Daisuke Koga

Initial Responses of Articular Tissues in a Murine High-Fat Diet-Induced Osteoarthritis Model: Pivotal Role of the IPFP as a Cytokine Fountain

Obesity and high body mass index are associated with a higher incidence of osteoarthritis (OA). The aim of this study is to investigate the involvement of the infrapatellar fat pad (IPFP) in the sub-acute effect of a high fat diet (HFD) on the development of knee-OA. C57BL/6J male mice were fed either a HFD or a normal diet beginning at seven weeks of age. Tissue sections were evaluated with immunohistological analysis. The IPFP was excised, and mRNA expression profiles were compared using real-time RT-PCR analysis. Osteoarthritic changes were initiated in the HFD group after eight weeks of the HFD. Increased synovial cell number and angiogenesis at the anterior edge of the tibial plateau were exhibited prior to osteophyte formation. Quantitative histological analysis indicated that osteophyte volume was significantly increased in the HFD group after eight weeks, along with an increase in the IPFP volume, the size of individual adipocytes and the number of vessels in the IPFP. Histomorphometrical analysis revealed osteophyte area was significantly associated with IPFP area, individual adipocyte area and vascular area. Real-time RT-PCR analysis demonstrated elevated mRNA expression of inflammatory cytokines, growth factor, and adipokines in the IPFP after eight weeks of the HFD. These findings are in parallel with increased expression of the CD68 macrophage marker after eight weeks of the HFD. Expression levels of the adipokines were significantly correlated with expression of TNF-α, VEGF and TGF-β. Immunohistological analysis revealed that the Nampt protein was highly expressed in the IPFP especially around the site of osteophyte formation. Apoptosis and proliferation of chondrocytes were both enhanced at the site of osteophyte formation, indicating higher cell turnover at this region. These observations suggest the IPFP plays a pivotal role in the formation of osteophytes and functions as a secretory organ in response to a HFD.

Sirt6 regulates postnatal growth plate differentiation and proliferation via Ihh signaling

Sirtuin 6 (Sirt6) is a mammalian homologue of NAD+-dependent histone deacetylase Sir2. Although Sirt6−/− mice exhibit growth retardation, the role of Sirt6 in cartilage metabolism is unclear. The aim of this study was to investigate the Sirt6 signaling pathway in cartilage metabolism. Immunohistological evaluation of the tibial growth plate in Sirt6−/− mice exhibited impaired proliferation and differentiation of chondrocytes, reduced expression of Indian hedgehog (Ihh), and a senescent phenotype. When Sirt6 was knocked down in chondrocytes in vitro, expression of Ihh and its downstream genes were reduced. Impaired differentiation by Sirt6 silencing was completely rescued by administration of a Hh signal agonist. When sirtuins were activated, chondrocyte differentiation was enhanced together with activation of Ihh signal, and these effects were abrogated by Sirt6 silencing. ChIP assay revealed the affinity of ATF4 to the Ihh promoter was markedly decreased by Sirt6 knockdown. These data indicate Sirt6 directly controls proliferation and differentiation of chondrocytes.

Procyanidin B3 Prevents Articular Cartilage Degeneration and Heterotopic Cartilage Formation in a Mouse Surgical Osteoarthritis Model

Osteoarthritis (OA) is a common disease in the elderly due to an imbalance in cartilage degradation and synthesis. Heterotopic ossification (HO) occurs when ectopic masses of endochondral bone form within the soft tissues around the joints and is triggered by inflammation of the soft tissues. Procyanidin B3 (B3) is a procyanidin dimer that is widely studied due to its high abundance in the human diet and antioxidant activity. Here, we evaluated the role of B3 isolated from grape seeds in the maintenance of chondrocytes in vitro and in vivo. We observed that B3 inhibited H2O2-induced apoptosis in primary chondrocytes, suppressed H2O2- or IL-1ß−induced nitric oxide synthase (iNOS) production, and prevented IL-1ß−induced suppression of chondrocyte differentiation marker gene expression in primary chondrocytes. Moreover, B3 treatment enhanced the early differentiation of ATDC5 cells. To examine whether B3 prevents cartilage destruction in vivo, OA was surgically induced in C57BL/6J mice followed by oral administration of B3 or vehicle control. Daily oral B3 administration protected articular cartilage from OA and prevented chondrocyte apoptosis in surgically-induced OA joints. Furthermore, B3 administration prevented heterotopic cartilage formation near the surgical region. iNOS protein expression was enhanced in the synovial tissues and the pseudocapsule around the surgical region in OA mice fed a control diet, but was reduced in mice that received B3. Together, these data indicated that in the OA model, B3 prevented OA progression and heterotopic cartilage formation, at least in a part through the suppression of iNOS. These results support the potential therapeutic benefits of B3 for treatment of human OA and heterotopic ossification.

Postoperative hip motion and functional recovery after simultaneous bilateral total hip arthroplasty for bilateral osteoarthritis

BackgroundSimultaneous bilateral total hip arthroplasty (THA) can offer a potential benefit of greater postoperative hip motion without the negative influence of contralateral hip disabilities, compared to two-stage THA. However, postoperative changes in hip motion after simultaneous bilateral THA have rarely been reported. The purpose of this study was to clarify the efficacy of simultaneous procedures on postoperative hip motion and functional recovery.MethodsWe retrospectively compared hip motion in 27 patients treated with simultaneous bilateral THA to those in 11 patients with two-stage bilateral THA, 35 patients with unilateral THA for unilateral disease, and 15 patients with unilateral THA for bilateral disease. We also evaluated the clinical manifestations according to the Japanese Orthopaedic Association (JOA) hip scores and compared the outcomes among the groups. All of the THA surgeries were primarily performed through a posterolateral approach using cement-less prostheses. The diagnosis at surgery was dysplastic osteoarthritis in all patients, and the patients were followed up for at least 4 years.ResultsThe postoperative improvement of motion in hip flexion was significantly greater in patients treated with simultaneous procedures compared to patients with two-stage THA and unilateral THA for bilateral disease. The differences in improvement of motion in hip abduction were less marked than the improvement in hip flexion among the groups. Although there were no significant differences in pain scores among the groups, the values for activity of daily living were significantly greater in patients treated with simultaneous bilateral THA and patients with unilateral THA for unilateral disease than in patients with unilateral and two-stage bilateral THA for bilateral disease.ConclusionsThe simultaneous procedure was considered to be more effective in patients with bilateral hip osteoarthritis and demonstrated a substantial improvement in hip motion and functional recovery after THA.

Is closed suction drainage effective in early recovery of hip joint function? Comparative evaluation in one-stage bilateral total hip arthroplasty.

One-stage primary bilateral cementless total hip arthroplasty with unilateral closed suction drainage (CSD) was prospectively performed for 51 patients (102 hips), and local effects of CSD were quantitatively evaluated. Postoperatively, pain scores evaluated by visual analog scale and periwound temperatures measured by thermography were lower in the CSD side than the non-CSD side. CT measurements also showed that postoperative cross-sectional area of the thigh was smaller in the CSD side. Active straight leg raising and weight bearing were more accelerated in the CSD side., showing earlier recovery of hip joint function. CSD for hip arthroplasty has an advantage in reducing postoperative local inflammation and be recommended from the viewpoint of postoperative pain relief and early recovery of hip joint function.

Is Drain Tip Culture Prognostic of Surgical Site Infection? Results of 1380 Drain Tip Cultures in Total Hip Arthroplasty

The purpose of this study was to evaluate a prognostic value of drain tip culture for surgical site infection (SSI) after total hip arthroplasty. A total of 1380 closed suction drain tips cultured after removal in primary total hip arthroplasty were included in this study. Drains were removed in 12-72 hours after surgery. Drain tip cultures were positive in 11 cases (0.8%). SSI was found in 4 cases (0.3%), where the drain tip cultures were all negative. The sensitivity of drain tip culture for infection after surgery was 0%, and the specificity was 99.7%. We concluded that, drain tip culture cannot be prognostic for SSI after total hip arthroplasty. Routine use of drain tip culture is not supported.

Technical Evaluation: Identification of Pathogenic Mutations in PKD1 and PKD2 in Patients with Autosomal Dominant Polycystic Kidney Disease by Next-Generation Sequencing and Use of a Comprehensive New Classification System.

Genetic testing of PKD1 and PKD2 is expected to play an increasingly important role in determining allelic influences in autosomal dominant polycystic kidney disease (ADPKD) in the near future. However, to date, genetic testing is not commonly employed because it is expensive, complicated because of genetic heterogeneity, and does not easily identify pathogenic variants. In this study, we developed a genetic testing system based on next-generation sequencing (NGS), long-range polymerase chain reaction, and a new software package. The new software package integrated seven databases and provided access to five cloud-based computing systems. The database integrated 241 polymorphic nonpathogenic variants detected in 140 healthy Japanese volunteers aged >35 years, who were confirmed by ultrasonography as having no cysts in either kidney. Using this system, we identified 60 novel and 30 known pathogenic mutations in 101 Japanese patients with ADPKD, with an overall detection rate of 89.1% (90/101) [95% confidence interval (CI), 83.0%–95.2%]. The sensitivity of the system increased to 93.1% (94/101) (95% CI, 88.1%–98.0%) when combined with multiplex ligation-dependent probe amplification analysis, making it sufficient for use in a clinical setting. In 82 (87.2%) of the patients, pathogenic mutations were detected in PKD1 (95% CI, 79.0%–92.5%), whereas in 12 (12.8%) patients pathogenic mutations were detected in PKD2 (95% CI, 7.5%–21.0%); this is consistent with previously reported findings. In addition, we were able to reconfirm our pathogenic mutation identification results using Sanger sequencing. In conclusion, we developed a high-sensitivity NGS-based system and successfully employed it to identify pathogenic mutations in PKD1 and PKD2 in Japanese patients with ADPKD.

Comparison of different distal designs of femoral components and their effects on bone remodeling in 1-stage bilateral total hip arthroplasty.

To evaluate the effects of distal design of a proximally coated femoral component on periprosthetic bone remodeling, we prospectively performed 21 one-stage bilateral total hip arthroplasties using a distally tapered and a distally cylindrical stem with the same proximal design, randomized to side. All hips showed good outcomes clinically and radiographically at the final follow-up, average of 7 years postoperatively. Cancellous condensation was always found in Gruens zones 2 and 6 around the cylindrical stem and in regions between zones 2 and 3 and between zones 6 and 5 around the tapered stem. Bone mineral density of Gruens zones 2 and 6 was significantly lower around the tapered stem. These results suggested more distal loading in hips with the tapered stem than in those with the cylindrical stem.

Comparison of Different Materials and Proximal Coatings Used for Femoral Components in One-Stage Bilateral Total Hip Arthroplasty

To evaluate the mid-term effects of different materials and coatings used for femoral components, we prospectively performed 21 one-stage bilateral total hip arthroplasties using 2 anatomical stems which have identical geometries, randomized to side. One stem was made of Ti6Al4V alloy and had a hydroxyapatite coating on grit-blasted surface proximally, and the other was made of TMZF™ alloy and had a proximal coating of hydroxyapatite in addition to an arc-deposited titanium surface coating. Although we found extensions of radiopaque lines to the surface of coatings of seven grit-blasted stems whereas we found none in the case of the arc-deposited titanium stems, all hips showed excellent clinical and radiological outcomes as shown by radiographs and bone mineral density at the final follow-up, average 5.5 years postoperatively.

Comparison of wear rate and osteolysis between second-generation annealed and first-generation remelted highly cross-linked polyethylene in total hip arthroplasty. A case control study at a minimum of five years

BACKGROUND There is no previous report that directly compared wear resistance of second-generation annealed highly cross-linked polyethylene with that of first-generation remelted highly cross-linked polyethylene. We therefore performed a retrospective study at a minimum of 5-year follow-up comparing second-generation annealed and first-generation remelted highly cross-linked polyethylene in order to: (1) assess wear rates and (2) compare the incidence of osteolysis between, (3) identify the frequency of complication related to the two types of highly cross-linked polyethylene. HYPOTHESIS There is a difference in the linear wear rate and the incidence of osteolysis between the two types of highly cross-linked polyethylene in total hip arthroplasty. MATERIALS AND METHODS In a single centre study, we reviewed 123 primary cementless total hip arthroplasties between 2010 and 2011 that were performed with 32mm alumina ceramic on second-generation annealed (X3) or first-generation remelted (Longevity) highly cross-linked polyethylene liner. There was no specific reason for the choice of the type of highly cross-linked polyethylene. There were no significant differences between the two groups in respect of gender, diagnosis, body mass index, pre- and post-operative functional and activity score, cup size, and cup orientation except the younger age in the X3 group. The mean wear rate and the incidence of osteolysis were evaluated at the latest follow-up. RESULTS One hundred nine cases followed over 5 years post-operatively (88.6% in all consecutive cases) were evaluated. X3 and Longevity were used in 54 and 55 cases, respectively. The mean follow-up was 5.3 years in both groups. The mean linear wear rate of X3 and Longevity group was 0.045±0.023mm/year and 0.076±0.031mm/year, respectively (P<0.001). No osteolysis was found on plain X-rays in both groups and no specific complication was related to these highly cross-linked components. DISCUSSION Excellent wear resistance of both types of highly cross-linked polyethylene liner was revealed in our study. The difference of wear rate between two materials should be monitored in a longer follow-up. LEVEL OF EVIDENCE Level III retrospective case control study.