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ABSTRACT: BACKGROUND: Proper treatment of bone loss is essential for the long term durability of revision TKA. However, the method of choice in managing large bone defects is still under debate. We therefore assessed the mid to long term clinical and radiographic results of revision TKA using a fresh frozen femoral head allograft and a standard condylar implant or varus-valgus constrained prosthesis with a diaphyseal-engaging stem. METHODS: We retrospectively reviewed the records of 27 patients who had undergone revision TKA between August 1997 and March 2003 using a fresh frozen femoral head allograft and a standard condylar implant or varus-valgus constrained prosthesis with a diaphyseal-engaging stem. The median follow-up period was 107months (range, 96-157months). RESULTS: Clinical evaluation revealed that the mean range of motion had increased from 71° to 113° and the mean Hospital for Special Surgery knee score had improved from 46 to 83 points. The overall tibio-femoral angle improved from varus 7.3° to valgus 6.l°. In 26 out of 27 knees, union was demonstrated at an average of seven months postoperatively, and there were no cases of collapse, disease transmission or stress fractures. In one knee, an infection recurred. CONCLUSIONS: Our results demonstrate that femoral head allografts in treatment of severe bone defects are reliable and durable. If possible, less constrained prostheses with diaphyseal-engaging stems should be chosen for increased durability. LEVEL OF EVIDENCE: Level IV, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.
The Knee 05/2013; · 1.74 Impact Factor
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ABSTRACT: MicroRNAs are endogenous gene regulators that have been implicated in various developmental and pathological processes. However, the precise identities and functions of the miRNAs involved in cartilage development are not yet well understood. Here, we report that miR-181b regulates chondrocyte differentiation and maintains cartilage integrity, and is thus a potent therapeutic target. MiR-181b was significantly down-regulated during chondrogenic differentiation of TGF-β3-stimulated limb mesenchymal cells, but it was significantly up-regulated in osteoarthritic chondrocytes isolated from the cartilage of osteoarthritis patients. The use of a mimic or an inhibitor to alter miR-181b levels in chondroblasts and articular chondrocytes showed that attenuation of miR-181b reduced MMP-13 expression while inducing type II collagen expression. Furthermore, over-expression of anti-miR-181b significantly reduced the cartilage destruction caused by DMM surgery in mice. In sum, our data suggest that miR-181b is a negative regulator of cartilage development, and that inhibition of miR-181b could be an effective therapeutic strategy for cartilage-related disease.
Biochemical and Biophysical Research Communications 01/2013; · 2.48 Impact Factor
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ABSTRACT: Endochondral bone formation requires a complex interplay among immature mesenchymal progenitor cells to form the cartilaginous anlagen, involving migration, aggregation and condensation. Even though condensation of chondrogenic progenitors is an essential step in this process, the mechanism(s) by which this occurs has not been well studied. Here, we investigated the involvement of microRNAs (miRNAs) in this process and found that the expression of miR-375 decreased upon chondrogenic differentiation of limb mesenchymal cells. Blockade of miR-375 via peptide nucleic acid (PNA)-based antisense oligonucleotides (ASOs) increased the migration of chondrogenic progenitors, the formation of precartilage condensations and the expression level of cadherin-7. Furthermore, miR-375 was necessary and sufficient to down-regulate cell migration through negative regulation of cadherin-7 by the direct interaction with 3' UTR of cadherin-7. In addition, miR-375 is also involved in the cell migration and precartilage condensation mediated by p38MAPK, a positive signaling in the chondrogenic differentiation. Collectively, our results suggest that miR-375 negatively modulates cell migration and subsequent precartilage condensation by targeting cadherin-7.
Cellular signalling 11/2012; · 4.09 Impact Factor
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ABSTRACT: There is a lack of histological studies investigating the presence of mechanoreceptors in anterior cruciate ligament (ACL) allografts.
Mechanoreceptors would not grow in Achilles allografts after ACL reconstruction.
Case series study; Level of evidence, 4.
Tissue samples were obtained from 11 patients who underwent ACL reconstruction using Achilles tendon allografts. They underwent biopsies during second-look arthroscopies. The mean period from ACL reconstruction to harvesting tissue was 26.63 months (range, 12-120 months). The control group consisted of 2 normal ACLs procured from 42- and 45-year-old men who underwent amputation above the knee due to trauma.
Ruffini corpuscles and free nerve endings were shown to be present in the specimens of the control group by processing hematoxylin-eosin stains and immunohistochemical stains with monoclonal antibodies against S-100. In the Achilles allografts, mechanoreceptors were not observed. However, fibroblasts, collagen fibers, and vessels that were not present in fresh-frozen Achilles allografts before surgery were observed.
The results demonstrate that Achilles tendon allografts appeared similar to normal ligaments except for the lack of histological evidence of mechanoreceptors. In other words, there are no newly ingrown mechanoreceptors in ACL allografts.
The American journal of sports medicine 07/2012; 40(9):2061-5. · 3.61 Impact Factor
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ABSTRACT: Dkk is a family of canonical Wnt antagonists with 4 members (Dkk-1, Dkk-2, Dkk-3, and Dkk-4). We undertook this study to explore the roles of Dkk-1 and Dkk-2 in osteoarthritic (OA) cartilage destruction in mice.
Expression of Dkk and other catabolic factors was determined at the messenger RNA and protein levels in human and mouse OA cartilage. Experimental OA in mice was induced by destabilization of the medial meniscus (DMM) or by intraarticular injection of Epas1 adenovirus (AdEPAS-1). The role of Dkk in OA pathogenesis was examined by intraarticular injection of AdDkk-1 or by using chondrocyte-specific Dkk1 (Col2a1-Dkk1)-transgenic mice and Dkk2 (Col2a1-Dkk2)-transgenic mice. Primary culture mouse chondrocytes were also treated with recombinant Dkk proteins.
We found opposite patterns of Dkk1 and Dkk2 expression in human and mouse experimental OA cartilage: Dkk1 was up-regulated and Dkk2 was down-regulated. Overexpression of Dkk1 by intraarticular injection of AdDkk-1 significantly inhibited DMM-induced experimental OA. DMM-induced OA was also significantly inhibited in Col2a1-Dkk1-transgenic mice compared with their wild-type littermates. However, Col2a1-Dkk2-transgenic mice showed no significant difference in OA pathogenesis. Wnt-3a, which activates the canonical Wnt pathway, induced Mmp13 and Adamts4 expression in primary culture chondrocytes, an effect that was significantly inhibited by Dkk-1 pretreatment or Dkk1 overexpression.
Our findings indicate that expression of Dkk1, but not Dkk2, in chondrocytes inhibits OA cartilage destruction. The protective effect of Dkk-1 appears to be associated with its capacity to inhibit Wnt-mediated expression of catabolic factors, such as Mmp13, providing evidence that Dkk-1 might serve as a therapeutic target for OA treatment.
Arthritis & Rheumatism 04/2012; 64(8):2568-78. · 7.87 Impact Factor
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Hwanhee Oh,
Je-Hwang Ryu,
Jimin Jeon,
Siyoung Yang, Churl-Hong Chun,
Hongryeol Park,
Hyung Joon Kim,
Woo-Shin Kim,
Hong-Hee Kim,
Young-Guen Kwon,
Jang-Soo Chun
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ABSTRACT: Developing cartilage serves as a template for long-bone development during endochondral ossification. Although the coupling of cartilage and bone development with angiogenesis is an important regulatory step for endochondral ossification, the molecular mechanisms are poorly understood. One possible mechanism involves the action of Dickkopf (DKK), which is a family of soluble canonical Wnt antagonists with four members (DKK1-4). We initially observed opposite expression patterns of Dkk1 and Dkk2 during angiogenesis and chondrocyte differentiation: downregulation of Dkk1 and upregulation of Dkk2. We examined the in vivo role of Dkk1 and Dkk2 in linking cartilage/bone development and angiogenesis by generating transgenic (TG) mice that specifically express Dkk1 or Dkk2 in chondrocytes, hypertrophic chondrocytes, or endothelial cells. Despite specific expression pattern during cartilage development, chondrocyte- and hypertrophic chondrocyte-specific Dkk1 and Dkk2 TG mice showed normal developmental phenotypes. However, Dkk1 misexpression in endothelial cells resulted in defects of endochondral ossification and reduced skeletal size. The defects are caused by the inhibition of angiogenesis in developing bone and subsequent inhibition of apoptosis of hypertrophic chondrocytes and cartilage resorption.
Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 03/2012; 27(6):1335-44. · 6.04 Impact Factor
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ABSTRACT: MicroRNAs (miRNAs) have been implicated in various cellular processes, such as cell fate determination, cell death, and tumorigenesis. In the present study, we investigated the role of miRNA-34a (miR-34a) in the reorganization of the actin cytoskeleton, which is essential for chondrocyte differentiation. miRNA arrays to identify genes that appeared to be up-regulated or down-regulated during chondrogenesis were applied with chondrogenic progenitors treated with JNK inhibitor. PNA-based antisense oligonucleotides and miRNA precursor were used for investigation of the functional roles of miR-34a. We found that, in chick chondroprogenitors treated with JNK inhibitor, which suppresses chondrogenic differentiation, the expression levels of miR-34a and RhoA1 are up-regulated through modulation of Rac1 expression. Blockade of miR-34a via the use of PNA-based antisense oligonucleotides was associated with decreased protein expression of RhoA (a known modulator of stress fiber expression), down-regulation of stress fibers, up-regulation of Rac1, and recovery of protein level of type II collagen. miR-34a regulates RhoA/Rac1 cross-talk and negatively modulates reorganization of the actin cytoskeleton, which is one of the essential processes for establishing chondrocyte-specific morphology.
Journal of Biological Chemistry 02/2012; 287(15):12501-9. · 4.77 Impact Factor
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ABSTRACT: Chondrocytes, a unique cell type in cartilage tissue, are responsible for the regulation of anabolic and catabolic homeostasis in cartilage-specific extracellular matrix synthesis. Activation of Wnt/β-catenin signaling induces dedifferentiation of articular chondrocytes, resulting in suppression of type II collagen expression. We have shown previously that α-catenin inhibits β-catenin-Tcf/Lef (T-cell factor/lymphoid-enhancing factor) transcriptional activity in articular chondrocytes with a concomitant recovery of type II collagen expression. In the current study, we elucidated the mechanism underlying this inhibition of β-catenin-Tcf/Lef transcriptional activity by α-catenin, showing that it requires direct interaction between α-catenin and β-catenin. We further showed that it involves recruitment of Gli3R, the short transcription-repressing form of the transcription factor Gli3, to β-catenin by α-catenin. The resulting inhibition of β-catenin transcriptional activity leads to increased expression of type II collagen. Gli3R and α-catenin actions are co-dependent: both are necessary for the observed inhibitory effects on β-catenin transcriptional activity. Reducing Gli3R expression levels through activation of Indian Hedgehog (Ihh) signaling also is sufficient to activate β-catenin transcriptional activity, suggesting that the ternary complex, Gli3R·α-catenin·β-catenin, mediates Ihh-dependent activation of Wnt/β-catenin signaling in articular chondrocytes. Collectively, this study shows that α-catenin functions as a nuclear factor that recruits the transcriptional repressor Gli3R to β-catenin to inhibit β-catenin transcriptional activity and dedifferentiation of articular chondrocytes. Finally, osteoarthritic cartilage showed elevated levels of β-catenin and decreased levels of α-catenin and Gli3R, suggesting that decreased levels of α-catenin and Gli3R levels contribute to increased β-catenin transcriptional activity during osteoarthritic cartilage destruction.
Journal of Biological Chemistry 02/2012; 287(15):11751-60. · 4.77 Impact Factor
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ABSTRACT: MicroRNAs function as an endogenous mode of fine gene regulation and have been implicated in multiple differentiation and developmental processes. In the present study, we investigated the role of miRNA-34 during chondrogenic differentiation of chick limb mesenchymal cells. We found that the expression of miR-34a increased upon chondrogenic inhibition. Blockade of miR-34a via PNA-based antisense oligonucleotides (ASOs) recovered the chondro-inhibitory actions of JNK inhibitor on migration of chondrogenic progenitors and the formation of precartilage condensation. Furthermore, we determined that EphA5 is a relevant target of miR-34a during chondrogenesis. MiR-34a was necessary and sufficient to down-regulate EphA5 expression, and up-modulation of EphA5 is sufficient to overcome inhibitory actions of miR-34 inhibition on cell migration and condensation of chick limb mesenchymal cells on collagen substrate. Taken together, our data suggest that miR-34a is a negative modulator of chondrogenesis, particularly in migration of chondroblasts, by targeting EphA5 and resulting inhibition of cellular condensation during chondrogenesis of chick limb mesenchymal cells.
Biochemical and Biophysical Research Communications 10/2011; 415(4):551-7. · 2.48 Impact Factor
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ABSTRACT: The purpose of this study was to compare the early clinical results of arthroscopic extensor carpi radialis brevis (ECRB) release with and without bone decortication in the treatment of lateral epicondylitis.
Thirty-eight patients who were surgically treated for lateral epicondylitis between 2004 and 2008 were included in this retrospective review. Among these 38 patients, 19 underwent arthroscopic ECRB release and 19 patients underwent both ECRB release with decortication of the lateral epicondyle. Outcome measures included pain assessment measured by visual analog scale (VAS) preoperatively, on postoperative day one, at two and 4 weeks postoperatively, and at the final follow-up visit. Functional evaluation was made with the Mayo Elbow Performance Index and grip strength measurement.
Patients who underwent simple ECRB release had significantly less pain than patients who underwent ECRB release and decortication immediately postoperatively (p < 0.05). This group also showed a lower VAS score on exertion 2 weeks and 4 weeks after simple ECRB release (p < 0.05). The mean time taken to return to work was 24.2 ± 18.3 days in the group that underwent simple ECRB release and 39 ± 22.7 days in the group that underwent ECRB release with decortication (p < 0.05).
Arthroscopic release of the ECRB is an effective method of treatment in patients with recalcitrant lateral epicondylitis. Decortication of the lateral epicondyle leads to increased pain postoperatively and did not improve clinical results.
Knee Surgery Sports Traumatology Arthroscopy 07/2011; 19(7):1178-83. · 2.21 Impact Factor
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ABSTRACT: We have shown that cytokine-like 1 (Cytl1) is a novel autocrine regulatory factor that regulates chondrogenesis of mouse mesenchymal cells (Kim, J. S., Ryoo, Z. Y., and Chun, J. S. (2007) J. Biol. Chem. 282, 29359-29367). In this previous work, we found that Cytl1 expression was very low in mesenchymal cells, increased dramatically during chondrogenesis, and decreased during hypertrophic maturation, both in vivo and in vitro. Moreover, exogenous addition or ectopic expression of Cytl1 caused chondrogenic differentiation of mouse limb bud mesenchymal cells. In the current study, we generated a Cytl1 knock-out (Cytl1(-/-)) mouse to investigate the in vivo role of Cytl1. Deletion of the Cytl1 gene did not affect chondrogenesis or cartilage development. Cytl1(-/-) mice also showed normal endochondral ossification and long bone development. Additionally, ultrastructural features of articular cartilage, such as matrix organization and chondrocyte morphology, were similar in wild-type and Cytl1(-/-) mice. However, Cytl1(-/-) mice were more sensitive to osteoarthritic (OA) cartilage destruction. Compared with wild-type littermates, Cytl1(-/-) mice showed more severe OA cartilage destruction upon destabilization of the medial meniscus of mouse knee joints. In addition, expression levels of Cytl1 were markedly decreased in OA cartilage of humans and experimental mice. Taken together, our results suggest that, rather than regulating cartilage and bone development, Cytl1 is required for the maintenance of cartilage homeostasis, and loss of Cytl1 function is associated with experimental OA cartilage destruction in mice.
Journal of Biological Chemistry 06/2011; 286(31):27206-13. · 4.77 Impact Factor
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ABSTRACT: We have shown that cytokine-like 1 (CYTL1) is a novel autocrine regulatory factor that regulates chondrogenesis of mesenchymal
cells (Kim et al., 2007; J. Biol. Chem. 282, 29359-29367). In this previous work, we found that Cytl1 expression was very low in mesenchymal cells, increased dramatically during chondrogenesis, and decreased during hypertrophic
maturation, both in vivo and in vitro. Moreover, exogenous addition or ectopic expression of CYTL1 caused chondrogenic differentiation
of mouse limb bud mesenchymal cells. In the current study, we generated a Cytl1 knockout mouse (Cytl1-/-) to investigate the in vivo role of CYTL1. Deletion of the Cytl1 gene did not affect chondrogenesis or cartilage development. (Cytl1-/-) mice also showed normal endochondral ossification and long bone development. Additionally, ultrastructural features of articular
cartilage, such as matrix organization and chondrocyte morphology, were similar in wild-type (WT) and (Cytl1-/-) mice. However, (Cytl1-/-) mice were more sensitive to osteoarthritic (OA) cartilage destruction. Compared with WT littermates, (Cytl1-/-) mice showed more severe OA cartilage destruction upon destabilization of the medial meniscus of mouse knee joints. In addition,
expression levels of Cytl1 were markedly decreased in OA cartilage of humans and experimental mice. Taken together, our results suggest that, rather
than regulating cartilage and bone development, CYTL1 is required for the maintenance of cartilage homeostasis, and loss of
CYTL1 function is associated with OA cartilage destruction.
Journal of Biological Chemistry 06/2011; · 4.77 Impact Factor
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ABSTRACT: Hypoxia-inducible factor 2α (HIF-2α) (encoded by Epas1) causes osteoarthritic (OA) cartilage destruction by regulating the expression of catabolic factor genes. We undertook this study to explore the role of interleukin-6 (IL-6) in HIF-2α-mediated OA cartilage destruction in mice.
The expression of HIF-2α, IL-6, and catabolic factors was determined at the messenger RNA and protein levels in primary culture mouse chondrocytes, human OA cartilage, and mouse experimental OA cartilage. Experimental OA in wild-type, HIF-2α-knockdown (Epas1+/-), and Il6-/- mice was caused by intraarticular injection of Epas1 adenovirus or destabilization of the medial meniscus. The role of IL-6 was determined by treating with recombinant IL-6 protein or by injecting HIF-2α adenovirus (AdEpas1) intraarticularly in mice with or without IL-6-neutralizing antibody.
We found that Il6 is a direct target gene of HIF-2α in articular chondrocytes. Both Epas1 and Il6 were up-regulated in human and mouse OA cartilage, whereas HIF-2α knockdown in mice led to inhibition of both Il6 expression and cartilage destruction. Treatment with IL-6 enhanced Mmp3 and Mmp13 expression; conversely, Il6 knockdown inhibited HIF-2α-induced up-regulation of Mmp3 and Mmp13. Injection of IL-6 protein into mouse knee joints triggered OA cartilage destruction, whereas IL-6 neutralization led to blocking of HIF-2α-induced cartilage destruction with concomitant modulation of Mmp3 and Mmp13 expression. Moreover, Il6 knockout resulted in inhibition of AdEpas1-induced and destabilization of the medial meniscus-induced cartilage destruction as well as inhibition of Mmp3 and Mmp13 expression.
Our findings indicate that IL-6 acts as a crucial mediator of HIF-2α-induced experimental OA cartilage destruction in mice via regulation of Mmp3 and Mmp13 levels.
Arthritis & Rheumatism 05/2011; 63(9):2732-43. · 7.87 Impact Factor
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ABSTRACT: Among the several rotenoids, amorphigenin is isolated from the leaves of Amopha Fruticosa and it is known that has anti-proliferative effects and anti-cnacer effects in many cell types. The main aim of this study was to investigate the effects of amorphigenin on osteoclast differentiation in vitro and on LPS treated inflammatory bone loss model in vivo. We show here that amorphigenin inhibited RANKL-induced osteoclast differentiation from bone marrow macrophages in a dose dependent manner without cellular toxicity. Anti-osteoclastogenic properties of amorphigenin were based on a down-regulation of c-fos and NFATc1. Amorphigenin markedly inhibited RANKL-induced p38 and NF-κB pathways, but other pathways were not affected. Micro-CT analysis of the femurs showed that amorphigenin protected the LPS-induced bone loss. We concluded that amorphigenin can prevent inflammation-induced bone loss. Thus we expect that amorphigenin could be a treatment option for bone erosion caused by inflammation.
Anatomy & cell biology 12/2010; 43(4):310-6.
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ABSTRACT: Osteoarthritic cartilage destruction is caused by an imbalance between anabolic and catabolic factors. Here, we show that hypoxia-inducible factor-2alpha (HIF-2alpha, encoded by EPAS1) is a catabolic transcription factor in the osteoarthritic process. HIF-2alpha directly induces the expression in chondrocytes of genes encoding catabolic factors, including matrix metalloproteinases (MMP1, MMP3, MMP9, MMP12 and MMP13), aggrecanase-1 (ADAMTS4), nitric oxide synthase-2 (NOS2) and prostaglandin-endoperoxide synthase-2 (PTGS2). HIF-2alpha expression was markedly increased in human and mouse osteoarthritic cartilage, and its ectopic expression triggered articular cartilage destruction in mice and rabbits. Moreover, mice transgenic for Epas1 only in chondrocytes showed spontaneous cartilage destruction, whereas heterozygous genetic deletion of Epas1 in mice suppressed cartilage destruction caused by destabilization of the medial meniscus (DMM) or collagenase injection, with concomitant modulation of catabolic factors. Our results collectively demonstrate that HIF-2alpha causes cartilage destruction by regulating crucial catabolic genes.
Nature medicine 06/2010; 16(6):687-93. · 27.14 Impact Factor
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ABSTRACT: With the aim of identifying novel genes regulating cartilage development and degeneration, we screened a cartilage-specific expressed sequence tag database. Esophageal cancer related gene 4 (ECRG4) was selected, based on the criteria of 'chondrocyte-specific' and 'unknown function.' ECRG4 expression was particularly abundant in chondrocytes and cartilage, compared to various other mouse tissues. ECRG4 is a secreted protein that undergoes cleavage after secretion. The protein is specifically expressed in chondrocytes in a manner dependent on differentiation status. The expression is very low in mesenchymal cells, and dramatically increased during chondrogenic differentiation. The ECRG4 level in differentiated chondrocytes is decreased during hypertrophic maturation, both in vitro and in vivo, and additionally in dedifferentiating chondrocytes induced by interleukin-1beta or serial subculture, chondrocytes of human osteoarthritic cartilage and experimental mouse osteoarthritic cartilage. However, ectopic expression or exogenous ECRG4 treatment in a primary culture cell system does not affect chondrogenesis of mesenchymal cells, hypertrophic maturation of chondrocytes or dedifferentiation of differentiated chondrocytes. Additionally, cartilage development and organization of extracellular matrix are not affected in transgenic mice overexpressing ECRG4 in cartilage tissue. However, ectopic expression of ECRG4 reduced proliferation of primary culture chondrocytes. While the underlying mechanisms of ECRG4 expression and specific roles remain to be elucidated in more detail, our results support its function as a marker of differentiated articular chondrocytes and cartilage destruction.
Gene 10/2009; 448(1):7-15. · 2.34 Impact Factor
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ABSTRACT: Osteoclasts are multinucleated cells that are formed by the fusion of mononuclear osteoclasts, which is an essential process in bone resorption leading to bone remodeling. Herein we show that GM-CSF promoted the fusion of prefusion osteoclasts (pOCs). The expression of GM-CSF receptor-alpha was significantly up-regulated at the fusion stage of pOCs induced by RANKL. GM-CSF induced the expression of dendritic cell-specific transmembrane protein (DC-STAMP), which was mediated by inducing NFATc1 via induction of c-Fos. The expression of c-Fos and NFATc1 was regulated by the ERK signaling pathway. Inhibition of ERK and NFATc1 suppressed the expression of DC-STAMP and led to the fusion inhibition of pOC. However, retrovirus-mediated expression of NFATc1 in pOCs rescued the defect in pOC fusion, despite the presence of U0126 and cyclosporin A. GM-CSF-stimulated pOCs had an intact actin ring and could resorb bone. Importantly, pOCs infected with constitutively active MEK adenovirus expressed c-Fos and NFATc1, followed by the binding of NFATc1 to the DC-STAMP promoter, which enables its transcription and expression. Constitutively active MEK-infected pOCs are able to resorb bone by undergoing cell-cell fusion. Taken together, our results demonstrated that GM-CSF induced fusion of pOCs to form multinucleated osteoclasts, making the osteoclast capable of bone resorption.
The Journal of Immunology 08/2009; 183(5):3390-9. · 5.79 Impact Factor
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Han Bok Kwak,
Hun Soo Kim,
Myeung Su Lee,
Kwang-Jin Kim,
Eun-Yong Choi,
Min-Kyu Choi,
Jeong-Joong Kim,
Hae Joong Cho,
Jeong Woo Kim,
Ji-Myung Bae,
Yun-Kyung Kim,
Byoung Hyun Park,
Hyunil Ha, Churl Hong Chun,
Jaemin Oh
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ABSTRACT: It has been reported that Janus tyrosine kinase (JAK)-dependent signaling pathways play a critical role in the pathogenesis of numerous malignancies and immune reactions, and inhibition of JAK has been implicated in cell growth inhibition. The role which JAK has on osteoclast differentiation and anti-bone resorptive activity is not well understood. In this study, we investigated the effects of a pan-JAK inhibitor, pyridone 6, on osteoclast differentiation and bone-resorption in vitro and ex vivo. Pyridone 6 inhibited osteoclast differentiation in mouse bone marrow macrophage (BMM) cultures stimulated by the receptor activator of nuclear factor-kappaB (NF-kappaB) ligand (RANKL) and co-cultures of bone marrow cells and osteoblasts. Pyridone 6 suppressed the expression of c-Fos and nuclear factor of activated T cells (NFAT) c1 in BMMs. It also inhibited the bone resorptive activity of mature osteoclasts that was accompanied by disruption of actin rings. Pyridone 6 also suppressed I-kappaB degradation and extracellular signal-regulated kinase (ERK) in mature osteoclasts, suggesting that these are the key molecules that pyridone 6 targets in the inhibition of osteoclast function. These results demonstrate inhibition of JAK may be useful for the treatment of bone-resorptive diseases, such as osteoporosis.
Biological & Pharmaceutical Bulletin 02/2009; 32(1):45-50. · 1.66 Impact Factor
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Hyun-Mee Oh,
Hyun-Ju Lee,
Geom-Seog Seo,
Eun-Young Choi,
Seok-Hyun Kweon, Churl-Hong Chun,
Weon-Cheol Han,
Kang-Min Lee,
Myeung-Su Lee,
Suck-Chei Choi,
Chang-Duk Jun
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ABSTRACT: NOD2 is mainly expressed in human monocytes/macrophages and intestinal epithelial cells and has been speculated to play in gut physiology. However, whether NOD2 is expressed in vascular endothelium is not currently determined. Human umbilical vascular endothelial cells (HUVECs) minimally expressed NOD2 gene, whereas stimulation of HUVEC with bacterial LPS, IL-1beta, or TNF-alpha resulted in significant up-regulation of NOD2. NOD2 protein was mostly localized in the cytoplasm. Overexpression of wild-type NOD2 (WT-NOD2) gene induced NF-kappaB-dependent transcriptional activity and this activity was further increased by muramyl dipeptide (MDP). Otherwise, down-regulation of WT-NOD2 gene by antisense NOD2 abolished NF-kappaB-dependent transcriptional activity mediated by either WT-NOD2 itself or MDP. Since vascular endothelial cells, like macrophages and epithelial cells, are critical targets for the circulating bacterial molecules such as MDP, collectively, the results presented here suggest that NOD2 may play an important role in recognizing structural patterns of bacterial pathogen in the endothelium.
Cellular Immunology 10/2005; 237(1):37-44. · 1.97 Impact Factor
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Hyun-Mee Oh,
Suck-Chei Choi,
Han-Sol Lee, Churl-Hong Chun,
Geom-Seog Seo,
Eun-Young Choi,
Hyun-Ju Lee,
Myeung-Su Lee,
Joo-Jin Yeom,
Suck-Jun Choi,
Weon-Cheol Han,
Jae-Min Oh,
Yeun-Tai Chung,
Jang-Soo Chun,
Kang-Min Lee,
Chang-Duk Jun
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ABSTRACT: The mechanisms that regulate nitric oxide (NO)-induced apoptosis, especially in T cell apoptosis, are largely uncharacterized. Here, we report that protection from NO-induced cell death by phorbol 12-myristate 13-acetate (PMA) is dependent on both p38 and extracellular signal-regulated kinase (ERK) activation. Exposure of Molt4 cells to NO donor S-nitroso-N-acetyl-DL-penicillamine (SNAP) induced both apoptotic and necrotic modes of cell death along with a sustained increase in p38 kinase phosphorylation. However, the p38 inhibitor SB202190 only slightly protected Molt4 cells from NO toxicity. In contrast, PMA rapidly phosphorylated both p38 kinase and ERK, and the phosphorylation statuses were not altered in the presence of SNAP. Interestingly, although each mitogen-activated protein kinase (MAPK) inhibitor by itself had only a modest effect, the combination of inhibitors for both MAPKs almost completely abolished the protective effect of PMA. Furthermore, dominant negative or catalytically inactive variants that modulate p38 and ERK mimicked the effects of MAPK inhibitors. We located the action of p38 and ERK upstream of the p53/mitochondrial membrane potential loss and caspases cascade. Together, these findings suggest that the PMA-induced activations of ERK and p38 kinase are parallel events that are both required for inhibition of NO-induced death of Molt4 cells.
Free Radical Biology and Medicine 09/2004; 37(4):463-79. · 5.42 Impact Factor
