Hiroshi Kawaguchi

Publications (227)949.27 Total impact

• Article: Cell-sheet technology combined with a thienoindazole derivative small compound TD-198946 for cartilage regeneration.

  Fumiko Yano, Hironori Hojo, Shinsuke Ohba, Taku Saito, Muneki Honnami, Manabu Mochizuki, Tsuyoshi Takato, Hiroshi Kawaguchi, Ung-Il Chung
  [show abstract] [hide abstract]
  ABSTRACT: Articular cartilage is a permanent tissue, with poor self-regenerative capacity. Consequently, a tissue engineering approach to cartilage regenerative therapy could greatly advance the current treatment options for patients with cartilage degeneration and/or defects. A successful tissue engineering approach would require not only induction of chondrogenic differentiation, but also suppression of subsequent endochondral ossification and chondrocyte dedifferentiation. We previously reported that direct injection of the thienoindazole derivative, TD-198946, into the knee joints of mice halted the progression of osteoarthritis; the compound induced chondrogenic differentiation without promoting endochondral ossification. In the present study, we applied TD-198946 to a cell-based cartilage reconstruction model, taking advantage of the cell-sheet technology. Cartilaginous cell-sheets were generated by culturing mouse and canine costal chondrocytes and human mesenchymal stem cells with TD-198946 on temperature-responsive dishes. The transplanted cell-sheets were then successfully used to promote the reconstruction of permanent cartilage, with no evidence of chondrocyte hypertrophy in the knee articular cartilage defects created in mice and canines. Thus, TD-198946 is a promising candidate for cell-based cartilage reconstruction therapies, enabling us to avoid any concern surrounding the use of scaffolds or cytokines to stimulate regeneration.
  Biomaterials 04/2013; · 7.40 Impact Factor
• Article: Grafting of poly(2-methacryloyloxyethyl phosphorylcholine) on polyethylene liner in artificial hip joints reduces production of wear particles.

  Toru Moro, Masayuki Kyomoto, Kazuhiko Ishihara, Kenichi Saiga, Masami Hashimoto, Sakae Tanaka, Hideya Ito, Takeyuki Tanaka, Hirofumi Oshima, Hiroshi Kawaguchi, Yoshio Takatori
  [show abstract] [hide abstract]
  ABSTRACT: Despite improvements in the techniques, materials, and fixation of total hip arthroplasty, periprosthetic osteolysis, a complication that arises from this clinical procedure and causes aseptic loosening, is considered to be a major clinical problem associated with total hip arthroplasty. With the objective of reducing the production of wear particles and eliminating periprosthetic osteolysis, we prepared a novel hip polyethylene (PE) liner whose surface graft was made of a biocompatible phospholipid polymer-poly(2-methacryloyloxyethyl phosphorylcholine (MPC)). This study investigated the wear resistance of the poly(MPC)-grafted cross-linked PE (CLPE; MPC-CLPE) liner during 15×10(6) cycles of loading in a hip joint simulator. The gravimetric analysis showed that the wear of the acetabular liner was dramatically suppressed in the MPC-CLPE liner, as compared to that in the non-treated CLPE liner. Analyses of the MPC-CLPE liner surface revealed that it suffered from no or very little wear even after the simulator test, whereas the CLPE liners suffered from substantial wears. The scanning electron microscope (SEM) analysis of the wear particles isolated from the lubricants showed that poly(MPC) grafting dramatically decreased the total number, area, and volume of the wear particles. However, there was no significant difference in the particle size distributions, and, in particular, from the SEM image, it was observed that particles with diameters less than 0.50μm were present in the range of the highest frequency. In addition, there were no significant differences in the particle size descriptors and particle shape descriptors. The results obtained in this study show that poly(MPC) grafting markedly reduces the production of wear particles from CLPE liners, without affecting the size of the particles. These results suggest that poly(MPC) grafting is a promising technique for increasing the longevity of artificial hip joints.
  Journal of the mechanical behavior of biomedical materials. 04/2013;
• Article: Association of dietary intake with joint space narrowing and osteophytosis at the knee in Japanese men and women: the ROAD study.

  Shigeyuki Muraki, Toru Akune, Yoshio En-Yo, Munehito Yoshida, Sakae Tanaka, Hiroshi Kawaguchi, Kozo Nakamura, Hiroyuki Oka, Noriko Yoshimura
  [show abstract] [hide abstract]
  ABSTRACT: OBJECTIVE: The objective of the present study is to identify dietary nutrients associated with joint space narrowing (JSN) and osteophytosis at the knee in a population-based cohort of the Research on Osteoarthritis/osteoporosis Against Disability (ROAD) study. METHODS: From the baseline survey of the ROAD study, 827 participants (305 men and 522 women) in a rural cohort were analyzed. Dietary nutrient intakes for the last month were assessed by a self-administered brief diet history questionnaire. Minimum joint space width (mJSW) and osteophyte area (OPA) in the medial compartment of the knee were measured using a knee osteoarthritis (OA) computer-aided diagnostic system. RESULTS: In men, there were no associations of dietary nutrient intakes with mJSW or OPA. In women, vitamins K, B1, B2, B6, and C were associated with mJSW after adjustment for age, body mass index, and total energy (p < 0.05). Vitamins E, K, B1, B2, niacin, and B6 were significantly associated with OPA (p < 0.05) in women. Vitamins K, B and C may have a protective role against knee OA in women and might lead to disease-modifying treatments. CONCLUSIONS: The present study revealed that low dietary intake of vitamins K, B, and C are associated with JSN and osteophytosis in women.
  Modern Rheumatology 03/2013; · 1.58 Impact Factor
• Article: Associations between radiographic lumbar spinal stenosis and clinical symptoms in the general population: The Wakayama Spine Study.

  Yuyu Ishimoto, Noriko Yoshimura, Shigeyuki Muraki, Hiroshi Yamada, Keiji Nagata, Hiroshi Hashizume, Noboru Takiguchi, Akihito Minamide, Hiroyuki Oka, Hiroshi Kawaguchi, Kozo Nakamura, Toru Akune, Munehito Yoshida
  [show abstract] [hide abstract]
  ABSTRACT: OBJECTIVE: Many asymptomatic individuals have radiographic lumbar spinal stenosis (LSS), but the prevalence of symptomatic individuals among those with radiographic LSS has not yet been clarified. The purpose of this study was to clarify the association between radiographic LSS and clinical symptoms in the general population. METHODS: In this cross-sectional study, 938 participants (308 men, 630 women; mean age, 66.3 years; range, 40-93 years) were analysed. The severity of radiographic LSS, including central stenosis, lateral stenosis, and foraminal stenosis, was assessed by mobile magnetic resonance imaging (MRI) and rated by qualitative measurements. Assessment of clinical symptoms was based on the definition of symptomatic LSS in the North American Spine Society (NASS) guideline. RESULTS: A total of 77.9% of participants had more than moderate central stenosis and 30.4% had severe central stenosis. Logistic regression analysis after adjustment for age, gender, BMI, and each severity of radiographic LSS showed that severe central stenosis was related to clinical symptoms. However, only 17.5% of the participants with severe central stenosis were symptomatic. CONCLUSION: Although radiographic LSS was prevalent in our cohort, which resembled the general Japanese population, symptomatic persons were relatively uncommon.
  Osteoarthritis and Cartilage 03/2013; · 3.90 Impact Factor
• Article: Mortality and morbidity after high-dose methylprednisolone treatment in patients with acute cervical spinal cord injury: a propensity-matched analysis using a nationwide administrative database.

  Hirotaka Chikuda, Hideo Yasunaga, Katsushi Takeshita, Hiromasa Horiguchi, Hiroshi Kawaguchi, Kazuhiko Ohe, Kiyohide Fushimi, Sakae Tanaka
  [show abstract] [hide abstract]
  ABSTRACT: OBJECTIVE: To examine the magnitude of the adverse impact of high-dose methylprednisolone treatment in patients with acute cervical spinal cord injury (SCI). METHODS: We examined the abstracted data from the Japanese Diagnosis Procedure Combination database, and included patients with ICD-10 code S141 who were admitted on an emergency basis between 1 July and 31 December in 2007-2009. The investigation evaluated the patients' sex, age, comorbidities, Japan Coma Scale, hospital volume and the amount of methylprednisolone administered. One-to-one propensity-score matching between high-dose methylprednisolone group (>5000 mg) and control group was performed to compare the rates of in-hospital death and major complications (sepsis; pneumonia; urinary tract infection; gastrointestinal ulcer/bleeding; and pulmonary embolism). RESULTS: We identified 3508 cervical SCI patients (2652 men and 856 women; mean age, 60.8±18.7 years) including 824 (23.5%) patients who received high-dose methylprednisolone. A propensity-matched analysis with 824 pairs of patients showed a significant increase in the occurrence of gastrointestinal ulcer/bleeding (68/812 vs 31/812; p<0.001) in the high-dose methylprednisolone group. Overall, the high-dose methylprednisolone group demonstrated a significantly higher risk of complications (144/812 vs 96/812;OR, 1.66; 95% CI 1.23 to 2.24; p=0.001) than the control group. There was no significant difference in in-hospital mortality between the high-dose methylprednisolone group and the control group (p=0.884). CONCLUSIONS: Patients receiving high-dose methylprednisolone had a significantly increased risk of major complications, in particular, gastrointestinal ulcer/bleeding. However, high-dose methylprednisolone treatment was not associated with any increase in mortality.
  Emergency Medicine Journal 02/2013; · 1.44 Impact Factor
• Article: Hedgehog-Gli activators direct osteo-chondrogenic function of bone morphogenetic protein toward osteogenesis in the perichondrium.

  Hironori Hojo, Shinsuke Ohba, Kiyomi Taniguchi, Masataka Shirai, Fumiko Yano, Taku Saito, Toshiyuki Ikeda, Keiji Nakajima, Yuske Komiyama, Naomi Nakagata, Kentaro Suzuki, Yuji Mishina, Masahisa Yamada, Tomohiro Konno, Tsuyoshi Takato, Hiroshi Kawaguchi, Hideki Kambara, Ung-Il Chung
  [show abstract] [hide abstract]
  ABSTRACT: Specification of progenitors into the osteoblast lineage is an essential event for skeletogenesis. During endochondral ossification, cells in the perichondrium give rise to osteoblast precursors. Hedgehog (Hh) and bone morphogenetic protein (BMP) are suggested to regulate the commitment of these cells. However, properties of perichondrial cells and regulatory mechanisms of the specification process are still poorly understood. Here, we investigated the machineries by combining a novel organ culture system and single-cell expression analysis with mouse genetics and biochemical analyses. In a metatarsal organ culture reproducing bone collar formation, activation of BMP signaling enhanced the bone collar formation cooperatively with Hh input, while the signaling induced ectopic chondrocyte formation in the perichondrium without Hh input. Similar phenotypes were also observed in compound mutant mice, where signaling activities of Hh and BMP were genetically manipulated. Single-cell RT-qPCR analyses showed heterogeneity of perichondrial cells in terms of natural characteristics and responsiveness to Hh input. In vitro analyses revealed that Hh signaling suppressed BMP-induced chondrogenic differentiation; Gli1 inhibited the expression of Sox5, Sox6, and Sox9 as well as transactivation by Sox9. Indeed, ectopic expression of chondrocyte maker genes were observed in the perichondrium of metatarsals in Gli1-/- fetuses, and the phenotype was more severe in Gli1-/-;Gli2-/- newborns. These data suggest that Hh-Gli activators alter the function of BMP to specify perichondrial cells into osteoblasts; the timing of Hh input and its target populations are critical for BMP function.
  Journal of Biological Chemistry 02/2013; · 4.77 Impact Factor
• Article: SOX11 contributes to the regulation of GDF5 in joint maintenance.

  Akinori Kan, Toshiyuki Ikeda, Atsushi Fukai, Takumi Nakagawa, Kozo Nakamura, Ung-Il Chung, Hiroshi Kawaguchi, Clifford J Tabin
  [show abstract] [hide abstract]
  ABSTRACT: BACKGROUND: Individual skeletal elements of the vertebrate limbs arise through a segmentation process introducing joints in specific locations. However, the molecular pathways controlling joint formation and subsequent joint maintenance are largely unknown. In this study, we focused on SOX11, and its contribution to the regulation of GDF5, a secreted signal necessary for proper joint formation and postnatal joint homeostasis. RESULTS: Sox11 is initially expressed broadly in the murine cartilage condensations at early stages of skeletal development, but its expression is specifically increased in the forming joint interzone as is forms. SOX11 overexpression can directly activate GDF5 expression both in vitro and in micromass cell cultures prepared from chick limb buds. Conserved SOX family binding sites are present in the 5' UTR region of the GDF5 gene and we show SOX11 can specifically bind to one of them. While misexpression of Sox11 in developing chick limbs through RCAS virus infection does not induce Gdf5 expression in ectopic locations, it does enhance its expression. To explore the roles of Sox11 in joint homeostasis, we analyzed adult knee joints in an osteoarthritis mouse model where the medial meniscus and the medial collateral ligament were removed. We also analyzed knee joints from human subjects who underwent total knee replacement surgery. We find that SOX11 is mainly expressed in the weight-bearing areas of knee joints, and its expression is decreased in degraded cartilage during progression of knee osteoarthritis in both mice and humans. CONCLUSIONS: This work implicates SOX11 as a potential regulator of GDF5 expression in joint maintenance and suggests a possible role in the pathogenesis of osteoarthritis.
  BMC Developmental Biology 01/2013; 13(1):4. · 2.79 Impact Factor
• Article: Notch signaling in chondrocytes modulates endochondral ossification and osteoarthritis development.

  Yoko Hosaka, Taku Saito, Shurei Sugita, Tomohiro Hikata, Hiroshi Kobayashi, Atsushi Fukai, Yuki Taniguchi, Makoto Hirata, Haruhiko Akiyama, Ung-Il Chung, Hiroshi Kawaguchi
  [show abstract] [hide abstract]
  ABSTRACT: Here we examined the involvement of Notch signaling in the endochondral ossification process, which is crucial for osteoarthritis (OA) development. Intracellular domains of Notch1 and -2 were translocated into the nucleus of chondrocytes with their differentiation in mouse limb cartilage and in mouse and human OA articular cartilage. A tissue-specific inactivation of the Notch transcriptional effector recombination signal binding protein for Ig kappa J (RBPjκ) in chondroprogenitor cells of SRY-box containing gene 9 (Sox9)-Cre;Rbpj(fl/fl) mouse embryos caused an impaired terminal stage of endochondral ossification in the limb cartilage. The RBPjκ inactivation in adult articular cartilage after normal skeletal growth using type II collagen (Col2a1)-Cre(ERT);Rbpj(fl/fl) mice by tamoxifen injection caused resistance to OA development in the knee joint. Notch intracellular domain with the effector RBPjκ stimulated endochondral ossification through induction of the target gene Hes1 in chondrocytes. Among the Notch ligands, Jagged1 was strongly induced during OA development. Finally, intraarticular injection of N-[N-(3,5-diflurophenylacetate)-l-alanyl]-(S)-phenylglycine t-butyl ester (DAPT), a small compound Notch inhibitor, to the mouse knee joint prevented OA development. The RBPjκ-dependent Notch signaling in chondrocytes modulates the terminal stage of endochondral ossification and OA development, representing an extracellular therapeutic target of OA.
  Proceedings of the National Academy of Sciences 01/2013; · 9.68 Impact Factor
• Article: Poly(2-methacryloyloxyethyl phosphorylcholine)-grafted highly cross-linked polyethylene liner in primary total hip replacement: one-year results of a prospective cohort study.

  Yoshio Takatori, Toru Moro, Morihide Kamogawa, Hiromi Oda, Shuhei Morimoto, Takashige Umeyama, Manabu Minami, Hideharu Sugimoto, Shigeru Nakamura, Tatsuro Karita, Juntaku Kim, Yurie Koyama, Hideya Ito, Hiroshi Kawaguchi, Kozo Nakamura
  [show abstract] [hide abstract]
  ABSTRACT: To control particle-induced osteolysis in total hip replacement (THR), we developed a new technique to graft poly(2-methacryloyloxyethyl phosphorylcholine) onto the surface of polyethylene liners. A prospective cohort study was conducted to investigate the clinical safety of this novel bearing surface. Between April 2007 and September 2008, we recruited a prospective consecutive series of 80 patients in five participating hospitals. These patients received a cementless THR; a 26-mm-diameter cobalt-chromium-molybdenum alloy ball and a poly(2-methacryloyloxyethyl phosphorylcholine)-grafted cross-linked polyethylene liner were used for the bearing couplings. These individuals were followed a year postoperatively. An evaluation of clinical performance was conducted through an assessment of hip joint function based on the evaluation chart authorized by the Japanese Orthopaedic Association. No patients were lost to follow-up. No adverse events were found to be correlated with the implanted liners. The average hip joint function score improved from 43.2 preoperatively to 91.7 postoperatively at 1 year. There was no implant migration nor periprosthetic osteolysis detected on radiographic analysis. On the basis of our results, we conclude that poly(2-methacryloyloxyethyl phosphorylcholine)-grafted cross-linked polyethylene liners are a safe implant option for hip replacement surgery for short-term clinical use.
  Journal of Artificial Organs 12/2012; · 1.59 Impact Factor
• Article: Factors affecting the occurrence of pulmonary embolism after spinal surgery: data from the national administrative database in Japan.

  Kazuhiro Masuda, Hirotaka Chikuda, Hideo Yasunaga, Nobuhiro Hara, Hiromasa Horiguchi, Shinya Matsuda, Katsushi Takeshita, Hiroshi Kawaguchi, Kozo Nakamura
  [show abstract] [hide abstract]
  ABSTRACT: BACKGROUND CONTEXT: Despite potentially devastating consequences, pulmonary embolism (PE) in patients undergoing spinal surgery remains poorly understood. To the best of our knowledge, few large studies have examined the prevalence and risk factors of PE after spinal surgery. PURPOSE: To investigate the prevalence of symptomatic PE in patients undergoing elective spinal surgery and to identify clinical variables associated with the occurrence of postoperative PE. STUDY DESIGN: A retrospective analysis of data abstracted from the diagnosis procedure combination (DPC) database, a nationally representative database in Japan. PATIENT SAMPLE: We included all patients with a diagnosis of spinal canal stenosis, disc herniation, spondylosis, spondylolisthesis, trauma, metastatic tumor, or infection who underwent spinal surgery between July 1 and December 31 of 2007 and 2008, respectively. OUTCOME MEASURES: The primary end point was defined as the occurrence of postoperative PE during hospitalization. The secondary end point was in-hospital death after postoperative PE. METHODS: We analyzed the association between the occurrence of postoperative PE and clinical variables recorded in the DPC database, including age, sex, comorbidities, location of surgery, primary diagnosis, anterior/posterior approach, use of instrumentation, and duration of anesthesia. RESULTS: A total of 47,743 patients were identified. Of these, 50 (0.10%) developed PE and four died as a result of PE. Logistic regression analyses revealed that occurrence of PE was associated with older age (70 years or older; odds ratio [OR], 3.15; 95% confidence interval [CI], 1.15-8.69; p=.026) and longer anesthesia time (more than 360 minutes; OR, 2.19; 95% CI, 0.88-5.44; p=.092). Patients with trauma were significantly more likely to have a PE than those with spinal canal stenosis (0.27% vs. 0.09%; OR, 2.86; 95% CI, 1.14-7.18; p=.026). CONCLUSIONS: This retrospective analysis of a nationally representative database identified older age, longer anesthesia time, and spinal trauma as risk factors for increased incidence of postoperative PE. Surgeons should be aware of the increased risk of postoperative PE in these subgroups of patients.
  The spine journal: official journal of the North American Spine Society 11/2012; · 2.90 Impact Factor
• Article: β-Catenin regulates PTH/PTHrP receptor signals and chondrocyte hypertrophy through binding to its intracellular C-terminal region.

  Fumiko Yano, Taku Saito, Naoshi Ogata, Toshiko Yamazawa, Masamitsu Iino, Ung-Il Chung, Hiroshi Kawaguchi
  [show abstract] [hide abstract]
  ABSTRACT: OBJECTIVE.: We identified β-catenin as a novel protein that interacts with the intracellular C-terminal portion of PTH/PTHrP receptor (PTH1R), and investigated its underlying mechanism and functional relevance in chondrocytes. METHODS.: The binding region was determined by the deletion and mutagenesis analyses of the PTH1R C-terminus using a mammalian two-hybrid assay. Physical interaction was examined by an in situ proximity ligation assay and immunostaining. The gain- and loss-of-function of β-catenin were examined by the constitutively active (ca) form and the siRNA overexpression, respectively, in cells co-transfected with wild-type PTH1R or the mutant which did not bind to β-catenin. Activation of Gαs, Gαq, and canonical Wnt pathways was measured by intracellular cAMP accumulation, [Ca(2+) ]i concentration, and TOPFLASH reporter assay, respectively. RESULTS.: β-catenin physically interacted and co-localized with the specific region of PTH1R (584-589) at the cell membrane of differentiated chondrocytes. The binding of β-catenin to PTH1R caused suppression of the Gαs/cAMP pathway and enhancement of the Gαq/Ca(2+) pathway, without affecting the canonical Wnt pathway. Inhibition of type X collagen expression by PTH was restored by the ca-β-catenin overexpression even after blocking the canonical Wnt pathway, and further decreased by the β-catenin knockout via the Cre recombinase in chondrocytes from β-catenin floxed (Ctnnb1(fl/fl) ) mice. A mutagenesis in PTH1R to block the β-catenin binding caused an inhibition of chondrocyte hypertrophy markers. CONCLUSION.: β-catenin binds to the PTH1R C-tail and switches the downstream pathway from Gαs/cAMP to Gαq/Ca(2+) , possibly regulating chondrocyte hypertrophy by the PTH/PTHrP signal independently of the canonical Wnt pathway. © 2012 American College of Rheumatology.
  Arthritis & Rheumatism 11/2012; · 7.87 Impact Factor
• Article: Risk factors for falls in a longitudinal population-based cohort study of Japanese men and women: The ROAD Study.

  Shigeyuki Muraki, Toru Akune, Yuyu Ishimoto, Keiji Nagata, Munehito Yoshida, Sakae Tanaka, Hiroyuki Oka, Hiroshi Kawaguchi, Kozo Nakamura, Noriko Yoshimura
  [show abstract] [hide abstract]
  ABSTRACT: The objective of this study was to clarify the associations of physical performance and bone and joint diseases with single and multiple falls in Japanese men and women using a population-based longitudinal cohort study known as Research on Osteoarthritis/osteoporosis Against Disability (ROAD). A total of 452 men and 896 women were analyzed in the present study (mean age, 63.9years). A questionnaire was used to assess the number of falls during the 3-year follow-up. Grip strength, 6-m walking time, and chair stand time were measured at baseline. Knee osteoarthritis (OA) and lumbar spondylosis were defined as Kellgren Lawrence=2, 3 or 4. Vertebral fracture (VFx) was assessed with the Japanese Society of Bone and Mineral Research criteria. Osteoporosis was defined by bone mineral density using dual energy X-ray absorptiometry based on World Health Organization criteria. Knee and lower back pain were estimated by an interview. During a 3-year follow-up, 79 (17.4%) men and 216 (24.1%) women reported at least one fall, and 54 (11.9%) men and 111 (12.4%) women reported multiple falls. Knee pain was a risk factor for multiple falls in women, but not in men. VFx tended to be associated with multiple falls in women, but not in men. A longer 6-m walking time was a risk factor for multiple falls in women, whereas a longer chair stand time was a risk factor for multiple falls in men. We found gender differences in risk factors for falls.
  Bone 10/2012; · 4.02 Impact Factor
• Article: A novel disease-modifying osteoarthritis drug candidate targeting Runx1.

  Fumiko Yano, Hironori Hojo, Shinsuke Ohba, Atsushi Fukai, Yoko Hosaka, Toshiyuki Ikeda, Taku Saito, Makoto Hirata, Hirotaka Chikuda, Tsuyoshi Takato, Hiroshi Kawaguchi, Ung-Il Chung
  [show abstract] [hide abstract]
  ABSTRACT: OBJECTIVES: To identify a new disease-modifying osteoarthritis drug (DMOAD) candidate that can effectively repair cartilage by promoting chondrogenic differentiation and halt osteoarthritis (OA) progression by suppressing aberrant hypertrophy. METHODS: We screened 2500 natural and synthetic small compounds for chondrogenic agents via four steps using the Col2GFP-ATDC5 system and identified a small thienoindazole derivative compound, TD-198946, as a novel DMOAD candidate. We tested its efficacy as a DMOAD via intra-articular injections directly into the joint space in a surgically-induced mouse model of OA both at the onset (prevention model) and 4 weeks after (repair model) OA induction. The downstream molecules were screened by microarray analysis. We further investigated the mechanism of the drug action and its molecular target using in vitro and in vivo assays. RESULTS: TD-198946 strongly induced chondrogenic differentiation without promoting hypertrophy in cell and metatarsal organ cultures. When administered directly into the joint space, TD-198946 successfully prevented and repaired degeneration of the articular cartilage. TD-198946 exerted its effect through the regulation of Runx1 expression, which was downregulated in both mouse and human OA cartilage compared with normal tissue. CONCLUSIONS: Our data suggest that TD-198946 is a novel class of DMOAD candidate, and that targeting Runx1 will provide a promising new approach in the development of disease-modifying drugs against OA.
  Annals of the rheumatic diseases 10/2012; · 8.11 Impact Factor
• Article: The mid-term efficacy of intra-articular hyaluronic acid injections on joint structure: a nested case control study.

  Hiroyuki Oka, Toru Akune, Shigeyuki Muraki, Sakae Tanaka, Hiroshi Kawaguchi, Kozo Nakamura, Noriko Yoshimura
  [show abstract] [hide abstract]
  ABSTRACT: OBJECTIVE: Intra-articular (IA) injection of hyaluronic acid (HA) has been shown to relieve osteoarthritis (OA)-related pain and improve joint structure within a 1-year period. We examined the mid-term (2-year) efficacy of IA-HA in Japanese subjects by using a large-scale population-based cohort of the Research on Osteoarthritis/Osteoporosis Against Disability study. METHODS: We performed a nested case control study of 60 case control pairs matched for age (within 1 year), sex, Kellgren and Lawrence grade, and history of knee pain. The mean follow-up period after IA-HA series was 2.9 years in case patients. We examined the association of IA-HA with knee radiographic severity and knee pain. To estimate radiographic severity of OA, six distinct features-joint space area and the minimum joint space width at medial and lateral sides, osteophyte area, and tibiofemoral angle-were measured using a fully automatic computer-assisted program. RESULTS: Comparison of the radiographic parameters between case patients and controls showed that the medial and lateral joint space areas were significantly bigger in case patients than in controls. After constructing a multivariate logistic regression model to examine the correlation of knee pain, IA-HA, and radiographic features, we found that unlike radiographic features, IA-HA was protectively associated with the presence of pain. CONCLUSION: IA-HA might effectively improve joint structure and relieve pain in patients with knee OA.
  Modern Rheumatology 08/2012; · 1.58 Impact Factor
• Article: Accumulation of metabolic risk factors such as overweight, hypertension, dyslipidaemia, and impaired glucose tolerance raises the risk of occurrence and progression of knee osteoarthritis: a 3-year follow-up of the ROAD study.

  N Yoshimura, S Muraki, H Oka, S Tanaka, H Kawaguchi, K Nakamura, T Akune
  [show abstract] [hide abstract]
  ABSTRACT: To clarify the association between the occurrence and progression of knee osteoarthritis (KOA) with components of metabolic syndrome (MS), including overweight (OW), hypertension (HT), dyslipidaemia (DL), and impaired glucose tolerance (IGT), in a general population. From the large-scale population-based cohort study entitled Research on Osteoarthritis/Osteoporosis Against Disability (ROAD) initiated in 2005, 1,690 participants (596 men, 1,094 women) residing in mountainous and coastal areas were enrolled. Of these, 1,384 individuals (81.9%; 466 men, 918 women) completed the second survey, including knee radiography, 3 years later. KOA was defined as Kellgren-Lawrence (KL) grade ≥ 2 using paired X-ray films. Based on changes in KL grades between the baseline and second surveys, cumulative incidence and progression of KOA were determined. OW, HT, DL, and IGT at baseline were assessed using standard criteria. The cumulative incidence of KOA among 1,384 completers over 3 years was 3.3%/year, and progression in KL grades for either knee, 8.0%/year. Logistic regression analyses after adjusting for potential risk factors revealed that the odds ratio (OR) for the occurrence of KOA significantly increased according to the number of MS components present (OR vs no component: one component, 2.33; two components, 2.82; ≥three components, 9.83). Similarly, progression of KOA significantly increased according to the number of MS components present (OR vs no component: one component, 1.38; two components, 2.29; ≥three components: 2.80). Accumulation of MS components is significantly related to both occurrence and progression of KOA. MS prevention may be useful in reducing future KOA risk.
  Osteoarthritis and Cartilage 07/2012; 20(11):1217-26. · 3.90 Impact Factor
• Article: Prevalence of symptomatic lumbar spinal stenosis and its association with physical performance in a population-based cohort in Japan: the Wakayama Spine Study.

  Y Ishimoto, N Yoshimura, S Muraki, H Yamada, K Nagata, H Hashizume, N Takiguchi, A Minamide, H Oka, H Kawaguchi, K Nakamura, T Akune, M Yoshida
  [show abstract] [hide abstract]
  ABSTRACT: The purpose of this study was to investigate the prevalence of symptomatic lumbar spinal stenosis (LSS) and to clarify the association between symptomatic LSS and physical performance using magnetic resonance imaging (MRI) in a population-based cohort. This cross-sectional study was performed as a part of the research on osteoarthritis/osteoporosis against disability (ROAD) in Japan and 1,009 subjects (335 men, 674 women, mean age 66.3 years, age range 21-97 years) were analyzed. An experienced orthopedic surgeon obtained the medical history and performed the physical testing for all participants. Symptomatic LSS diagnostic criteria required the presence of both symptoms and radiographic LSS findings. A 6-m walking time, chair standing time, and one-leg standing time were obtained from all participants. The prevalence of symptomatic LSS was 9.3% (95% confidence interval [CI]: 7.7-11.3) overall, 10.1% (CI: 7.4-13.8) in men and 8.9% (CI: 7.0-11.3) in women. There was a difference in the prevalence with increasing age by gender. The LSS prevalence showed little difference with age greater than 70 years for men, but the LSS prevalence for women was higher with increasing age. Among physical performance measures, 6-m walking time at a maximal pace was significantly associated with symptomatic LSS (P = 0.03). The prevalence of symptomatic LSS was approximately 10% in a cohort resembling the general Japanese population. A 6-m walking time at a maximal pace was a more sensitive index than walking at a usual pace in assessing decreased physical performance associated with symptomatic LSS.
  Osteoarthritis and Cartilage 07/2012; 20(10):1103-8. · 3.90 Impact Factor
• Article: GSK-3α and GSK-3β proteins are involved in early stages of chondrocyte differentiation with functional redundancy through RelA protein phosphorylation.

  Shozo Itoh, Taku Saito, Makoto Hirata, Masahiro Ushita, Toshiyuki Ikeda, James R Woodgett, Hana Algül, Roland M Schmid, Ung-Il Chung, Hiroshi Kawaguchi
  [show abstract] [hide abstract]
  ABSTRACT: Here we examine the roles of two isoforms of glycogen synthase kinase-3 (GSK-3), GSK-3α and GSK-3β, in skeletal development. Both isoforms were unphosphorylated and active in chondrocyte differentiation stages during SOX9 and type II collagen (COL2A1) expression. Although knock-out of both alleles of Gsk3a (Gsk3a(-/-)) or a single allele of Gsk3b (Gsk3b(+/-)) in mice did not significantly affect skeletal development, compound knock-out (Gsk3a(-/-);Gsk3b(+/-)) caused dwarfism with impairment of chondrocyte differentiation. GSK-3α and GSK-3β induced differentiation of cultured chondrocytes with functional redundancy in a cell-autonomous fashion, independently of the Wnt/β-catenin signal. Computational predictions followed by SOX9 and COL2A1 transcriptional assays identified RelA (NF-κB p65) as a key phosphorylation target of GSK-3. Among several phosphorylation residues in RelA, Thr-254 was identified as the critical phosphorylation site for GSK-3 that modulated chondrocyte differentiation. In conclusion, redundant functions of GSK-3α and GSK-3β through phosphorylation of RelA at Thr-254 play a crucial role in early stages of chondrocyte differentiation.
  Journal of Biological Chemistry 07/2012; 287(35):29227-36. · 4.77 Impact Factor
• Article: Nanog promotes osteogenic differentiation of the mouse mesenchymal cell line C3H10T1/2 by modulating bone morphogenetic protein (BMP) signaling.

  Toru Ogasawara, Shinsuke Ohba, Fumiko Yano, Hiroshi Kawaguchi, Ung-Il Chung, Tadahito Saito, Yoshiyuki Yonehara, Takashi Nakatsuka, Yoshiyuki Mori, Tsuyoshi Takato, Kazuto Hoshi
  [show abstract] [hide abstract]
  ABSTRACT: How the pluripotency of stem cells is maintained and the role of transcription factors in this maintenance remain major questions. In the present study, in order to clarify the mechanism underlying the pluripotency of stem cells for the advancement of regenerative medicine, we examined the effect of forced Nanog expression in mesenchymal cells, with a particular focus on osteogenic differentiation. The human mesenchymal stromal cells (hMSCs) or mouse mesenchymal cell line C3H10T1/2 cells were transduced with the Nanog gene or control green fluorescent protein (GFP) gene by using retrovirus vectors. Short-term, forced Nanog gene expression had few effects on the terminal osteogenic differentiation of either hMSCs or C3H10T1/2 cells. To determine its long-term effects, we established C3H10T1/2 cells expressing Nanog constitutively. Constitutive Nanog expression strongly induced osteogenic differentiation of C3H10T1/2 cells. In regard to cell proliferation, constitutive Nanog expression only repressed the proliferation of the cells treated with rhBMP-2. Moreover, Nanog also had the potential to promote the proliferation of C3H10T1/2 cells in the absence of rhBMP-2. Constitutive Nanog expression enhanced phosphorylation of Smad1/5/8 and suppressed Cdk4 and cyclinD1. The promoter activities of both the osteocalcin and Id-1 genes were activated in cells expressing Nanog constitutively. To identify downstream molecules of Nanog involved in the promotion of osteogenic differentiation, we performed a DNA microarray analysis and discovered that NFATc1 was one of the downstream effectors of Nanog. These results indicate that Nanog functions as a modulator of BMP signaling in C3H10T1/2 cells probably through a genome reprogramming process. J. Cell. Physiol. 228: 163-171, 2013. © 2012 Wiley Periodicals, Inc.
  Journal of Cellular Physiology 05/2012; 228(1):163-71. · 3.87 Impact Factor
• Article: Prevalence of cervical cord compression and its association with physical performance in a population-based cohort in Japan: the wakayama spine study.

  Keiji Nagata, Noriko Yoshimura, Shigeyuki Muraki, Hiroshi Hashizume, Yuyu Ishimoto, Hiroshi Yamada, Noboru Takiguchi, Yukihiro Nakagawa, Hiroyuki Oka, Hiroshi Kawaguchi, Kozo Nakamura, Toru Akune, Munehito Yoshida
  [show abstract] [hide abstract]
  ABSTRACT: STUDY DESIGN.: A population-based magnetic resonance imaging (MRI) study of the cervical spine. OBJECTIVE.: This study was undertaken in order to investigate the prevalence of cervical cord compression (CCC) and to examine the association between CCC and physical performance measures in a population-based cohort established in Japan. SUMMARY OF BACKGROUND DATA.: Population-based cohort studies of the prevalence of CCC, although essential for clarification of the prevalence of slowly progressive disease and specification of the time of incidence of CCC, are not available. METHODS.: This cross-sectional study was performed as a part of the Research on Osteoarthritis/osteoporosis Against Disability study, a large-scale population-based cohort study in Japan. From 1011 inhabitants who underwent MRI examinations, images of the cervical spine of 977 subjects (324 men and 653 women, mean age of 66.4 yr) were evaluated. CCC was assessed by sagittal T2-weighted MRI and was defined as spinal cord compression. The prevalence of CCC and its association with myelopathic signs (hyper-reflexia of the patellar tendon and Hoffmann and Babinski reflexes) were examined. In addition, physical performance measures (grip and release test, grip strength, 6-m walking time, step length, chair-stand time, and one-leg standing time) were tested. RESULTS.: The prevalence of CCC was 24.4% and was significantly higher in men (29.3% in men and 21.9% in women, P = 0.011). The prevalence of CCC was higher with increasing age in both sexes. CCC was not significantly associated with any myelopathic signs but was significantly associated with grip and release test, 6-m walking time, step length, and chair-stand time. CONCLUSION.: In this MRI study, the prevalence of CCC was examined. The present results indicate that CCC correlates with physical performance measures from an early stage of the disease before myelopathic signs appear.
  Spine 05/2012; 37(22):1892-8. · 2.08 Impact Factor
• Article: Scaffolds for Skeletal Regeneration

  Ung-il Chung, Keiji Itaka, Nobuhiro Nishiyama, Tsuyoshi Takato, Hiroshi Kawaguchi, Kozo Nakamura, Kazunori Kataoka
  [show abstract] [hide abstract]
  ABSTRACT: Although current treatment modalities for bone defects include autograft, allograft, and artificial bone substitutes, they have problems concerning invasiveness, safety, and performance, respectively, calling for development of innovative artificial bones with better handling and mechanical strength, better control of external and internal structures, and better biodegradability and osteo-inductive ability. We propose to fabricate novel high-performance artificial bones using 3D inkjet printer based on the image data of bone defect/deformity. Shape precisely fitting to the defect/deformity, internal structure facilitating cell invasion, and good biodegradability are achieved. Bioactive substances can be incorporated by printing in combination with drug delivery system to induce bone regeneration at the desired locations. These osteo-inductive artificial bones will help efficiently treat various types of bone defect/deformity in a less invasive and safe manner.
  Nanobiotechnology 04/2012; 3(2):104-106.