Churl Hong Chun

GM-CSF Regulates Fusion of Mononuclear Osteoclasts into Bone-Resorbing Osteoclasts by Activating the Ras/ERK Pathway

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-α 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.

NAMPT (visfatin), a direct target of hypoxia-inducible factor-2α, is an essential catabolic regulator of osteoarthritis

Objective Hypoxia-inducible factor 2α (HIF-2α), encoded by Epas1, causes osteoarthritic cartilage destruction by regulating the expression of matrix-degrading enzymes. We undertook this study to explore the role of nicotinamide phosphoribosyltransferase (NAMPT or visfatin) in HIF-2α-mediated osteoarthritic cartilage destruction. Methods The expression of HIF-2α, NAMPT and matrix-degrading enzymes was determined at the mRNA and protein levels in human osteoarthritis (OA) cartilage, mouse experimental OA cartilage and primary cultured mouse chondrocytes. Experimental OA in mice was induced by destabilisation of the medial meniscus (DMM) surgery or intra-articular injection of Ad-Epas1 or Ad-Nampt in wild-type, Epas1+/−, Epas1fl/fl;Col2a1-Cre and Col2a1-Nampt transgenic (TG) mice. Primary cultured mouse chondrocytes were treated with recombinant NAMPT protein or were infected with adenoviruses. Results We found that the Nampt gene is a direct target of HIF-2α in articular chondrocytes and OA cartilage. NAMPT protein, in turn, increased mRNA levels and activities of MMP3, MMP12 and MMP13 in chondrocytes, an action that was necessary for HIF-2α-induced expression of catabolic enzymes. Gain-of-function studies (intra-articular injection of Ad-Nampt; Col2a1-Nampt TG mice) and loss-of-function studies (intra-articular injection of the NAMPT inhibitor FK866) demonstrated that NAMPT is an essential catabolic regulator of osteoarthritic cartilage destruction caused by HIF-2α or DMM surgery. Conclusions Our findings indicate that NAMPT, whose corresponding gene is a direct target of HIF-2α, plays an essential catabolic role in OA pathogenesis and acts as a crucial mediator of osteoarthritic cartilage destruction caused by HIF-2α or DMM surgery.

Hypoxia-inducible factor-2α is an essential catabolic regulator of inflammatory rheumatoid arthritis.

Hypoxia-inducible factor-2α (HIF-2α) is sufficient to cause experimental rheumatoid arthritis and acts to regulate the functions of fibroblast-like cells from tissue surrounding joints, independent of HIF-1α.

Histologic Findings of Anterior Cruciate Ligament Reconstruction with Achilles Allograft

The purpose of the current study was to evaluate the remodeling process of Achilles allograft for anterior cruciate ligament reconstruction under light microscopic and electron microscopic evaluations. In 12 patients, histologic examinations were done preoperatively and during arthroscopy at 6, 12, and 24 months. Gross observations were made with respect to width, vascularity, elasticity, and stability of the Achilles allograft. Biopsy specimens were obtained at the followup arthroscopic study. Light microscopic examinations done at 6 months showed many fibroblasts with spindle-shaped nuclei and hypercellularity. At 12 months, the small folds pattern of collagen bundles and decreased cellularity were observed. At 24 months, gross and findings of the light microscopic evaluations of the allograft tendons were similar to those of the normal anterior cruciate ligaments. On electron microscopic examinations done at 24 months, the allograft had fibroblasts with much cytoplasm and densely packed parallel-laid collagen fibrils, which showed the characteristic cross striations, but the Achilles allograft ligaments did not show similar findings compared with biopsy samples from normal anterior cruciate ligaments.

Clinical and radiological results of femoral head structural allograft for severe bone defects in revision TKA--a minimum 8-year follow-up.

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 107 months (range, 96-157 months). 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.

Infection Following Total Knee Arthroplasty

For most orthopedists, total knee arthroplasty (TKA) has been regarded as the most effective surgery for patients with severe knee diseases. Though seldom occur, postoperative infection certainly remains one of the most devastating and dreaded complications of TKA. Thus, careful and early diagnosis is needed. After diagnosis, categorize the infection type and choose a rightful and sequential step of treatment are recommended.

Histological Assessment of Mechanoreceptors in Achilles Allografts After Anterior Cruciate Ligament Reconstruction

Background: There is a lack of histological studies investigating the presence of mechanoreceptors in anterior cruciate ligament (ACL) allografts. Hypothesis: Mechanoreceptors would not grow in Achilles allografts after ACL reconstruction. Study Design: Case series study; Level of evidence, 4. Methods: 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. Results: 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. Conclusion: 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.

Amorphigenin inhibits Osteoclast differentiation by suppressing c-Fos and nuclear factor of activated T cells

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.

Arthroscopic Bioabsorbable Screw Fixation of Unstable Osteochondritis Dissecans in Adolescents: Clinical Results, Magnetic Resonance Imaging, and Second-Look Arthroscopic Findings

Background This study aimed to evaluate the clinical and radiological outcomes of arthroscopic bioabsorbable screw fixation in osteochondritis dissecans (OCD) in adolescent patients with unstable lesions causing pain. Methods The study included 11 patients (10 males and 1 female) with OCD who underwent arthroscopic bioabsorbable screw fixation between July 2007 and February 2014 and were available for follow-up for more than 12 months. The mean age at diagnosis was 16.3 years (range, 11 to 19 years), and the average follow-up period was 51 months (range, 12 to 91 months). Clinical results were evaluated using the Knee Injury and Osteoarthritis Outcome Score (KOOS), Lysholm knee score, and International Knee Documentation Committee (IKDC) score measured before surgery and at follow-up. Functional evaluation was made using the Tegner activity scale. Magnetic resonance imaging (MRI) and second-look arthroscopy were performed at the 12-month follow-up. Results Between the preoperative assessment and follow-up, improvements were seen in the KOOS (range, 44.9 to 88.1), Lysholm knee score (range, 32.6 to 82.8), and IKDC score (range, 40.8 to 85.6). The Tegner activity scale also improved from 2.8 to 6.1. Based on postoperative MRI, there were eight Dipaola grade I cases and three grade II cases. No complications due to fixation failure developed in any case. Second-look arthroscopy at 12 months postoperatively revealed that the lesion was covered with cartilage in all cases. Conclusions For unstable OCD lesions causing pain in adolescents, arthroscopic bioabsorbable screw fixation provided favorable outcomes with reduced pain and restoration of movement. Therefore, it should be considered as an effective treatment for OCD.

The Results of All-Inside Meniscus Repair Using the Viper Repair System Simultaneously with Anterior Cruciate Ligament Reconstruction.

Background Meniscus tears are commonly associated with anterior cruciate ligament (ACL) ruptures. It is essential to repair meniscal tears as much as possible to prevent early osteoarthritis and to gain additional stability in the knee joint. We evaluated the results of arthroscopic all-inside repair using the Meniscal Viper Repair System (Arthrex) on meniscus tears simultaneously with ACL reconstruction. Methods Nineteen out of 22 patients who were treated with arthroscopic all-inside repair using the Meniscal Viper Repair System for meniscus tear associated with ACL rupture were evaluated. ACL reconstructions were performed at the same period. The mean follow-up period was 16.5 months (range, 12 to 24 months). The clinical results of the meniscus repair were evaluated by symptoms (such as catching or locking), tenderness, effusion, range of motion limitation, and the McMurray test. Clinical success was defined by negative results in all five categories. The Hospital for Special Surgery (HSS) score was evaluated. Objective results were evaluated with secondary look arthroscopy or magnetic resonance imaging (MRI). The MRI results were categorized as completely repaired, incompletely repaired, and failure by Hennings classification. The results of second-look arthroscopy were evaluated with the criteria of meniscal healing. Results The clinical success rate was 95.4% and the HSS scores were 93.9 ± 5.4 at the final follow-up. According to Hennings classification, 15 out of 18 cases showed complete healing (83.3%) and two cases (11.1%) showed incomplete healing. Seventeen out of 18 cases that underwent second-look arthroscopy showed complete healing (94.4%) according to the criteria of meniscal healing. Only one case showed failure and the failure was due to a re-rupture at the sutured area. Complications of ACL reconstruction or meniscus repair were not present. Conclusions The results demonstrate that arthroscopic all-inside repair using the Meniscal Viper Repair System is an effective treatment method when it is performed simultaneously with ACL reconstruction.