Current research progress in targeted anti-angiogenesis therapy for osteosarcoma.

Osteosarcoma (OS) is the most common primary malignant bone tumour with a peak in incidence during adolescence. Delayed patient presentation and diagnosis is common with approximately 15% of OS patients presenting with metastatic disease at initial diagnosis. With the introduction of neoadjuvant chemotherapy in the 1970s, disease prognosis improved from 17% to 60%-70% 5-year survival, but outcomes have not significantly improved since then. Novel and innovative therapeutic strategies are urgently needed as an adjunct to conventional treatment modalities to improve outcomes for OS patients. Angiogenesis is crucial for tumour growth, metastasis and invasion, and its prevention will ultimately inhibit tumour growth and metastasis. Dysregulation of angiogenesis in bone microenvironment involving osteoblasts and osteoclasts might contribute to OS development. This review summarizes existing knowledge regarding pre-clinical and developmental research of targeted anti-angiogenic therapy for OS with the aim of highlighting the limitations associated with this application. Targeted anti-angiogenic therapies include monoclonal antibody to VEGF (bevacizumab), tyrosine kinase inhibitors (Sorafenib, Apatinib, Pazopanib and Regorafenib) and human recombinant endostatin (Endostar). However, considering the safety and efficacy of these targeted anti-angiogenesis therapies in clinical trials cannot be guaranteed at this point, further research is needed to completely understand and characterize targeted anti-angiogenesis therapy in OS.

Horizontal fissuring at the osteochondral interface: a novel and unique pathological feature in patients with obesity-related osteoarthritis.

OBJECTIVES: Obesity is a well-recognised risk factor for osteoarthritis (OA). Our aim is to characterise body mass index (BMI)-associated pathological changes in the osteochondral unit and determine if obesity is the major causal antecedent of early joint replacement in patients with OA. METHODS: We analysed the correlation between BMI and the age at which patients undergo total knee replacement (TKR) in 41 023 patients from the Australian Orthopaedic Association National Joint Replacement Registry. We then investigated the effect of BMI on pathological changes of the tibia plateau of knee joint in a representative subset of the registry. RESULTS: 57.58% of patients in Australia who had TKR were obese. Patients with overweight, obese class I & II or obese class III received a TKR 1.89, 4.48 and 8.08 years earlier than patients with normal weight, respectively. Microscopic examination revealed that horizontal fissuring at the osteochondral interface was the major pathological feature of obesity-related OA. The frequency of horizontal fissure was strongly associated with increased BMI in the predominant compartment. An increase in one unit of BMI (1 kg/m2) increased the odds of horizontal fissures by 14.7%. 84.4% of the horizontal fissures were attributable to obesity. Reduced cartilage degradation and alteration of subchondral bone microstructure were also associated with increased BMI. CONCLUSIONS: The key pathological feature in OA patients with obesity is horizontal fissuring at the osteochondral unit interface. Obesity is strongly associated with a younger age of first TKR, which may be a result of horizontal fissures.

The repair and autophagy mechanisms of hypoxia-regulated bFGF-modified primary embryonic neural stem cells in spinal cord injury.

There is no effective strategy for the treatment of spinal cord injury (SCI), a devastating condition characterized by severe hypoxia and ischemic insults. In this study, we investigated the histology and pathophysiology of the SCI milieu in a rat model and found that areas of hypoxia were unevenly interspersed in compressed SCI. With this new knowledge, we generated embryonic neural stem cells (NSCs) expressing basic fibroblast growth factor (bFGF) under the regulation of five hypoxia-responsive elements (5HRE) using a lentiviral vector (LV-5HRE-bFGF-NSCs) to specifically target these hypoxic loci. SCI models treated with bFGF expressed by the LV-5HRE-bFGF-NSCs viral vector demonstrated improved recovery, increased neuronal survival, and inhibited autophagy in spinal cord lesions in the rat model due to the reversal of hypoxic conditions at day 42 after injury. Furthermore, improved functional restoration of SCI with neuron regeneration was achieved in vivo, accompanied by glial scar inhibition and the evidence of axon regeneration across the scar boundary. This is the first study to illustrate the presence of hypoxic clusters throughout the injury site of compressed SCI and the first to show that the transplantation of LV-5HRE-bFGF-NSCs to target this hypoxic microenvironment enhanced the recovery of neurological function after SCI in rats; LV-5HRE-bFGF-NSCs may therefore be a good candidate to evaluate cellular SCI therapy in humans.

Non-traumatic musculoskeletal pain in Western Australian hospital emergency departments: A clinical audit of the prevalence, management practices and evidence-to-practice gaps.

OBJECTIVES: Musculoskeletal pain (MSP) conditions are a leading cause of morbidity worldwide and a common reason for ED presentation. Little is currently known about non-traumatic MSP (NTMSP) presenting to EDs. The present study described the prevalence and management practices of NTMSP in EDs. METHODS: The design was a retrospective clinical audit in two hospital EDs in Western Australia covering 3 months beginning 1 January 2016. We defined NTMSP as pain of musculoskeletal origin occurring in the absence of external force or excessive physical loading. The outcomes measured included: patient, condition and hospital-episode characteristics, as well as management practices. Management practices were compared to recommended care derived from guideline recommendations. These included: assessment for red flags and psychosocial risk factors, appropriate use of diagnostic imaging, provision of patient education, administration and prescription of analgesic medication, and assessment of risk factors for opioid-related harm. RESULTS: Eight hundred and eighty-eight patients were included in the present study. NTMSP accounted for 3.0% of all ED presentations. According to clinician documentation, red flag and psychosocial assessments were recorded in 73.3 and 10.5% of patients. Forty-one percent of patients were referred for imaging, of which 39.7% were inconsistent with guideline recommendations. Education was recorded 52.0% of the time. At least one opioid medication was administered to 55.3% of patients and there was no documented assessment of risk factors for opioid-related harm. CONCLUSIONS: NTMSP is a relatively common reason for ED presentation. Documented management practices are discordant with guideline recommendations. Strategies to improve the concordance between management and guideline recommendations are needed.

Fabrication of a silver nanoparticle-coated collagen membrane with anti-bacterial and anti-inflammatory activities for guided bone regeneration.

Alveolar bone loss is a common problem that affects dental implant placement. A barrier between the bone substitute and gingiva that can prevent fibro-tissue ingrowth, bacterial infection and induce bone formation is a key factor in improving the success of alveolar ridge reconstruction. This study aims to develop a bioactive collagen barrier material for guided bone regeneration, that is coupled with anti-bacterial and anti-inflammatory properties. We have evaluated two silver coating methods and found controllable and precise coating achieved by sonication compared with sputtering. The optimized AgNP-coated collagen membrane exhibited excellent anti-bacterial effects against Staphylococcus aureus (S. aureus) and Pseudomonas aeruginosa (P. aeruginosa) with limited cellular toxicity. It also displayed effective anti-inflammatory effects by reducing the expression and release of inflammatory cytokines including IL-6 and TNF-alpha. Additionally, AgNP-coated collagen membranes were able to induce osteogenic differentiation of mesenchymal stem cells that guide bone regeneration. These findings demonstrate the potential application of AgNP-coated collagen membranes to prevent infection after bone graft introduction in alveolar ridge reconstruction.

Coupling factors and exosomal packaging microRNAs involved in the regulation of bone remodelling.

Bone remodelling is a continuous process by which bone resorption by osteoclasts is followed by bone formation by osteoblasts to maintain skeletal homeostasis. These two forces must be tightly coordinated not only quantitatively, but also in time and space, and its malfunction leads to diseases such as osteoporosis. Recent research focusing on the cross-talk and coupling mechanisms associated with the sequential recruitment of osteoblasts to areas where osteoclasts have removed bone matrix have identified a number of osteogenic factors produced by the osteoclasts themselves. Osteoclast-derived factors and exosomal-containing microRNA (miRNA) can either enhance or inhibit osteoblast differentiation through paracrine and juxtacrine mechanisms, and therefore may have a central coupling role in bone formation. Entwined with angiocrine factors released by vessel-specific endothelial cells and perivascular cells or pericytes, these factors play a critical role in angiogenesis-osteogenesis coupling essential in bone remodelling.

Natural Compounds for the Treatment of Psoriatic Arthritis: A Proposal Based on Multi-Targeted Osteoclastic Regulation and on a Preclinical Study.

BACKGROUND: Psoriatic arthritis (PsA) is a chronic inflammatory arthritis affecting approximately 2% to 3% of the population globally, and is characterized by both peripheral articular manifestations and axial skeletal involvement. Conventional therapies for PsA have not been fully satisfactory, though natural products (NPs) have been shown to be highly effective and represent important treatment options for psoriasis. PsA is a multigenic autoimmune disease with both environmental and genetic factors contributing to its pathogenesis. Accordingly, it is likely that the use of natural compounds with a multi-targeted approach will enable us to develop better therapies for PsA and related disorders. OBJECTIVE: PsA, either on joint damage or on bone erosion, has been shown to respond to anti-psoriatic pharmacotherapy (APP), APP-like NPs, and their natural compounds. This study aims to uncover specific natural compounds for improved PsA remedies. Specifically, by targeting bone erosion caused by increased osteoclastic bone resorption, we aim to predict the key signaling pathways affected by natural compounds. Further, the study will explore their anti-arthritis effects using an in silico, in vitro, and in vivo approach. Following the signaling pathway prediction, a preclinical efficacy study on animal models will be undertaken. Collectively, this work will discover lead compounds with improved therapeutic effects on PsA. METHODS: We hypothesize that 9 potential APP-like NPs will have therapeutic effects on arthritis via the modulation of osteoclast bone resorption and signaling pathways. For in silico identification, the Latin name of each NP will be identified using the Encyclopedia of Traditional Chinese Medicine (Encyclopedia of TCM). The biological targets of NPs will be predicted or screened using the Herbal Ingredients' Targets (HIT) database. With the designed search terms, DrugBank will be used to further filter the above biological targets. Protein ANnotation THrough Evolutionary Relationship (PANTHER) will be used to predict the pathways of the natural compound sources. Subsequently, an in vitro sample preparation including extraction, fractionation, isolation, purification, and bioassays with high-speed counter-current chromatography-high-performance liquid chromatography-diode array detection (HSCCC-HPLC-DAD) will be carried out for each identified natural source. In vitro investigations into the effect of NPs on osteoclast signaling pathways will be performed. The experimental methods include cell viability assays, osteoclastogenesis and resorption pit assays, quantitative reverse transcription polymerase chain reaction (RT-PCR), western blot, and luciferase reporter gene assays. Finally, an in vivo preclinical efficacy on a collagen-induced arthritis rat model will be carried out using a treatment group (n=10), a control group (n=10), and a non-arthritis group (n=10). Main outcome measure assessments during intervention include daily macroscopic scores and a digital calipers measurement. Post-treatment tissue measurements will be analyzed by serological testing, radiographic imaging, and histopathological assessment. RESULTS: Studies are currently underway to evaluate the in silico data and the in vitro effects of compounds on osteoclastogenesis and bone resorption. The preclinical study is expected to start a year following completion of the in silico analysis. CONCLUSIONS: The in silico rapid approach is proposed as a more general method for adding value to the results of a systematic review of NPs. More importantly, the proposed study builds on a multi-targeted approach for the identification of natural compounds for future drug discovery. This innovative approach is likely to be more precise, efficient, and compatible to identify the novel natural compounds for effective treatment of PsA.

Evaluation of insoluble bone gelatin as a carrier for enhancement of osteogenic protein-1-induced intertransverse process lumbar fusion in a rabbit model.

STUDY DESIGN: Postero-lateral lumbar fusion in a rabbit model was performed to compare the bone induction potential of autograft, insoluble bone gelatin (ISBG), osteogenic protein-1 (OP-1), and the combination of ISBG and OP-1. OBJECTIVE: To evaluate the efficiency of ISBG as a carrier/enhancer for OP-1 in a rabbit spinal fusion model. SUMMARY OF BACKGROUND DATA: OP-1 or recombinant human BMP-7 has been shown to be effective in inducing new bone formation in surgical applications such as spinal arthrodesis. However, the lack of an ideal carrier contributes to its associated comorbidities (e.g., uncontrolled bone growth, local inflammatory over-response, nonfusion) and limits its use clinically. METHODS: Adult New Zealand white rabbits (n = 32) underwent bilateral lumbar intertransverse process fusion procedures at L5 to L6 and were randomized to receive: (1) autograft; (2) ISBG; (3) OP-1; or (4) ISBG in combination with OP-1 (ISBG + OP-1). Spinal fusion masses were evaluated by manual palpation, biomechanical testing, radiographic assessment, microcomputer tomography scanning and histologic examination at 6 weeks after surgery. RESULTS: Treatment of ISBG + OP-1 resulted in higher spinal fusion rates (7 of 7, 100%) than that of autograft (3 of 7, 43%), ISBG (2 of 8, 25%), and OP-1 (2 of 7, 29%) based on manual palpation (P < 0.01). Greater fusion rates in the ISBG + OP-1 group were also evidenced by radiographic examination (P < 0.01), microcomputer tomography bone volume analysis (P < 0.01), and biomechanical testing (P < 0.05). Histologic assessment demonstrated that treatment of ISBG + OP-1 induces new contiguous bone formation in the interval between the transverse processes which was absent in the other groups. CONCLUSION: In this study, ISBG + OP-1 resulted in more effective lumbar intertransverse process fusion than autograft, OP-1 putty or ISBG alone. ISBG is capable of enhancing OP-1-induced bone formation.

Comparison of the risk of viral infection between the living and nonliving musculoskeletal tissue donors in Australia.

Screening of musculoskeletal tissue donors with nucleic acid testing (NAT) for human immunodeficiency virus (HIV) and hepatitis C virus (HCV) has been implemented in the United States and other developed nations. However, in contrast to the donor demographics in the United States, the majority of Australian musculoskeletal tissue donations are primarily from living surgical donors. The objective of our study was to determine and compare the risk of viral infection associated with musculoskeletal tissue donation from living and nonliving donors in Australia. We studied serum samples from 12 415 consecutive musculoskeletal tissue donors between 1993 and 2004. This included 10 937 surgical donations, and 1478 donations obtained from postmortem organ donation patients and cadaveric donors. Current mandatory retesting of surgical donors 6 months postdonation reduces the risk of viral infection by approximately 95% by eliminating almost all donors in the window period. The addition of nucleic acid amplification testing for nonliving donors would similarly reduce the window period, and consequently the residual risk by approximately 50% for hepatitis B virus, 55% for HIV, and 90% for HCV. NAT, using appropriately validated assays for nonliving donors, would reduce the residual risk to levels comparable to that in living donors (where the 95% reduction for quarantining pending the 180-day re-test is included).

Capsular-enhanced repair of the short external rotators after total hip arthroplasty.

Higher dislocation rates have been reported with the posterior approach to the hip. Empirical studies suggest that careful repair of the posterior structures significantly reduces this risk. However, studies examining the integrity of repair using plain radiographs and metallic markers have reported high failure rates. To explain this discrepancy, we performed a study using radiostereometric analysis to assess the repair. Ten patients were recruited. Markers were placed into the capsule and bone. The capsule and conjoined short external rotators were repaired through drill holes in bone. At 3 months, stress radiostereometric analysis radiographs were taken in internal and external rotation. Eight of 10 patients had a mean of 3.51-mm difference in separation, suggesting that the repair was intact. We recommend careful repair of posterior structures when using the posterior approach to reduce the risk of dislocation.

Less invasive total hip arthroplasty: description of a new technique.

We describe a new technique and aim to justify its use in total hip arthroplasty. The incision is short and there is minimal soft tissue dissection: piriformis and most of quadratus femoris remain intact. A meticulous capsular repair is performed. Patients are mobilized without restrictions. One hundred total hip arthroplasties by the standard posterior approach (group 1) were compared with 100 by the less invasive approach (group 2). Minimum follow-up was 2 years. Mean blood loss in group 1 was higher (P < .0001) and inpatient stay longer (P < .0001). There was greater improvement in WOMAC scores for up to 1 year in the less invasive group (P = .027). In conclusion, the less invasive approach is safe and the functional benefits last up to 1 year.

Mobile vs. fixed bearing unicondylar knee arthroplasty: A randomized study on short term clinical outcomes and knee kinematics.

The literature contains limited yet controversial information regarding whether a fixed or a mobile bearing implant should be used in unicompartmental knee arthroplasty (UKA). This randomized study was to further document the performance and comparison of the two designs. Fifty-six knees in 48 patients (mean age of 72 years) undergoing medial UKA were randomized into a fixed bearing (Miller/Galante) or a mobile bearing (Oxford) UKA. The 2 year clinical outcomes (clinical scores), radiographic findings, and weight bearing knee kinematics (assessed using RSA) were compared between the two groups. The mobile bearing knees displayed a larger and an incrementally increased tibial internal rotation (4.3 degrees, 7.6 degrees, 9.5 degrees vs. 3.0 degrees, 3.0 degrees, 4.2 degrees respectively at 30 degrees, 60 degrees, 90 degrees of knee flexion) compared to the fixed ones. The medial femoral condyle in the mobile bearing knees remained 2 mm from the initial position vs. a 4.2 mm anterior translation in the fixed bearing knees during knee flexion. The contact point in the mobile bearing implant moved 2 mm posteriorly vs. a 6 mm anterior movement in the other group. The mobile bearing knees had a lower incidence of radiolucency at the bone implant interface (8% vs. 37%, p < 0.05). The incidence of lateral compartment OA and progression of OA at patello-femoral joint were equal. No differences were found regarding Knee Society Scores, WOMAC, and SF-36 scores (p > 0.05). This study indicates that mobile bearing knees had a better kinematics, a lower incidence of radiolucency but not yet a better knee function at 2 years.