Yuanqing Mao

Inhibition of titanium particle-induced osteoclastogenesis through inactivation of NFATc1 by VIVIT peptide

Osteoclastogenesis induced by particulate wear debris is a major pathological factor contributing to periprosthetic osteolysis. Although the nuclear factor of activated T cells c1 (NFATc1) is known to be involved in osteoclast differentiation, its effect on osteoclastogenesis in response to wear particles remains unclear. In the present study, we investigated the role of NFATc1 in the regulation of osteoclast differentiation from bone marrow macrophages (BMMs) stimulated with titanium (Ti) particles. The results showed that Ti particles could stimulate BMMs to produce proinflammatory cytokines (tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, and IL-6) and differentiate into multinucleated osteoclasts in the presence of receptor activator of nuclear factor-kappaB ligand (RANKL). NFATc1 was expressed in BMMs and multinucleated cells cultured with Ti particles and RANKL. Inactivation of NFATc1 by 11R-VIVIT peptide potently impeded the Ti particle-induced osteoclastogenesis. 11R-VIVIT peptide does not have toxic effect on BMMs. Based on these data, we conclude that inactivation of NFATc1 by VIVIT peptide would provide a promising therapeutic target for the treatment of periprosthetic osteolysis.

Strontium ranelate reduces cartilage degeneration and subchondral bone remodeling in rat osteoarthritis model.

Aim:To investigate whether strontium ranelate (SR), a new antiosteoporotic agent, could attenuate cartilage degeneration and subchondral bone remodeling in osteoarthritis (OA).Methods:Medial meniscal tear (MMT) operation was performed in adult SD rats to induce OA. SR (625 or 1800 mg·kg−1·d−1) was administered via gavage for 3 or 6 weeks. After the animals were sacrificed, articular cartilage degeneration was evaluated using toluidine blue O staining, SOX9 immunohistochemistry and TUNEL assay. The changes in microarchitecture indices and tissue mineral density (TMD), chemical composition (mineral-to-collagen ratio), and intrinsic mechanical properties of the subchondral bones were measured using micro-CT scanning, confocal Raman microspectroscopy and nanoindentation testing, respectively.Results:The high-dose SR significantly attenuated cartilage matrix and chondrocyte loss at 6 weeks, and decreased chondrocyte apoptosis, improved the expression of SOX9, a critical transcription factor responsible for the expression of anabolic genes type II collagen and aggrecan, at both 3 and 6 weeks. Meanwhile, the high-dose SR also significantly attenuated the subchondral bone remodeling at both 3 and 6 weeks, as shown by the improved microarchitecture indices, TMD, mineral-to-collagen ratio and intrinsic mechanical properties. In contrast, the low-dose SR did not significantly change all the detection indices of cartilage and bone at both 3 and 6 weeks.Conclusion:The high-dose SR treatment can reduce articular cartilage degeneration and subchondral bone remodeling in the rat MMT model of OA.

Risk Factors for Periprosthetic Joint Infection after Total Hip Arthroplasty and Total Knee Arthroplasty in Chinese Patients

Purpose The purpose of this hospital-based case–control study was to evaluate the risk factors for periprosthetic joint infection (PJI) of total hip arthroplasty (THA) and total knee arthroplasty (TKA) in Chinese patients. Method From January 2000 to December 2012, 45 patients undergoing THA and TKA who developed PJI were recruited for case subjects; controls were 252 without PJI, matched by year of index for surgery and type of surgery. Conditional logistic regressions were run to compute odds ratios (ORs) and 95% confidence intervals (CIs). Results Demographic factors and comorbid conditions associated with an increased adjusted risk of PJI (in decreasing order of significance) were diabetes (OR = 5.47, 95% CI: 1.77–16.97; p = 0.003), age (65–75 vs. 45–65 years) (OR = 3.36, 95% CI: 1.30–8.69; p = 0.013), BMI (≥28 vs. 18.5–28 kg/m2) (OR = 2.77, 95% CI: 1.20–6.40; p = 0.017), place of residence (rural) (OR = 2.63, 95% CI: 1.13–6.10; p = 0.025) and alcohol abuse (OR = 2.95, 95% CI: 1.06–8.23; p = 0.039). Conclusion Patients with diabetes, older age, BMI of ≥28 kg/m2 and alcohol abuse or living in rural areas, had increased PJI risk. Additional systematic large-scale studies are needed to verify these results.

Efficacy of zoledronic acid in treatment of teoarthritis is dependent on the disease progression stage in rat medial meniscal tear model

Aim:To investigate whether the stage of osteoarthritis (OA) progression influenced the efficacy of the third-generation bisphosphonate zoledronic acid in a rat medial meniscal tear model.Methods:Medial meniscal tear (MMT) was surgically induced in adult male Sprague Dawley rats. Zoledronic acid (ZOL, 100 μg/kg, sc, twice a week) was administered starting immediately, early (from 4 weeks) or late (from 8 weeks) after OA induction. The degeneration of articular cartilage was evaluated with toluidine blue O staining. Subchondral bone remodeling was evaluated with X-ray micro-CT scanning. Joint pain was measured with respect to weight-bearing asymmetry. Calcitonin gene-related peptide (CGRP) expression in dorsal root ganglia (DRGs) was examined using immunofluorescence analysis. The afferent neurons in DRGs innervating the joint were identified by retrograde labeling with fluorogold.Results:Progressive cartilage loss was observed during 12 weeks after OA induction. Subchondral bone remodeling manifested as increased bone resorption at early stage (4 weeks), but as increased bone accretion at advanced stages (8 weeks). Immediately and early ZOL administration significantly improved subchondral microstructural parameters, attenuated cartilage degeneration, reduced weight-bearing asymmetry and CGRP expression, whereas the late ZOL administration had no significant effects.Conclusion:The stage of OA progression influences the efficacy of ZOL in treating joint degeneration and pain. To obtain the maximum efficacy, bisphosphonate treatment should be initiated in rat with early stages of OA pathogenesis.

Custom Acetabular Cages Offer Stable Fixation and Improved Hip Scores for Revision THA With Severe Bone Defects.

BackgroundRevision THA is particularly challenging in hips with severe acetabular bone loss. When the extent or geometry of the acetabular bone loss precludes more-straightforward techniques such as jumbo hemispheric cementless shells, reconstruction with morselized allograft protected by a custom cage may offer an alternative, but, to our knowledge, few series have reported on results with this approach.Questions/purposesFor patients with severe (Paprosky IIIB) defects, we asked: do individualized custom cages result in (1) improved Harris hip scores; (2) restoration of hip center; and (3) a low incidence of surgical complications?MethodsTwenty-six patients (26 hips) with a massive acetabular defect were involved in this study from 2003 to 2013. During this period, one patient was lost to followup and one died, leaving 24 patients (eight males, 16 females) in this retrospective analysis. The customized cages were individualized to each patient’s bone defect based on rapid-prototype three-dimensional printed models. Mean followup was 67 months (range, 24–120 months). Harris hip scores were assessed before surgery and at each followup. Postoperative radiographs were evaluated for cage position, migration, and graft incorporation. Complications and reoperations were assessed by chart review.ResultsThe mean Harris hip score improved from 36 (SD, 8; range, 20–49) to 82 (SD, 18; range, 60–96) (p < 0.001). Individualized custom cages resulted in generally reliable restoration of the hip center. No rerevisions have been performed. None of the cups showed radiographic migration, but one cage was believed to be loose, based on a circumferential 2-mm radiolucent line. Cancellous allografts appeared to be incorporated in 23 of 24 patients. One deep infection and one superficial infection were observed and treated with irrigation, débridement, and vacuum-sealing drainage. One dislocation and one suspected injury of the superior gluteal nerve also were observed and treated conservatively.ConclusionsIndividualized custom cages using rapid prototyping and three-dimensional printing appeared to provide stable fixation and improved hip scores at short-term followup in this small, single-center series. As further improvements in the design and manufacturing process are made, future studies should evaluate larger patient groups for longer times, and, ideally, compare this approach with alternatives for these complex bone defects.Level of EvidenceLevel IV, therapeutic study.

The Inhibition of Subchondral Bone Lesions Significantly Reversed the Weight-Bearing Deficit and the Overexpression of CGRP in DRG Neurons, GFAP and Iba-1 in the Spinal Dorsal Horn in the Monosodium Iodoacetate Induced Model of Osteoarthritis Pain

Background Chronic pain is the most prominent and disabling symptom of osteoarthritis (OA). Clinical data suggest that subchondral bone lesions contribute to the occurrence of joint pain. The present study investigated the effect of the inhibition of subchondral bone lesions on joint pain. Methods Osteoarthritic pain was induced by an injection of monosodium iodoacetate (MIA) into the rat knee joint. Zoledronic acid (ZOL), a third generation of bisphosphonate, was used to inhibit subchondral bone lesions. Joint histomorphology was evaluated using X-ray micro computed tomography scanning and hematoxylin-eosin staining. The activity of osteoclast in subchondral bone was evaluated using tartrate-resistant acid phosphatase staining. Joint pain was evaluated using weight-bearing asymmetry, the expression of calcitonin gene-related peptide (CGRP) in the dorsal root ganglion (DRG), and spinal glial activation status using glial fibrillary acidic protein (GFAP) and ionized calcium binding adaptor molecule-1 (Iba-1) immunofluorescence. Afferent neurons in the DRGs that innervated the joints were identified using retrograde fluorogold labeling. Results MIA injections induced significant histomorphological alterations and joint pain. The inhibition of subchondral bone lesions by ZOL significantly reduced the MIA-induced weight-bearing deficit and overexpression of CGRP in DRG neurons, GFAP and Iba-1 in the spinal dorsal horn at 3 and 6 weeks after MIA injection; however, joint swelling and synovial reaction were unaffected. Conclusions The inhibition of subchondral bone lesions alleviated joint pain. Subchondral bone lesions should be a key target in the management of osteoarthritic joint pain.

The use of combined anteversion in total hip arthroplasty for patients with developmental dysplasia of the hip.

The combined anteversion technique has been proposed recently and proved to be an applicable technique in general THA. The corresponding author routinely applied this approach to DDH patients in clinical practice. The current study aimed to provide clinical evidence for this approach. We studied 35 DDH patients (47 hips). Every patient underwent pelvic CT scans before and after surgery and the HHs was recorded. The data indicate a high accuracy of controlling components orientation and satisfactory clinical outcomes. Using this approach, we reduced dislocation risk and got better impingement free range of motion. Therefore, we conclude that combined anteversion is effective for DDH patients who receive a THA. This approach could guarantee stable and functioning joints for DDH patients receiving THA.

Utility of Intraoperative Frozen Section in the Diagnosis of Periprosthetic Joint Infection

Purpose Intraoperative frozen section (FS) is an effective diagnostic test for periprosthetic joint infection (PJI). We evaluated the diagnostic characteristics of single- and multiplex-site intraoperative FS, and evaluated the results of single-site FS combined with those of C-reactive protein (CRP) level and erythrocyte sedimentation rate (ESR) for assessing PJI. Methods We studied 156 painful joint arthroplasties in 152 consecutive patients presenting for revision total joint arthroplasty due to PJI. Receiver operating characteristic analysis was used to determine the optimal cutoff values for CRP level, ESR, and intraoperative FS histopathology. Sensitivity, specificity, positive and negative predictive values, and accuracy of the diagnostic tests were assessed using a 2×2 table. Results We investigated the diagnostic utility of polymorphonuclear leukocyte number (PMN) per high-power field (HPF) on FS. Our data showed that 5 PMNs per HPF is a suitable diagnostic threshold, with a high accuracy in single- and multiplex-site FS. Five PMNs in any 1 of 5 sites had the highest sensitivity of 0.86 and a specificity of 0.96. Five PMNs in every 1 of 5 sites had greater diagnostic utility, with a specificity of 1; however, the sensitivity of this measure fell to 0.62. Five PMNs in single-site FS had a sensitivity of 0.70 and a specificity of 0.94. Five PMNs in single-site FS or CRP level ≥15 mg/L increased the sensitivity to 0.92; however, the specificity decreased to 0.79. Conclusion Compared with single-site FS, any 1 positive site on multiplex-site FS may improve sensitivity, while every 1 positive site on multiplex-site FS may improve specificity. Five PMNs in any 1 of 5 sites on FS has excellent utility for the diagnosis of PJI. Additional systematic large-scale studies are needed to verify this result.

The Inhibition of RANKL-Induced Osteoclastogenesis through the Suppression of p38 Signaling Pathway by Naringenin and Attenuation of Titanium-Particle-Induced Osteolysis

The aim of this study was to assess the effect of naringenin on osteoclastogenesis and titanium particle-induced osteolysis. Osteolysis from wear-induced particles and aseptic loosening are the most frequent late complications of total joint arthroplasty leading to revision of the prosthesis. Osteolysis during aseptic loosening is most likely due to increased bone resorption by osteoclasts. Through in vitro studies, we demonstrated that naringenin, a naturally occurring flavanone in grapefruit and tomatoes, exerts potent inhibitory effects on the ligand of the receptor activator of nuclear factor-κB (RANKL)-induced osteoclastogenesis and revealed that the mechanism of action of naringenin, which inhibited osteoclastogenesis by suppression of the p38 signaling pathway. Through in vivo studies, we proved that naringenin attenuated titanium particle-induced osteolysis in a mouse calvarial model. In general, we demonstrated that naringenin inhibited osteoclastogenesis via suppression of p38 signaling in vitro and attenuated titanium particle-induced osteolysis in vivo. This study also suggested that naringenin has significant potential for the treatment of osteolysis-related diseases caused by excessive osteoclast formation and activity.

Calcineurin/NFAT pathway mediates wear particle-induced TNF-α release and osteoclastogenesis from mice bone marrow macrophages in vitro

Aim:To investigate the roles of the calcineurin/nuclear factor of activated T cells (NFAT) pathway in regulation of wear particles-induced cytokine release and osteoclastogenesis from mouse bone marrow macrophages in vitro.Methods:Osteoclasts were induced from mouse bone marrow macrophages (BMMs) in the presence of 100 ng/mL receptor activator of NF-κB ligand (RANKL). Acridine orange staining and MTT assay were used to detect the cell viability. Osteoclastogenesis was determined using TRAP staining and RT-PCR. Bone pit resorption assay was used to examine osteoclast phenotype. The expression and cellular localization of NFATc1 were examined using RT-PCR and immunofluorescent staining. The production of TNFα was analyzed with ELISA.Results:Titanium (Ti) or polymethylmethacrylate (PMMA) particles (0.1 mg/mL) did not significantly change the viability of BMMs, but twice increased the differentiation of BMMs into mature osteoclasts, and markedly increased TNF-α production. The TNF-α level in the PMMA group was significantly higher than in the Ti group (96 h). The expression of NFATc1 was found in BMMs in the presence of the wear particles and RANKL. In bone pit resorption assay, the wear particles significantly increased the resorption area and total number of resorption pits in BMMs-seeded ivory slices. Addition of 11R-VIVIT peptide (a specific inhibitor of calcineurin-mediated NFAT activation, 2.0 μmol/L) did not significantly affect the viability of BMMs, but abolished almost all the wear particle-induced alterations in BMMs. Furthermore, VIVIT reduced TNF-α production much more efficiently in the PMMA group than in the Ti group (96 h).Conclusion:Calcineurin/NFAT pathway mediates wear particles-induced TNF-α release and osteoclastogenesis from BMMs. Blockade of this signaling pathway with VIVIT may provide a promising therapeutic modality for the treatment of periprosthetic osteolysis.