Background. Multiple Myeloma is a hematological malignancy of terminally differentiated plasma cells associated with increased osteoclast activity and decreased osteoblast functions. Systemic antiproliferative treatment includes proteasome inhibitors such as bortezomib, a clinical potent antimyeloma agent. Local delivery of biological active molecules via biomaterial composite implants to the site of the lesion has been shown to be beneficial for bone and implant-associated infections. In anticancer treatment local delivery of anticancer agents to the neoplasia via biomaterial carriers has never been reported before. The purpose of the current is to present the concepts and the first in vivo results for proteasome inhibitor composite biomaterials for local delivery of bortezomib to proliferative multiple myeloma bone lesions including concentration measurements at different anatomical regions in a rat model. Methods. 80 female Sprague-Dawley rats were randomised into five different treatment groups (n=16/group): 1) Empty (2) Xerogel-granulat: XG (3) Xerogel-granulat+100mgbortezomib [b]: XG100b (4) Xerogel-granulat+500mgb:XG500b (5) Xerogel-granulat+2500mgb:XG2500b. A 2.5 mm drill hole was then created in the metaphysis of the left femur. The defect was then either filled with the previously mentioned substitutes or left empty to serve as a control. After 4 weeks femora were harvested followed by histological, histomorphometrical and immunohistochemical (BMP2; bone-morphogenic protein 2, OPG; osteoprotegerin, RANKL; Receptor activator of nuclear factor kappa-B ligand, ASMA; alpha smooth muscle actin, ED1;CD68 antibody). TOF-SIMS was used to assess the distribution of released strontium ions. Statistical analysis was done using SPSS software. Data was not found normally distributed and hence Mann-Whitney U with bonferroni correction was used. To avoid type I errors due to unequal variances and group sizes Games-Howell test was also performed

Multiple myeloma (MM) is a chronic, malignant B-cell disorder, with a less than 50% 5-year survival rate [1]. This disease is responsible for vertebral compression fractures (VCFs) in 34 to 64% of diagnosed patients [1], and at least 80% of MM patients experience pathological fractures [3]. Even though reduced DXA-derived bone mineral density (BMD) has been observed in MM patients with vertebral fractures [4], the current quantitative standard method is insufficient in MM due to the osteo-destructive bone changes. Finite-element (FE) analysis is a computational and non-destructive modeling and testing approach to determine bone strength using 3D bone models from CT images. Thus, this study aimed to assess the differences in FE-predicted critical fracture load in MM patients with and without VCFs in the thoracic and lumbar segments of the spine. Multi-detector CT (MDCT) images of two radiologically assessed MM patients (1 with VCFs and 1 without VCFs) were used to generate three-dimensional (3D) models of the whole spine. For each subject, the thoracic segments, 1 to 12 (T1-T12) and lumbar segments, 1 to 5 (L1-L5) were segmented and meshed. Heterogeneous, non-linear anisotropic material properties were applied by discretizing each vertebral segment into 10 distinct sets of materials. A compressive load was simulated by constraining the surface nodes on the inferior endplate in all directions, and a displacement load was applied on the surface nods on the superior endplate [2]. This analysis was performed using ABAQUS version 6.10 (Hibbitt, Karlsson, and Sorensen, Inc., Pawtucket, RI, USA). The MM subject with VCFs had originally experienced fractures in the T4, T5, T12, L1, and L5 segments whereas the MM subject without VCFs experienced none. The former displayed large and abrupt differences in fracture loads between adjacent vertebrae segments, unlike the latter, which exhibited progressive differences instead (no abrupt changes between adjacent vertebrae segments observed). Results from this preliminary study suggest that segments at high risk of fracture are collectively involved in an unstable network, which place the vertebral segments with high values of fracture loads (peaks) as well as the adjacent segments at risk of VCF. For instance, the high fracture load at T11 places T10, T11 and T12 at risk of fracture. Accordingly, T12 has already fractured, and T10 and T11 remain at risk. The relative changes between adjacent vertebrae segments that indicate instability (extremely high fracture load values) enables ease of identification of segments at high fracture risk. Clinicians would be able to work with pre-emptive treatment strategies in future as they can focus on more targeted therapy options at the high-risk vertebrae segments [3]

Multiple myeloma (MM) is an incurable hematological tumor stemming from malignant plasma cells. MM cells accumulate in the bone marrow (BM) and shape the BM niche by establishing complex interactions with normal BM cells, boosting osteoclasts (OCLs) differentiation and causing bone disease. This unbalance in bone resorption promotes tumor survival and the development of drug resistance. The communication between tumor cells and stromal cells may be mediated by: 1) direct cell-cell contact; 2) secretion of soluble factors, i.e. chemokines and growth factors; 3) release of extracellular vesicles/exosomes (EVs) which are able to deliver mRNAs, miRNAs, proteins and metabolites in different body district. Primary CD138+ MM cells were isolated from patients BM aspirates. MM cell lines were cultured alone in complete RPMI-1640 medium or co-cultured with murine (NIH3T3) or human (HS5) BMSC cell lines or murine Raw264.7 monocytes in DMEM medium supplemented with 10% V/V FBS. Silencing of Jagged1 and Jagged2 was obtained by transient expression of specific siRNAs or by lentiviral transduction using a Dox-inducible system (pTRIPZ). EVs were isolated using differential ultracentrifugation. EVs concentration and size were analyzed using Nano Track Analysis (NTA) system. The uptake of PKH26-labelled MM-derived EVs by HS5 or Raw264.7 was measured after 48 hours by confocal microscopy and flow cytometry. Osteoclast (OCL) differentiation of Raw264.7 cells was induced by 50ng/ml mRANKL, co-culturing with MM cells, CM or EVs. OCLs were stained by TRAP Kit and counted. Bone resorption was assessed by Osteo Assay Surface plates. Flow cytometric detection of apoptotic cells was performed after staining with Annexin V. Gene expression was analyzed by qRT-PCR, while protein levels were determined using flow cytometry ELISA or WB. Notch oncogenic signaling is dysregulated in several hematological and solid malignancies. Notch receptors and ligands are key players in the crosstalk between tumor cells and BM cells. We have demonstrated that: 1) the dysregulated Jagged ligands on MM cells trigger the activation of Notch receptors in the nearby stromal cells by cell-cell contact. This results in the release of anti-apoptotic and growth stimulating factors, i.e. IL6 and SDF1; 2) MM cells promote the development of bone lesions boosting osteoclast differentiation by secreting soluble factors (i.e. RANKL) and by the activation of Notch signaling mediated by direct contact with osteoclast precursors; 3) Finally, we present evidences that EVs play a crucial role in the dysregulated interactions of MM cells with the microenvironment and that Notch signaling regulates their release and participate in this cross-talk. These evidences supports the hypothesis that Jagged targeting on MM cells may interrupt the communication between tumor cells and the surrounding milieu, blocking the activation of the oncogenic Notch pathway and finally resulting in the a reduction of MM-associated bone disease and drug resistance

This case report describes a patient with thoracic plasmacytoma, an uncommon haematological malignancy, who presented with neck pain. Plasmacytoma is a neoplastic proliferation of B cell lineage but is much less common than multiple myeloma. The histological examination of multiple myeloma and plasmacytoma is identical however in plasmacytoma there is a solitary lesion with negative skeletal survey, negative bone marrow aspirate and little or no myeloma protein detected in the blood. This makes it more challenging to diagnose and a high index of suspicion is required

Introduction. Hyaluronan (HA) is assumed to have a regulatory role in the bone remodelling process by influencing the behaviour of mesenchymal stem cells (MSCs), osteoblasts and osteoclasts. The hyaluronan synthases (HAS1, HAS2 and HAS3) which are responsible for the formation of HA are expressed in human MSCs (hMSCs). Although HAS are only active when they are located in the plasma membrane and an intracellular storage pool of the HAS is assumed, the mechanisms controlling the intracellular traffic of HAS are hardly investigated. Since chitin synthases and cellulose synthases, members of the same enzyme family like the HAS, are regulated by interaction with the cytoskeleton, we hypothesize that HAS interrelate somehow with the cytoskeleton and that their expression, their transport and/or their activity are regulated via mechanotransduction. Methods and Results. We generated immortalized hMSCs (SCP-1) constitutively expressing eGFP-tagged HAS by lentiviral gene transfer (SCP1-HAS1-eGFP, SCP1-HAS2-eGFP and SCP1-HAS3-eGFP). The expression of the transgene HAS was verified by RT-PCR, western blot, FACS analysis and direct fluorescence microscopy or immunofluorence. The enzymatic activity of the transgene HAS was determined by HA-ELISA and by staining of HA. hMSCs expressing lifeact-RFPruby and HAS-eGFP were investigated in a video timelapse analysis in order to study the putative interaction of HAS-eGFP with the actin cytoskeleton. The HAS-eGFP proteins are globular structured and aligned along the actin filaments. The timelapse pictures show that the HAS-eGFP moves without loss of their alignment to actin. In addition we investigated the impact of shear stress on hMSCs under defined flow conditions. The upregulation of the expression levels of the three HAS isoforms was shown by quantitative real time RT-PCR after exposure to the stimulus. Discussion. Here, we were able to show the regulation of HAS expression via mechanotransduction. At the moment we investigate if HAS activity and their transport towards the plasma membrane are changed by shear stress. Furthermore we generate hMSCs expressing eGFP tagged HAS in their active form. We have first hints for an interaction of the transgene HAS with the actin cytoskeleton. Our cells can be used for further investigation of the functional and regulatory role of HAS in the bone microenvironment. In some bone diseases such as osteogenesis imperfecta, multiple myeloma and osteoporosis, the HA content in the bone or HAS expression in the hMSCs are changed. Understanding the role of HA in bone regeneration and the regulatory mechanisms of HAS in the hMSCs will provide therapeutic starting points for an improved fracture healing in patients suffering from one of these bone diseases

Demographics changes and the increasing incidence of metastatic bone disease are driving the significant issues of vertebral body (VB) fractures as an important consideration in the quality of life of the elderly. Whilst osteoporotic vertebral fractures have been widely studies both clinically and biomechanically, those fractures arising from metastatic infiltration in the spine are relatively poorly understood. Biomechanical in-vitro assessment of these structurally weaker specimens is an important methodology for gaining an understanding of the mechanics of such fractures in which a key aspect is the development of methodologies for predicting the failure load. Here we report on a method to predict the vertebral strength by combining computed tomography assessment with an engineering beam theory as an alternative to more complex finite element analyses and its verification within a laboratory scenario. Ninety-two human vertebral bodies with 3 different pathologies: osteoporosis, multiple myeloma (MM) and specimens containing cancer metastases were loaded using a define protocol and the failure loads recorded. Analysis of the resulting data demonstrated that the mean difference between predicted and experimental failure loads was 0.25kN, 0.41kN and 0.79 kN, with adjunct correlation coefficients of 0.93, 0.64 and 0.79 for osteoporotic, metastatic and MM VBs, respectively. Issues in predicting vertebral fracture arise from extra-vertebral bony formations which add to vertebral strength in osteoporotic VB but are structurally incompetent in metastatic disease. The methodology is currently used in providing better experimental design/benchmarking within in-vitro investigations together with further exploration of its utility in the clinical arena

INTRODUCTION. Over 85% of patients with multiple myeloma (MM) have bone disease, mostly affecting thoraco-lumbar vertebrae. Vertebral fractures can lead to pain and large spinal deformities requiring application of vertebroplasty (PVP). PVP could be enhanced by use of Coblation technique to remove lesions from compromised MM vertebrae prior to cement injection (C-PVP). METHODS. 28 cadaveric MM vertebrae, were initially fractured (IF) up to 75% of its original height on a testing machine, with rate of 1mm/min. Loading point was located at 25% of AP-diameter, from anterior. Two augmentation procedure groups were investigated: PVP and C-PVP. All vertebrae were augmented with 15% of PMMA cement. At the end of each injection the perceived injection force (PIF) was graded on a 5-point scale (1 very easy to 5 almost impossible). Augmented MM vertebrae were re-fractured, following the same protocol as for IF. Failure load (FL) was defined as 0.1% offset evaluated from load displacement curves. RESULTS. Mean initial FL was 2.5kN (STD=1.8kN) and 2.7kN (STD=1.8kN) for PVP and C-PVP, respectively. Mean augmented FL was 3.5kN (STD=3.1kN) and 4.2kN (STD=2.3kN)for PVP and C-PVP, respectively. Only the effect of augmentation was significant(p=0.006). Median PIF on the RIGHT side of vertebrae was 3.0 in PVP group and 2.5 in C-PVP (p=0.054). On the LEFT side it was 3.5 in PVP group and 3.0 in C-PVP (p=0.028). DISCUSSION. Results suggest that Coblation did not compromise strength of augmented MM vertebrae. The PIF was lower for C-PVP, as compared to PVP group, probably due to removal of lesion tissue

Summary. Metastatic spinal disease is a common entity of much debate in terms of ideal surgical treatment. The introduction of MIS can be a game-changer in the treatment of MSD due to less peri-operative morbidity and allowing earlier radiotherapy and/or chemotherapy. Introduction. Less invasive techniques have always been welcome for management of patients with ‘Metastatic Spinal Disorders’. This is because these patients can be poor candidates for extensive / major invasive surgery even though radiologically, there may be an indication for one. The aim of the treatment with Minimal Invasive Fixation (MIS) systems is mainly for ‘pain relief’ than to radically decrease tumour burden or to achieve near total spinal cord decompression, which could be major presentations in these patients. These procedures address the ‘spinal instability’ very well and they can address pain associated with compression fractures resulting from metastatic disease from a solid organ as well as multiple myeloma with minimal complications. These procedures can be combined with radiology and chemotherapy without much concern for wound problems in the way of infection or dehiscence. They also have a great advantage of timing of adjunct therapy closer to the index procedure. The disadvantage, however, are they do not allow thorough decompression of the spinal cord. There could also be problem in addressing patients who have severe vertebral height loss or loss of integrity of the anterior column where anterior column reconstruction may be required. There is a risk of inadequate fixation or implant loosening or failure. We aim to examine the results of MIS surgery in our department and support the rationale for its use. Patients and Methods. We prospectively collected data of patients who underwent MIS posterior instrumentation for MSD. Between June 2011 and December 2012, 10 patients presented with acute motor deficit, instability and/or threatening radiological features. Effectiveness of MIS was assessed in terms of operative parameters and clinical outcomes. Results. No patient suffered intra-operative complications. The median surgical time was 198 minutes (range: 149 – 403), median blood loss was 100 ml (range: 60 – 400). All patients maintained full neurological function and reported effective pain reduction. All patients were discharged with a median hospital stay was 13 days (range: 4 – 45) post-surgery. 9 patients started oncological treatment as planned. The median time in 7 patients who had radiotherapy post-surgery was 23 days (range: 20 – 40). Chemotherapy was initiated in 4 patients at a median of 9 days post-surgery (range: 6 – 23). No patient as yet has required open procedure due to progression of the disease. Discussion/Conclusion. We have shown that satisfactory outcomes are achievable with MIS in a selected group of patients with MSD. While our results are limited by small study size, we have been able to improve patient quality of living through minimally invasive intervention. By reducing surgical morbidity and enabling early implementation of oncological treatment, MIS has the potential to re-evaluate multi-disciplinary decision making for early surgery in MSD

Osteoporosis is a systemic skeletal disorder characterized by reduced bone mass and deterioration of bone microarchitecture, which results in increased bone fragility and fracture risk. Casein kinase 2-interacting protein-1 (CKIP-1) is a protein that plays an important role in regulation of bone formation. The effect of CKIP-1 on bone formation is mainly mediated through negative regulation of the bone morphogenetic protein pathway. In addition, CKIP-1 has an important role in the progression of osteoporosis. This review provides a summary of the recent studies on the role of CKIP-1 in osteoporosis development and treatment.

Cite this article: X. Peng, X. Wu, J. Zhang, G. Zhang, G. Li, X. Pan. The role of CKIP-1 in osteoporosis development and treatment. Bone Joint Res 2018;7:173–178. DOI: 10.1302/2046-3758.72.BJR-2017-0172.R1.

Objectives

This study aimed to explore the role of miR-320a in the pathogenesis of osteoarthritis (OA).

Previous research has shown an increase in chromosomal aberrations in patients with worn implants. The type of aberration depended on the type of metal alloy in the prosthesis. We have investigated the metal-specific difference in the level of DNA damage (DNA stand breaks and alkali labile sites) induced by culturing human fibroblasts in synovial fluid retrieved at revision arthroplasty.

All six samples from revision cobalt-chromium metal-on-metal and four of six samples from cobalt-chromium metal-on-polyethylene prostheses caused DNA damage. By contrast, none of six samples from revision stainless-steel metal-on-polyethylene prostheses caused significant damage. Samples of cobalt-chromium alloy left to corrode in phosphate-buffered saline also caused DNA damage and this depended on a synergistic effect between the cobalt and chromium ions.

Our results further emphasise that epidemiological studies of orthopaedic implants should take account of the type of metal alloy used.