, and two triplanar deformities. The deformity was in the tibia in eight patients and in the femur in seven. The average angle of the femoral deformities was 15.1° in the coronal plane and 8.1° in the sagittal plane. Two femora had a rotational deformity, consisting of 20° of internal rotation in one and 10° of external rotation in the other. The average angle of the tibial deformities was 19° in the coronal plane. Results: The duration of follow-up averaged thirty-eight months. The average Knee Society knee score improved from 22.3 points preoperatively to 91.7 points at the time of the last follow-up, and the average Knee Society function score improved from 28.0 points preoperatively to 87.3 points at the time of the last follow-up. The average arc of knee motion improved from 77.7° preoperatively to 103.7° postoperatively. The average mechanical axis of the knee improved from 22.7° of varus preoperatively to 0.3° of varus at the time of the last follow-up. Two patients had an unsatisfactory clinical result, which was not related to the total knee arthroplasty. There were no complications such as infection, ligament instability, or component loosening. Conclusions: Total knee arthroplasty in conjunction with intra-Articular Bone resection is an effective procedure for patients with arthritis of the knee and extra-Articular varus deformity of <20° in the femur or £30° in the tibia in the coronal plane.
Nicole C Walsh - One of the best experts on this subject based on the ideXlab platform.
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resolution of inflammation induces osteoblast function and regulates the wnt signaling pathway
Arthritis & Rheumatism, 2012Co-Authors: Melissa M Matzelle, Nicole C Walsh, Catherine A Manning, Keith W Condon, David B Burr, Maxime A Gallant, Gary S Stein, Jane B Lian, Ellen M GravalleseAbstract:Objective Inflammation in the Bone microenvironment stimulates osteoclast differentiation, resulting in uncoupling of resorption and formation. Mechanisms contributing to the inhibition of osteoblast function in inflammatory diseases, however, have not been elucidated. Rheumatoid arthritis (RA) is a prototype of an inflammatory arthritis that results in focal loss of Articular Bone. The paucity of Bone repair in inflammatory diseases such as RA raises compelling questions regarding the impact of inflammation on Bone formation. The aim of this study was to establish the mechanisms by which inflammation regulates osteoblast activity. Methods We characterized an innovative variant of a murine model of arthritis in which inflammation is induced in C57BL/6J mice by transfer of arthritogenic K/BxN serum and allowed to resolve. Results In the setting of resolving inflammation, Bone resorption ceased and appositional osteoblast-mediated Bone formation was induced, resulting in repair of eroded Bone. Resolution of inflammation was accompanied by striking changes in the expression of regulators of the Wnt/β-catenin pathway, which is critical for osteoblast differentiation and function. Down-regulation of the Wnt antagonists secreted frizzled-related protein 1 (sFRP1) and sFRP2 during the resolution phase paralleled induction of the anabolic and pro–matrix mineralization factors Wnt10b and DKK2, demonstrating the role of inflammation in regulating Wnt signaling. Conclusion Repair of Articular Bone erosion occurs in the setting of resolving inflammation, accompanied by alterations in the Wnt signaling pathway. These data imply that in inflammatory diseases that result in persistent Articular Bone loss, strict control of inflammation may not be achieved and may be essential for the generation of an anabolic microenvironment that supports Bone formation and repair.
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osteoblast function is compromised at sites of focal Bone erosion in inflammatory arthritis
Journal of Bone and Mineral Research, 2009Co-Authors: Nicole C Walsh, Catherine A Manning, Susan Reinwald, Keith W Condon, Ken Iwata, David B Burr, Ellen M GravalleseAbstract:In rheumatoid arthritis (RA), synovial inflammation results in focal erosion of Articular Bone. Despite treatment attenuating inflammation, repair of erosions with adequate formation of new Bone is uncommon in RA, suggesting that Bone formation may be compromised at these sites. Dynamic Bone histomorphometry was used in a murine model of RA to determine the impact of inflammation on osteoblast function within eroded arthritic Bone. Bone formation rates at Bone surfaces adjacent to inflammation were similar to those observed in nonarthritic Bone; therefore, osteoblast activity is unlikely to compensate for the increased Bone resorption at these sites. Within arthritic Bone, the extent of actively mineralizing surface was reduced at Bone surfaces adjacent to inflammation compared with Bone surfaces adjacent to normal marrow. Consistent with the reduction in mineralized Bone formation, there was a notable paucity of cells expressing the mid- to late stage osteoblast lineage marker alkaline phosphatase, despite a clear presence of cells expressing the early osteoblast lineage marker Runx2. In addition, several members of the Dickkopf and secreted Frizzled-related protein families of Wnt signaling antagonists were upregulated in arthritic synovial tissues, suggesting that inhibition of Wnt signaling could be one mechanism contributing to impaired osteoblast function within arthritic Bone. Together, these data indicate that the presence of inflammation within arthritic Bone impairs osteoblast capacity to form adequate mineralized Bone, thus contributing to the net loss of Bone and failure of Bone repair at sites of focal Bone erosion in RA.
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rankl protein is expressed at the pannus Bone interface at sites of Articular Bone erosion in rheumatoid arthritis
Rheumatology, 2006Co-Authors: Allison R Pettit, Nicole C Walsh, Catherine A Manning, Steven R Goldring, Ellen M GravalleseAbstract:Objectives. Receptor activator of NF-kappa B ligand (RANKL) and osteoprotegerin (OPG) have been demonstrated to be critical regulators of osteoclast generation and activity. In addition, RANKL has been implicated as an important mediator of Bone erosion in rheumatoid arthritis (RA). However, the expression of RANKL and OPG at sites of pannus invasion into Bone has not been examined. The present study was undertaken to further elucidate the contribution of this cytokine system to osteoclastogenesis and subsequent Bone erosion in RA by examining the pattern of protein expression for RANKL, OPG and the receptor activator of NF-kappa B (RANK) in RA at sites of Articular Bone erosion. Methods. Tissues from 20 surgical procedures from 17 patients with RA were collected as discarded materials. Six samples contained only synovium or tenosynovium remote from Bone, four samples contained pannus-Bone interface with adjacent synovium and 10 samples contained both synovium remote from Bone and pannu-Bone interface with adjacent synovium. Immunohistochemistry was used to characterize the cellular pattern of RANKL, RANK and OPG protein expression immediately adjacent to and remote from sites of Bone erosion. Results. Cellular expression of RANKL protein was relatively restricted in the Bone microenvironment; staining was focal and confined largely to sites of osteoclast-mediated erosion at the pannus-Bone interface and at sites of subchondral Bone erosion. RANK-expressing osteoclast precursor cells were also present in these sites. OPG protein expression was observed in numerous cells in synovium remote from Bone but was more limited at sites of Bone erosion, especially in regions associated with RANKL expression. Conclusions. The pattern of RANKL and OPG expression and the presence of RANK-expressing osteoclast precursor cells at sites of Bone erosion in RA contributes to the generation of a local microenvironment that favours osteoclast differentiation and activity. These data provide further evidence implicating RANKL in the pathogenesis of arthritis-induced joint destruction.
