Impaired Autophagy in the Fibroblasts by Titanium Particles Increased the Release of CX3CL1 and Promoted the Chemotactic Migration of Monocytes.

Aseptic loosening (AL) is the most frequent cause of failure of total hip arthroplasties (THA). Prosthetic wear particle-induced monocyte recruitment to the periprosthetic tissue and subsequent inflammatory response are thought to be the major contribution to AL. Fibroblast is a dominant cell type in interfacial membrane (IFM) which is the main pathological feature of periprosthetic osteolysis in failed THAs. Considering the role of fibroblasts, as sentinel cells, in the synthesis of chemokines and regulation of inflammation, we hypothesize that fibroblasts might be involved in the monocyte recruitment in the pathogenesis of periprosthetic osteolysis associated with particle debris. This study explored the induction of fibroblasts on the monocyte recruitment. The results showed that titanium (Ti) particle-stimulated fibroblasts isolated from IFMs of loosened THAs significantly promoted the chemotactic migration of THP-1 cells by increasing the release of CX3CL1 (C-X3-C motif chemokine ligand 1). Further investigation demonstrated that Ti particle stimulation increased the expression of ADAM10 (ADAM metallopeptidase domain 10) by impairing autophagy in the fibroblasts and in turn increased the cleavage and shedding of CX3CL1. Thus, we propose a new insight to the pathogenesis of aseptic loosening which implies that autophagy-ADAM10-CX3CL1 signaling pathway in fibroblasts can be leveraged to alleviating inflammation caused by monocyte recruitment in aseptic loosening and improving performance of articulation of the joint device.

Local Dynamic Stability of the Locomotion of Lower Extremity Joints and Trunk During Backward Upslope Walking.

Backward slope walking was considered as a practical rehabilitation and training skill. However, its gait stability has been hardly studied, resulting in its limited application as a rehabilitation tool. In this study, the effect of walking direction and slope grade were investigated on the local dynamic stability of the motion of lower extremity joints and trunk segment during backward and forward upslope walking (BUW/FUW). The local divergence exponents (λS) of 16 adults were calculated during their BUW and FUW at grades of 0%, 5%, 10%, and 15%. Mean standard deviation over strides (MeanSD) was analyzed as their gait variability. Backward walking showed larger λS for the abduction-adduction and rotational angles of knee and ankle on inclined surface than forward walking, while λS for hip flexion-extension angle at steeper grades was opposite. No grade effect for any joint existed during BUW, while λS increased with the increasing grade during FUW. As to the trunk, walking direction did little impact on λS. Still, significant larger λS for its medial-lateral and vertical motion were found at the steeper grades during both FUW and BUW. Results indicate that during BUW, the backward direction may influence the stability of joint motions, while the trunk stability was challenged by the increasing grades. Therefore, BUW may be a training tool for the stability of both upper and lower body motion during gait.

Functional differences between AMPK α1 and α2 subunits in osteogenesis, osteoblast-associated induction of osteoclastogenesis, and adipogenesis.

The endocrine role of the skeleton-which is impaired in human diseases including osteoporosis, obesity and diabetes-has been highlighted previously. In these diseases, the role of AMPK, a sensor and regulator of energy metabolism, is of biological and clinical importance. Since AMPK's main catalytic subunit α has two isoforms, it is unclear whether functional differences between them exist in the skeletal system. The current study overexpressed AMPKα1 and α2 in MC3T3-E1 cells, primary osteoblasts and mouse BMSCs by lentiviral transduction. Cells overexpressing AMPKα2 showed higher osteogenesis potential than AMPKα1, wherein androgen receptor (AR) and osteoactivin played important roles. RANKL and M-CSF were secreted at lower levels from cells overexpressing α2 than α1, resulting in decreased osteoblast-associated osteoclastogenesis. Adipogenesis was inhibited to a greater degree in 3T3-L1 cells overexpressing α2 than α1, which was modulated by AR. An abnormal downregulation of AMPKα2 was observed in human BMSCs exhibiting the fibrous dysplasia (FD) phenotype. Overexpression of AMPKα2 in these cells rescued the defect in osteogenesis, suggesting that AMPKα2 plays a role in FD pathogenesis. These findings highlight functional differences between AMPKα1 and α2, and provide a basis for investigating the molecular mechanisms of diseases associated with impaired functioning of the skeletal system.

AMPK promotes osteogenesis and inhibits adipogenesis through AMPK-Gfi1-OPN axis.

Several metabolic, genetic and oncogenic bone diseases share the common pathological phenotype of defective bone marrow stromal cell (BMSC) differentiation. Many reports in bone science in the past several years have suggested that the skeleton also has an endocrine role. The role of AMP-activated protein kinase (AMPK) as an energy metabolism sensor and how it regulates BMSC differentiation is largely unknown. In the current study, we used AMPK agonists to activate AMPK in MC3T3-E1 cells to investigate the functional roles of AMPK in osteogenesis. However, metformin and AICAR failed to activate AMPK consistently. Therefore, we established MC3T3-E1 and 3T3-L1 cell models of AMPK α subunit overexpression through lentivirus vector, in which AMPK was overactivated. AMPK hyperactivation stimulated MC3T3-E1 cell osteogenesis and inhibited 3T3-L1 cell adipogenesis. Osteopontin (OPN) mediated AMPK regulation of osteogenesis and adipogenesis. Furthermore, we provided evidence that the transcriptional repressor growth factor independence-1 (Gfi1) was downregulated and disassociated from the OPN promoter in response to AMPK activation, resulting in the upregulation of OPN. Overexpression of wild-type and dominant-negative Gfi1 modulated MC3T3-E1 osteogenesis and 3T3-L1 adipogenesis. Further evidence suggested that AMPK enhanced ectopic bone formation of MC3T3-E1 cells through the AMPK-Gfi1-OPN axis. In conclusion, AMPK was sufficient to stimulate osteogenesis of MC3T3-E1 cells and inhibit adipogenesis of 3T3-L1 cells through the AMPK-Gfi1-OPN axis. These findings helped elucidate the molecular mechanisms underlying AMPK regulation of osteogenesis and adipogenesis.

Effect of active arm swing to local dynamic stability during walking.

Arm swing is an essential component in regulating dynamic stability of the whole body during walking, while the contribution of active arm swing to local dynamic stability of different motion segments remains unclear. This study investigated the effects of arm swing under natural arm swing condition and active arm swing condition on local dynamic stability and gait variability of the trunk segments (C7 and T10 joint) and lower extremity joints (hip, knee and ankle joint). The local divergence exponents (λs) and mean standard deviation over strides (MeanSD) of 24 young healthy adults were calculated while they were walking on treadmill with two arm swing conditions at their preferred walking speed (PWS). We found that in medial-lateral direction, both λs and MeanSD values of the trunk segments (C7 and T10 joint) in active arm swing condition were significantly lower than those in natural arm swing condition (p<0.05), while no significant difference of λs or MeanSD in lower extremity joints (hip, knee and ankle joint) was found between two arm swing conditions (p>0.05, respectively). In anterior-posterior and vertical direction, neither λs nor MeanSD values of all body segments showed significant difference between two arm swing conditions (p>0.05, respectively). These findings indicate that active arm swing may help to improve the local dynamic stability of the trunk segments in medial-lateral direction.

CXCR1 knockdown improves the sensitivity of osteosarcoma to cisplatin.

Chemotherapy resistance is a major cause of poor prognoses for osteosarcoma patients. This study aimed to determine whether CXCR1 gene knockdown improves the sensitivity of osteosarcomas to chemotherapy. Both CXCR1 expression and cisplatin sensitivity were investigated and compared in two osteosarcoma cell lines. Sensitivity to the chemotherapy drug cisplatin and apoptosis were investigated with or without stimulation via Interleukin-8 (IL-8), which is a ligand of CXCR1. Furthermore, activation of the Akt signaling pathway was determined. Finally, luciferase-labeled CXCR1-knockdown Saos2-lung cells were injected into the tibiae of nude mice that were treated with cisplatin thereafter. We found that CXCR1 expression and cisplatin sensitivity were negatively correlated in osteosarcoma cell lines. IL-8-induced reduction in sensitivity could be blocked by silencing CXCR1, and CXCR1 knockdown suppressed the Akt signaling pathway. Moreover, CXCR1-knockdown tumors were significantly smaller than control tumors, which was consistent with the luciferase intensity results. The expression levels of IL-8, CXCR1 and p-Akt were suppressed in CXCR1-knockdown cells. Taken together, these data indicate that CXCR1 gene knockdown in osteosarcoma cells improved the sensitivity to chemotherapy and that this process might be regulated in part by the IL-8/CXCR1/Akt signaling pathway.

Bilateral decompression using a unilateral pedicle construct for lumbar stenosis.

PURPOSE: To determine the effectiveness of bilateral decompression via a unilateral approach using unilateral pedicle screw fixation for two-level lumbar stenosis with instability. METHODS: Between October 2006 and October 2010, 98 patients (61 men and 37 women) who had reached the three-year follow-up interval were treated with unilateral pedicle screw fixation at the authors' institution. All patients underwent two-level transforaminal lumbar interbody fusion (TLIF), and the mean age was 59.6 years (range, 40-72). Visual analog scale (VAS) scores and Oswestry Disability Index (ODI) were used to assess the pre-operative and postoperative clinical results. Fusion status, the disc space height, and the whole lumbar lordotic angle were analysed for the radiological evaluation. RESULTS: The ODI scores decreased significantly in both early and late follow-up evaluations and the visual analog scale (VAS) score demonstrated significant improvement in late follow-up (P < 0.01). The disc space height (P < 0.05) and the whole lumbar lordotic angle (P < 0.05) were increased at the final follow-up. Successful fusion was achieved in all patients. CONCLUSION: Bilateral decompression via a unilateral approach using unilateral pedicle screw fixation for two-level lumbar stenosis with instability, which can maintain the lumbar lordosis and the disc space height, is an effective and less invasive method than with bilateral constructs.

Comprehensive treatment for gas gangrene of the limbs in earthquakes.

BACKGROUND: Mortality rates for patients with gas gangrene from trauma or surgery are as high as 25%, but they increase to 50%-80% for patients injured in natural hazards. Early diagnosis and treatment are essential for these patients. METHODS: We retrospectively analyzed the clinical characteristics and therapeutic results of 19 patients with gas gangrene of the limbs, who were injured in the May 2008 earthquake in the Wenchuan district of China's Sichuan province and treated in our hospital, to seek how to best diagnose and treat earthquake-induced gas gangrene. RESULTS: Of 226 patients with limbs open injuries sustained during the earthquake, 53 patients underwent smear analysis of wound exudates and gas gangrene was diagnosed in 19 patients. The average elapsed time from injury to arrival at the hospital was 72 hours, from injury to definitive diagnosis was 4.3 days, and from diagnosis to conversion of negative findings on wound smear analysis to positive findings was 12.7 days. Anaerobic cultures were also obtained before wound closure. The average elapsed time from completion of surgery to recovery of normal vital signs was 6.3 days. Of the 19 patients, 16 were treated with open amputation, two with closed amputation, and 1 with successful limb salvage; 18 patients were successfully treated and one died. CONCLUSIONS: In earthquakes, rapid, accurate screening and isolation are essential to successful treatment of gas gangrene and helpful in preventing nosocomial diffusion. Early and thorough debridement, open amputation, and active supportive treatment can produce satisfactory therapeutic results.

Mesoporous bioactive glass as a drug delivery system: fabrication, bactericidal properties and biocompatibility.

Implant-associated infection remains a difficult medical problem in orthopaedic surgery. Here, we report on the fabrication of gentamicin-loaded mesoporous bioactive glass (Gent-MBG) for use as a controlled antibiotic delivery system to achieve the sustained release of antibiotics in the local sites of bone defects. The high surface area and mesoporous structure of MBG enable higher drug loading efficiency (79-83 %) than non-mesoporous biological glass (NBG) (18-19 %). Gent-MBG exhibits sustained drug release for more than 6 days, and this controlled release of gentamicin significantly inhibits bacterial adhesion and prevents biofilm formation by S. aureus (ATCC25923) and S. epidermidis (ATCC35984). Biocompatibility tests with human bone marrow stromal cells (hBMSCs) indicate that MBG has better biocompatibility than NBG. Therefore, Gent-MBG can be used as a controlled drug delivery system to prevent and/or treat orthopedic peri-implant infections.

Long-term effects of alendronate on fracture healing and bone remodeling of femoral shaft in ovariectomized rats.

AIM: To investigate the long-term effects of alendronate (Aln), a widely used oral bisphosphonate, on fracture healing and bone remodeling in ovariectomized rats. METHODS: Adult female SD rats underwent ovariectomy, and then bilateral femoral osteotomy at 12 weeks post-ovariectomy. From d 2 post-ovariectomy, the animals were divided into 3 groups, and treated with Aln (3 mg·kg(-1)·d(-1), po) for 28 weeks (Aln/Aln), Aln for 12 weeks and saline for 16 weeks (Aln/Saline) or saline for 28 weeks (Saline/Saline). At 6 and 16 weeks post-fracture, the fracture calluses were examined with X-ray radiography, and biomechanical testing and histological analysis were performed. The calluses were labeled with tetracycline and calcein to evaluate the mineral apposition rate (MAR). RESULTS: The fracture line was less distinct in the 2 Aln-treated groups at 6 weeks post-fracture, and disappeared in all the 3 groups at 16 weeks post-fracture. The size of the callus and radiographic density of the femora in the Aln/Aln group were the highest among the 3 groups at 6 and 16 weeks post-fracture. Similar results were observed in the ultimate load at failure and energy absorption. However, the treatment with Aln delayed endochondral ossification of the callus, and significantly increased the total sagittal-sectional area, percentage callus area and callus thickness, and decreased the MAR at 6 and 16 weeks post-fracture. CONCLUSION: In the ovariectomized rat model, Aln is beneficial for the mechanical properties of the callus, but delays callus remodeling by suppressing the remodeling of woven bone into lamellar bone.

Effects of Baduanjin () exercise on knee osteoarthritis: a one-year study.

OBJECTIVES: Knee osteoarthritis (OA) is a major cause of pain and functional limitation. Short-term Baduanjin () exercise had been testified to be beneficial to the disease. This study conducted an initial assessment of the one-year Baduanjin exercise on knee OA. METHODS: The recruited patients practiced Baduanjin at the community recreational center. Sessions were held for 30 min five times a week for one year. Knee pain, stiffness, physical disability, general health, knee extensors and flexors strength, and aerobic ability were measured using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), the Medical Outcomes Study Short Form-36 (SF-36), the 6-Minute Walk Test (6-MWT), and the Isokinetic Strength of the Knee Extensors and Flexors (ISKEF). Body mass index (BMI) was also calculated before and after the study period for comparison. RESULTS: Twenty-eight patients signed the informed consent. Six patients withdrew from the trial. Twenty-two patients (29 knees) completed the one-year study. After one-year Baduanjin exercise, WOMAC pain (132.0±69.6 vs. 56.2±67.6, P=0.000), stiffness (64.7±54.8 vs. 22.3±34.6, P=0.000), and physical function subscales (386.1±275.8 vs. 182.0±235.7, P=0.003); SF-36 body pain (45.7±20.0 vs. 57.4±17.9, P=0.005), general health (50.5±20.0 vs. 62.1±16.1, P=0.004), role emotional (64.4±26.1 vs. 73.5±21.3, P=0.047), and health transition (3.3±1.0 vs. 2.6±1.0, P=0.008); BMI (25.0±2.9 vs. 24.4±2.9, P=0.032); 6-MWT (565.7±94.6 vs. 610.5±66.7, P=0.036); and ISKEF Peak Torque (the Knee Extensors: 60.5±25.5 vs. 76.8±31, P=0.000; the Knee Flexors: 29.3±15.9 vs. 37.1±15.8, P=0.001) were significantly improved. No adverse effects resulted from the exercise. CONCLUSIONS: It suggested that the long-term Baduanjin could be a feasible and safe exercise option for knee OA.

Effects of sex and lower extremity alignment on orientation of the knee joint line in knee surgery.

BACKGROUND: Determination of the proper orientation of the knee articular surface is required both for correction of knee malalignment by osteotomy and for correct component alignment in knee arthroplasty. We sought to determine whether the patients' sex and lower extremity alignment (hip-knee-ankle angle) affects proper knee realignment in osteotomy or component alignment in total knee arthroplasty. METHODS: We examined 199 healthy adult knees with malalignment of < 5° to determine the mechanical medial distal femoral angle, mechanical medial proximal tibial angle, surgical transepicondylar axis angle, and discrepancies between bone-cut orientations of osteotomy or total knee arthroplasty and the joint line of the distal femoral condyles, posterior femoral condyles and proximal tibial plateaus, using a three-dimensional computed tomography model. RESULTS: The mean mechanical medial distal femoral angle and mean mechanical medial proximal tibial angle were (94.4 ± 1.9)° and (87.6 ± 1.8)° respectively for women and (93.8 ± 2.0)° and (87.1 ± 1.4)° respectively for men. The surgical transepicondylar axis angle was (2.9 ± 1.6)° for women and (3.2 ± 1.7)° for men. Independent of sex, the hip-knee-ankle angle was closely related to the mechanical medial distal femoral angle and mechanical medial proximal tibial angle, but not to the surgical transepicondylar axis angle. A slightly more valgus alignment of the knee and a more valgus angulation of the distal femoral joint line were found in women, whereas a more varus angulation of the proximal tibial joint line was found in men. Sex had the greatest effect on knee joint line orientation when the lower extremity was valgus in alignment. CONCLUSIONS: A more valgus femoral joint line can be expected in women and in persons with valgus lower extremity alignment; a more varus tibial joint line can be found in men and in persons with varus lower extremity alignment.

Prevention of wear particle-induced osteolysis by a novel V-ATPase inhibitor saliphenylhalamide through inhibition of osteoclast bone resorption.

Wear particle-induced peri-implant loosening (Aseptic prosthetic loosening) is one of the most common causes of total joint arthroplasty. It is well established that extensive bone destruction (osteolysis) by osteoclasts is responsible for wear particle-induced peri-implant loosening. Thus, inhibition of osteoclastic bone resorption should prevent wear particle induced osteolysis and may serve as a potential therapeutic avenue for prosthetic loosening. Here, we demonstrate for the first time that saliphenylhalamide, a new V-ATPase inhibitor attenuates wear particle-induced osteolysis in a mouse calvarial model. In vitro biochemical and morphological assays revealed that the inhibition of osteolysis is partially attributed to a disruption in osteoclast acidification and polarization, both a prerequisite for osteoclast bone resorption. Interestingly, the V-ATPase inhibitor also impaired osteoclast differentiation via the inhibition of RANKL-induced NF-κB and ERK signaling pathways. In conclusion, we showed that saliphenylhalamide affected multiple physiological processes including osteoclast differentiation, acidification and polarization, leading to inhibition of osteoclast bone resorption in vitro and wear particle-induced osteolysis in vivo. The results of the study provide proof that the new generation V-ATPase inhibitors, such as saliphenylhalamide, are potential anti-resorptive agents for treatment of peri-implant osteolysis.

The CREB-Smad6-Runx2 axis contributes to the impaired osteogenesis potential of bone marrow stromal cells in fibrous dysplasia of bone.

Fibrous dysplasia (FD) is characterized by the replacement of normal bone with abnormal fibro-osseous tissue. This disorder is due to activating missense mutations in the GNAS gene and resultant over-production of cAMP. However, the signalling pathways that contribute to FD pathogenesis remain unknown. In the current study, bone marrow stromal cells (BMSCs) carrying GNAS R201H mutation were isolated from lesion site of FD patients. cAMP accumulation, enhanced proliferation and impaired osteogenesis potential were observed. Two cell models, BMSCs treated with excess exogenous cAMP and BMSCs infected with lentivirus GNAS R201H, were established to model the pathological conditions of FD and used to investigate its pathogenesis. The results suggest that the CREB-Smad6-Runx2 axis is involved in osteogenesis dysfunction of BMSCs with the FD phenotype. We confirmed the results in FD lesion-derived BMSCs and observed that the impaired osteogenesis potential of BMSCs infected with lentivirus GNAS (R201H) was recovered in vitro through modulation of the CREB-Smad6-Runx2 axis. This study provides useful insight into the signalling pathways involved in the FD phenotype and facilitates dissection of the molecular pathogenesis of FD and testing of novel therapies.

Contribution of arm swing to dynamic stability based on the nonlinear time series analysis method.

It is human nature to swing their arms at the frequency of leg motion during walking, but the contribution of arm swing to dynamic stability of human motion segments was poorly understood. Based on the nonlinear time series analysis method, the objective of this study was to investigate the effects of arm swing in three conditions (natural, active and restricted arm swing) on the dynamic stability of spine and lower extremity joints, and to further assess the contribution of arm swing to the human dynamic stability in relation with age. Gait experiments were carried out for 10 young and 8 middle-aged healthy volunteers while walking with natural, active and restricted arm swing. The maximum finite time lyapunov exponents were calculated to quantify the local dynamic stability of spine and lower extremity joints under three arm swing conditions, and the percentage change of the maximum Lyapunov exponents was compared between two groups to evaluate the effectiveness of active arm swing in relation with age. For both young and middle-aged groups, no significant difference of the maximum lyapunov exponents of all motion segments was found between walking with natural arm swing and with restricted arm swing (P>0.05). However, the maximum lyapunov exponents of all motion segments while walking with active arm swing was significantly lower than those while walking with natural arm swing and restricted arm swing, respectively (P<0.05), and the percentage decrease of the maximum lyapunov exponents for all motion segments while walking with active arm swing was significantly higher in middle-aged group than in young group (P<0.05). These results indicated that active arm swing would help to improve dynamic stability of human motion segments, especially more effective with age.

Nickel-titanium shape-memory sawtooth-arm embracing fixator for periprosthetic femoral fractures.

PURPOSE: We reviewed data to determine outcomes for 21 consecutive Vancouver type B1 or type C periprosthetic fractures that we treated between 2001 and 2008 using a nickel-titanium shape-memory sawtooth-arm embracing fixator. METHODS: The study participants were 12 men and 9 women (mean age, 70.8 years; range, 42-85 years). The average duration of follow-up monitoring was 39.7 months (range, 1-78 months). In five cases, cables and screws were used for further stabilisation. No bone grafting was performed for any of the patients. RESULTS: Results were satisfactory, except for one patient who died one month after surgery from a cause unrelated to arthroplasty. Bone union was achieved in the remaining 20 cases within an average of 5.25 months. No implant failures or malunions occurred in any of the patients. The average Harris hip score at the final follow-up examination was 79.3 points. CONCLUSIONS: Our results show that the embracing fixator is a valid alternative treatment for Vancouver type B1 or type C periprosthetic femoral fractures.

An experimental study of artificial murine bladder reflex arc established by abdominal reflex.

BACKGROUND: The neurogenic bladder dysfunction caused by spinal cord injury is difficult to treat clinically. The aim of this research was to establish an artificial bladder reflex arc in rats through abdominal reflex pathway above the level of spinal cord injury, reinnervate the neurogenic bladder and restore bladder micturition. METHODS: The outcome was achieved by intradural microanastomosis of the right T13 ventral root to S2 ventral root with autogenous nerve grafting, leaving the right T13 dorsal root intact. Long-term function of the reflex arc was assessed from nerve electrophysiological data and intravesical pressure tests during 8 months postoperation. Horseradish peroxidase (HRP) tracing was performed to observe the effectiveness of the artificial reflex. RESULTS: Single stimulus (3 mA, 0.3 ms pulses, 20 Hz, 5-second duration) on the right T13 dorsal root resulted in evoked action potentials, raised intravesical pressures and bladder smooth muscle, compound action potential recorded from the right vesical plexus before and after the spinal cord transaction injury between L5 and S4 segmental in 12 Sprague-Dawley rats. There were HRP labelled cells in T13 ventral horn on the experimental side and in the intermediolateral nucleus on both sides of the L6-S4 segments after HRP injection. There was no HRP labelled cell in T13 ventral horn on the control side. CONCLUSION: Using the surviving somatic reflex above the level of spinal cord injury to reconstruct the bladder autonomous reflex arc by intradural microanastomosis of ventral root with a segment of autologous nerve grafting is practical in rats and may have clinical applications for humans.

siRNA therapy for cancer and non-lethal diseases such as arthritis and osteoporosis.

IMPORTANCE OF THE FIELD: Gene silencing mediated by siRNA has been widely investigated as a potential therapeutic approach. The success of these therapies depends on effective systems capable of selectively and efficiently conveying siRNA to targeted cells/organs with minimal toxicity. AREAS COVERED IN THIS REVIEW: This review discusses current experimental approaches to siRNA delivery strategies available for arthritis treatment and the management of other musculoskeletal disorders. The review covers literature on the subject from 2000 to 2010. WHAT THE READER WILL GAIN: In the last decade, extensive improvements have been made to optimize siRNA-based gene therapy and have been tested on several arthritis and orthopedic conditions. However, except for Phase I - II DNA-based gene therapy trials on arthritis, no clinical studies have reported siRNA application in these domains. TAKE HOME MESSAGE: Most musculoskeletal disorders, such as rheumatoid arthritis, osteoarthritis, fracture, aseptic loosening, cartilage and intervertebral disc degeneration are non-fatal and age-related chronic inflammatory conditions, but represent significant morbidity and a socio-economic burden. siRNA-based gene therapy offers treatment opportunities that are less invasive, more effective and less expensive than existing modalities. Future directions for siRNA therapy include the development of safe and more efficient delivery systems and the selection of optimal gene targets for disease control.

New variables for measuring joint space width to evaluate knee osteoarthritis.

BACKGROUND: Assessing the radiographic features of knee osteoarthritis (OA), especially joint space narrowing, is important for evaluating disease progression. The purpose of this study was to quantitatively analyze joint space narrowing by measuring 2 new variables: the average joint space width (aJSW) and the articulate angle (AA) on X-ray films, and to evaluate the relationship between the 2 variables, knee function and OA symptoms. METHODS: Using the web-based radiology viewer (Cedara I-Reach™ 4.1.1), we measured the 2 variables in 50 knees of 41 patients with knee OA participating in the Shanghai OA Study. We also evaluated the Kellgren-Lawrence (K-L) grade, the Western Ontario and McMaster Universities OA Index (WOMAC), and additional questionnaire in OA knees. The study was approved by the ethics committee of Shanghai Ninth People's Hospital (No. 2009 - 28). RESULTS: The aJSW correlated with the K-L grade (r = -0.57, P < 0.001), kneeling (r = -0.29, P = 0.04), sitting cross-legged on the floor (r = -0.31, P = 0.03), WOMAC pain (r = -0.31, P = 0.03), WOMAC disability (r = -0.35, P = 0.01), pain while squatting (r = -0.37, P = 0.01), and defecating in a squatting position (r = -0.39, P = 0.01). The AA correlated with defecating in a squatting position (r = 0.29, P = 0.05), WOMAC disability (r = 0.30, P = 0.04) and K-L grade (r = 0.44, P = 0.003). The K-L grade also correlated with pain while squatting (r = -0.40, P = 0.005) and defecating in a squatting position (r = -0.34, P = 0.02), WOMAC pain (r = 0.30, P = 0.04), and WOMAC disability (r = 0.30, P = 0.04). CONCLUSIONS: The aJSW closely correlated with knee OA symptoms and function scores, and was more sensitive to knee OA related disabilities than K-L grade and the AA. The aJSW could be used as a new variable for knee OA evaluation.