Epigenetics in Knee Osteoarthritis: A 2020-2023 Update Systematic Review.

Osteoarthritis is a leading cause of disability in the world. The scientific literature highlights the critical importance of epigenetic regulatory effects, intertwined with biomechanical and biochemical peculiar conditions within each musculoskeletal district. While the contribution of genetic and epigenetic factors to knee OA is well-recognized, their precise role in disease management remains an area of active research. Such a field is particularly heterogeneous, calling for regular analysis and summarizing of the data that constantly emerge in the scientific literature, often sparse and scant of integration. The aim of this study was to systematically identify and synthesize all new evidence that emerged in human and animal model studies published between 2020 and 2023. This was necessary because, to the best of our knowledge, articles published before 2019 (and partly 2020) had already been included in systematic reviews that allowed to identify the ones concerning the knee joint. The review was carried out in accordance with Preferential Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Only peer-reviewed articles were considered for inclusion. A total of 40 studies were identified, showing promising results in terms either of biomarker identification, new insight in mechanism of action or potential therapeutic targets for knee OA. DNA methylation, histone modification and ncRNA were all mechanisms involved in epigenetic regulation of the knee. Most recent evidence suggests that epigenetics is a most promising field with the long-term goal of improving understanding and management of knee OA, but a variety of research approaches need greater consolidation.

Autologous microfragmented adipose tissue treatment of knee osteoarthritis demonstrates effectiveness in 68% of patients at 4-year follow-up.

BACKGROUND: Adipose tissue-derived stem cells are an interesting therapeutic option for early knee osteoarthritis (OA) treatment due to their high plasticity, easiness of harvesting and rapidity of administration. The aim of this study was to evaluate the medium-term effectiveness and safety of Microfragmented Autologous Fat Tissue (MFAT) injection treatment at 4-year follow-up and to investigate potential correlations among patients' pre-treatment clinical condition and clinical outcomes to identify possible predicting factors for procedure success or failure. PATIENTS AND METHODS: This is a prospective trial enrolling 46 patients with diagnosis of symptomatic knee OA and failure of previous conservative measures who underwent diagnostic arthroscopy and single autologous MFAT injection between June 2017 and July 2018. Patients were assessed with repeated clinical scoring systems at baseline, 6 months, 1 and 4 years after surgery. The evaluation included demographic characteristics, arthroscopic findings, and stem cell number from injected tissue. RESULTS: No major complications were reported during follow-up period and there was a significant increase of Lysholm knee score from baseline value of 61.7 ± 13.8 to 79.5 ± 16.9 at 4 years (p < 0.001). The WOMAC score increased from a baseline value of 66.5 ± 14.7 to 82.8 ± 15.7 at 4 years (p < 0.001) and there was a significant decrease of VAS pain score from baseline value of 6.3 ± 1.5 to 3.5 ± 2.6 at 4-year follow-up (p < 0.001). ROM improved significantly from 118.4 ± 2.6 to 122.5 ± 2.5 at 12 months (p < 0.001), but did not improve at 4 years (p > 0.05). 15 patients (32.6%) were considered treatment failures, because they required secondary surgery, further injection therapy or experienced symptoms persistence. Patient with synovitis had 75% failure rate, although synovitis did not result as a statistically significant factor influencing clinical outcome up to 4-year follow-up (p = 0.058). Age, cartilage defects severity, BMI, concomitant procedures, and stem cell number from injected MFAT did not show any significant correlation with the results. CONCLUSIONS: MFAT intra-articular injection is a safe procedure with positive improvements up to 4-year follow-up in patients with early knee OA. These findings suggest MFAT could be a minimally invasive treatment of early knee OA with durable benefits at mid-term evaluation. TRIAL REGISTRATION: IRB number ID-3522.

Senescent Markers Expressed by Periodontal Ligament-Derived Stem Cells (PDLSCs) Harvested from Patients with Periodontitis Can Be Rejuvenated by RG108.

Periodontal ligament (PDL) has become an elective source of mesenchymal stem cells (PDLSCs) in dentistry. This research aimed to compare healthy PDLSCs (hPDLSCs) and periodontitis PDLSCs (pPDLSCs) to ascertain any possible functional differences owing to their milieux of origin. Cells were tested in terms of colony-forming unit efficiency; multi differentiating capacity; immunophenotype, stemness, and senescent state were studied by flow cytometry, immunofluorescence, and ß-galactosidase staining; gene expression using RT-PCR. Both hPDLSCs and pPDLSCs were comparable in terms of their immunophenotype and multilineage differentiation capabilities, but pPDLSCs showed a senescent phenotype more frequently. Thus, a selective small molecule inhibitor of DNA methyltransferase (DNMT), RG108, known for its effect on senescence, was used to possibly reverse this phenotype. RG108 did not affect the proliferation and apoptosis of PDLSCs, and it showed little effect on hPDLSCs, while a significant reduction of both p16 and p21 was detected along with an increase of SOX2 and OCT4 in pPDLSCs after treatment at 100 µM RG108. Moreover, the subset of PDLSCs co-expressing OCT4 and p21 decreased, and adipogenic potential increased in pPDLSCs after treatment. pPDLSCs displayed a senescent phenotype that could be reversed, opening new perspectives for the treatment of periodontitis.

Murine models to study human NK cells in human solid tumors.

Since the first studies, the mouse models have provided crucial support for the most important discoveries on NK cells, on their development, function, and circulation within normal and tumor tissues. Murine tumor models were initially set to study murine NK cells, then, ever more sophisticated human-in-mice models have been developed to investigate the behavior of human NK cells and minimize the interferences from the murine environment. This review presents an overview of the models that have been used along time to study NK cells, focusing on the most popular NOG and NSG models, which work as recipients for the preparation of human-in-mice tumor models, the study of transferred human NK cells, and the evaluation of various enhancers of human NK cell function, including cytokines and chimeric molecules. Finally, an overview of the next generation humanized mice is also provided along with a discussion on how traditional and innovative in-vivo and in-vitro approaches could be integrated to optimize effective pre-clinical studies.

Machine learning algorithms distinguish discrete digital emotional fingerprints for web pages related to back pain.

Back pain is the leading cause of disability worldwide. Its emergence relates not only to the musculoskeletal degeneration biological substrate but also to psychosocial factors; emotional components play a pivotal role. In modern society, people are significantly informed by the Internet; in turn, they contribute social validation to a "successful" digital information subset in a dynamic interplay. The Affective component of medical pages has not been previously investigated, a significant gap in knowledge since they represent a critical biopsychosocial feature. We tested the hypothesis that successful pages related to spine pathology embed a consistent emotional pattern, allowing discrimination from a control group. The pool of web pages related to spine or hip/knee pathology was automatically selected by relevance and popularity and submitted to automated sentiment analysis to generate emotional patterns. Machine Learning (ML) algorithms were trained to predict page original topics from patterns with binary classification. ML showed high discrimination accuracy; disgust emerged as a discriminating emotion. The findings suggest that the digital affective "successful content" (collective consciousness) integrates patients' biopsychosocial ecosystem, with potential implications for the emergence of chronic pain, and the endorsement of health-relevant specific behaviors. Awareness of such effects raises practical and ethical issues for health information providers.

CD73/Adenosine Pathway Involvement in the Interaction of Non-Small Cell Lung Cancer Stem Cells and Bone Cells in the Pre-Metastatic Niche.

Adenosinergic signaling is an important regulator of tissue homeostasis and extracellular accumulation of adenosine (Ado) and is associated with different pathologies, such as cancer. In non-small-cell lung cancer (NSCLC), a subset of CD133/CXCR4+ cancer stem cell (CSCs) has been demonstrated to initiate bone metastases. Here we investigated how NSCLC CSCs interact with osteoclasts (OCs) and osteoblasts (OBs) by modulating Ado production and OC activity. We proved that CSC-spheres, generated in vitro from NSCLC cell lines, express CD38, PC-1, and CD73, enzymes of the non-canonical adenosinergic pathway, produce high level of Ado, and down-regulate A1R and A3R inhibitory receptors, while expressing A2AR and A2BR. To address the Ado role and modulation of the in-bone pre-metastatic niche, we performed co-cultures of CSC-spheres with OCs and OBs cells. Firstly, we verified that active OCs do not activate non-canonical the adenosinergic pathway, conversely to OBs. OCs co-cultured with CSC-spheres increase Ado production that is related to the OC resorption activity and contributes to T-cell suppression. Finally, we proved the efficacy of anti-CD73 agents in blocking NSCLC cell migration. Overall, we assessed the importance of adenosinergic signaling in the interaction between CSCs and OCs at the pre-metastatic niche, with therapeutic implications related to Ado production.

Biomimetic Citrate-Coated Luminescent Apatite Nanoplatforms for Diclofenac Delivery in Inflammatory Environments.

Luminescent nanoparticles are innovative tools for medicine, allowing the imaging of cells and tissues, and, at the same time, carrying and releasing different types of molecules. We explored and compared the loading/release ability of diclofenac (COX-2 antagonist), in both undoped- and luminescent Terbium3+ (Tb3+)-doped citrate-coated carbonated apatite nanoparticles at different temperatures (25, 37, 40 °C) and pHs (7.4, 5.2). The cytocompatibility was evaluated on two osteosarcoma cell lines and primary human osteoblasts. Biological effects of diclofenac-loaded-nanoparticles were monitored in an in vitro osteoblast's cytokine-induced inflammation model by evaluating COX-2 mRNA expression and production of PGE2. Adsorption isotherms fitted the multilayer Langmuir-Freundlich model. The maximum adsorbed amounts at 37 °C were higher than at 25 °C, and particularly when using the Tb3+ -doped particles. Diclofenac-release efficiencies were higher at pH 5.2, a condition simulating a local inflammation. The luminescence properties of diclofenac-loaded Tb3+ -doped particles were affected by pH, being the relative luminescence intensity higher at pH 5.2 and the luminescence lifetime higher at pH 7.4, but not influenced either by the temperature or by the diclofenac-loaded amount. Both undoped and Tb3+-doped nanoparticles were cytocompatible. In addition, diclofenac release increased COX-2 mRNA expression and decreased PGE2 production in an in vitro inflammation model. These findings evidence the potential of these nanoparticles for osteo-localized delivery of anti-inflammatory drugs and the possibility to localize the inflammation, characterized by a decrease in pH, by changes in luminescence.

Microfragmented Adipose Tissue (M-FATS) for Improved Healing of Surgically Repaired Achilles Tendon Tears: A Preliminary Study.

INTRODUCTION: Tendon healing is a complicated process that results in inferior structural and functional properties when compared with healthy tendon; the purpose of this study was to assess the effects of the adjunct of microfragmented adipose tissue (M-FATS) after the suture of a series of Achilles tendons. METHODS: After complete Achilles tendon tear, 8 patients underwent open suture repair in conjunction with perilesional application of a preparation of M-FATS rich in mesenchymal stem cells. Results were compared with a similar group of patients treated with conventional open suture. Outcomes were evaluated based on range of motion, functional recovery, and complications according to the American Orthopedic Foot and Ankle Society (AOFAS) score and Foot and Ankle Disability Index (FADI). Achilles tendons were examined by ultrasound (US) at 3 months. RESULTS: The AOFAS and FADI scores showed no differences between the 2 groups. US evaluation showed quicker tendon remodeling in the M-FATS group. Adverse events were not documented for both procedures. CONCLUSIONS: The combined application of derived M-FATS for tendon rupture is safe and presents new possibilities for enhanced healing. LEVELS OF EVIDENCE: Level IIIb: Case control study.

Biohybrid Bovine Bone Matrix for Controlled Release of Mesenchymal Stem/Stromal Cell Lyosecretome: A Device for Bone Regeneration.

SmartBone® (SB) is a biohybrid bone substitute advantageously proposed as a class III medical device for bone regeneration in reconstructive surgeries (oral, maxillofacial, orthopedic, and oncology). In the present study, a new strategy to improve SB osteoinductivity was developed. SB scaffolds were loaded with lyosecretome, a freeze-dried formulation of mesenchymal stem cell (MSC)-secretome, containing proteins and extracellular vesicles (EVs). Lyosecretome-loaded SB scaffolds (SBlyo) were prepared using an absorption method. A burst release of proteins and EVs (38% and 50% after 30 min, respectively) was observed, and then proteins were released more slowly with respect to EVs, most likely because they more strongly adsorbed onto the SB surface. In vitro tests were conducted using adipose tissue-derived stromal vascular fraction (SVF) plated on SB or SBlyo. After 14 days, significant cell proliferation improvement was observed on SBlyo with respect to SB, where cells filled the cavities between the native trabeculae. On SB, on the other hand, the process was still present, but tissue formation was less organized at 60 days. On both scaffolds, cells differentiated into osteoblasts and were able to mineralize after 60 days. Nonetheless, SBlyo showed a higher expression of osteoblast markers and a higher quantity of newly formed trabeculae than SB alone. The quantification analysis of the newly formed mineralized tissue and the immunohistochemical studies demonstrated that SBlyo induces bone formation more effectively. This osteoinductive effect is likely due to the osteogenic factors present in the lyosecretome, such as fibronectin, alpha-2-macroglobulin, apolipoprotein A, and TGF-ß.

Treatment of knee osteoarthritis by intra-articular injection of concentrated autologous adipose tissue: a twenty four month follow-up study.

PURPOSE: To evaluate the safety and efficacy of autologous concentrated adipose tissue for the treatment of knee OA. METHODS: Eighty-seven patients with knee arthritis from grade 1 to 3, according to Kellgren-Lawrence scale, have been treated with knee arthroscopy and successive intra-articular injection of concentrated adipose tissue. The efficacy of the treatment has been evaluated by the Knee Society Score, Lysholm Score, Forgotten Joint Score, Knee Injury and Osteoarthritis Outcome Score and Noise Reporting Scale. RESULTS: A total of 78/87 patients concluded the study. Overall, the patients were satisfied with the intervention and a significant reduction of the pain was observed in 67 patients, while the others did not report any change in pain severity or worsening. A statistically significant improvement was observed in the considered orthopaedic index, and no major adverse effects were described. The first week after the intervention, most patients reported knee swelling. Five patients failed because they underwent knee replacement surgery between five and nine months from treatment. CONCLUSIONS: In patients with knee OA, a single intra-articular injection of autologous adipose tissue reduced knee pain, stiffness, improved knee function and quality of life without severe complications.

Rehabilitation Protocol After Hip Arthroscopy: A 2015-2020 Systematic Review.

OBJECTIVE: Although many rehabilitation protocols after hip arthroscopy have been described, there is still significant variability about duration, goals, restrictions, and techniques to apply by the physical therapy after the surgical procedure. The aim of the study was to systematically review rehabilitation after hip arthroscopy. DESIGN: The data sources were PubMed, Scopus, and Cochrane Library. The Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines were used for the systematic review. Level I-IV evidence clinical studies and clinical reviews that focused on rehabilitation protocols after hip arthroscopy have been used as study eligibility criteria. Major limitations include the retrospective nature of most of the studies selected (level IV evidence) and the use of different clinical scores to report the outcomes. RESULTS: This review showed that although a standardized guideline on rehabilitation after hip arthroscopy is still missing, the most recent studies and clinical trials are focusing on a four-phase program, which includes goals, recommendations, and a progression of exercises. CONCLUSIONS: Rehabilitation after hip arthroscopy is strongly suggested, but different authors recommended different rehabilitation programs. There is not a defined program, but as of today, the current standard of care is composed of phase-based programs.

Functional results of allograft vs. autograft tendons in anterior cruciate ligament (ACL) reconstruction at 10-year follow-up.

PURPOSE: The anterior cruciate ligament (ACL) tear is one of the most common sports injuries of the knee, and the arthroscopic reconstruction is the gold standard. Nevertheless, controversies about the surgical techniques and the type of graft still exist. Allografts have been considered by many surgeons as valid alternative to autografts. The aim of this study was to assess the effectiveness of allografts compared to autografts at approximately 10 years of follow-up, investigating the level of physical activity currently performed by patients of each group. METHODS: Ninety-four patients, divided into two groups (allografts and autografts), have been retrospectively studied. The two groups did not significantly differ in preoperative sport activity level, age (mean 40.70 years for autografts and 41.23 for allografts) and characteristics. Allograft group received a fresh-frozen graft from the musculoskeletal tissues bank. Evaluations were made using the International Knee Documentation Committee (IKDC) and Lysholm score; every patient was interviewed for complications. RESULTS: The mean follow-up time was approximately 10 years for both groups, with a minimum of 8 years. There were no statistically significant differences between the two groups. Average IKDC scores were 75.21 (SD 15.36) and 80.69 (SD 13.65) for the allograft and autograft groups, respectively. The mean Lysholm score was 87.57 (SD 9.43) for the allografts and 89.10 (SD 8.33) for the autografts. No major complications linked to the allograft tissue arose. CONCLUSION: Both groups achieved almost the same functional outcomes at an average 10 years of follow-up, indicating fresh-frozen allografts as a reasonable alternative for ACL reconstruction. LEVEL OF EVIDENCE: IV, Retrospective case-control study.

Histological evaluation of acetabular bone quality during revision hip arthroplasty.

PURPOSE: Aim of this study was to evaluate acetabular bone vitality during revision hip arthroplasty and to compare the bone quality between revision and primary acetabular arthroplasty. METHODS: During primary and revision total hip arthroplasty surgeries, biopsies were taken from the acetabulum after reaming. The samples (osteochondral cylinders of approximately ⩽1 cm long and 3 mm thickness), after removing the mineral component, were cut longitudinally with a thickness section of 5 µm and colored with hematoxylin-eosin dichromic dye and then evaluated histologically by optical microscopy with 40× magnification. Preoperative radiographs were evaluated. RESULTS: According to inclusion and exclusion criteria, 14 patients formed the revision group patients (mean age: 67.9 years, average time before revision 8.8 years, SD ± 7.06) and 5 patients formed the control primary group (mean age: 61.4 years). The bone quality of the revision group was generally poorer than the primary group, while similar vitality and bone quality has been found between septic and aseptic group. Variables such as age, gender and BMI did not significantly contribute to define bone quality classes. CONCLUSIONS: The study confirms the differences in quality and bone vitality between cases and controls and the necessity to find strategies to improve the osteointegrative processes in revision arthroplasties.

CXCR4 Inhibition Counteracts Immunosuppressive Properties of Metastatic NSCLC Stem Cells.

Cancer stem cells (CSCs) are functionally defined as the cell subset with greater potential to initiate and propagate tumors. Within the heterogeneous population of lung CSCs, we previously identified highly disseminating CD133+CXCR4+ cells able to initiate distant metastasis (metastasis initiating cells-MICs) and to resist conventional chemotherapy. The establishment of an immunosuppressive microenvironment by tumor cells is crucial to sustain and foster metastasis formation, and CSCs deeply interfere with immune responses against tumors. How lung MICs can elude and educate immune cells surveillance to efficiently complete the metastasis cascade is, however, currently unknown. We show here in primary tumors from non-small cell lung cancer (NSCLC) patients that MICs express higher levels of immunoregulatory molecules compared to tumor bulk, namely PD-L1 and CD73, an ectoenzyme that catalyzes the production of immunosuppressive adenosine, suggesting an enhanced ability of MICs to escape immune responses. To investigate in vitro the immunosuppressive ability of MICs, we derived lung spheroids from cultures of adherent lung cancer cell lines, showing enrichment in CD133+CXCR4+MICs, and increased expression of CD73 and CD38, an enzyme that also concurs in adenosine production. MICs-enriched spheroids release high levels of adenosine and express the immunosuppressive cytokine IL-10, undetectable in an adherent cell counterpart. To prevent dissemination of MICs, we tested peptide R, a novel CXCR4 inhibitor that effectively controls in vitro lung tumor cell migration/invasion. Notably, we observed a decreased expression of CD73, CD38, and IL-10 following CXCR4 inhibition. We also functionally proved that conditioned medium from MICs-enriched spheroids compared to adherent cells has an enhanced ability to suppress CD8+ T cell activity, increase Treg population, and induce the polarization of tumor-associated macrophages (TAMs), which participate in suppression of T cells. Treatment of spheroids with anti-CXCR4 rescued T cell cytotoxic activity and prevented TAM polarization, likely by causing the decrease of adenosine and IL-10 production. Overall, we provide evidence that the subset of lung MICs shows high potential to escape immune control and that inhibition of CXCR4 can impair both MICs dissemination and their immunosuppressive activity, therefore potentially providing a novel therapeutic target in combination therapies to improve efficacy of NSCLC treatment.

Bone Loss in Distal Radial Fractures Treated with A Composite Xenohybrid Bone Substitute: A Two Years Follow-Up Retrospective Study.

(1) Background: Recently, surgical treatment of distal radius fractures has increased exponentially. Many locking plates' fixation systems have been developed allowing a more stable reduction and early mobilization. Sometimes, open reduction and fixation of distal radius fractures may leave a residual bone loss requiring grafting. This retrospective study reports clinical and radiologic outcomes of distal radius fractures treated with xenohybrid bone grafting in order to assess (i) the safety of the investigated bone graft; (ii) its radiological integration and biomechanical performances, and (iii) clinical outcomes of the patients; (2) Methods: We performed a retrospective study on a cohort of 19 patients. Preoperative X-ray and CT scan were performed. The mean clinical and radiographical follow-up was two years. Safety of the xenohybrid bone graft was constantly evaluated. Clinical results were assessed through the DASH score and Mayo wrist score; (3) Results: No adverse reactions, infections, and local or general complication were related to the use of xenohybrid bone graft. The radiolucency of the xenografts suggested progressive osteointegration. No evidence of bone graft resorption was detected. All the patients reached consolidation with good to excellent clinical results; and (4) Conclusions: Clinical and radiological data demonstrated that xenohybrid bone grafting promotes new bone formation and healing in osteopenic areas caused by fracture reduction.

Third generation delta ceramic-on-ceramic bearing for total hip arthroplasty at mid-term follow-up.

PURPOSE: to evaluate the results of Delta ceramic-on-ceramic (CoC) for total-hip-arthroplasty (THA). METHODS: 261 THA using Delta-CoC, retrospectively analyzed. A 36 mm head was used in 189 cases and a 32/40 mm in the others. The series have been compared to a group of 89 THA with Forte-CoC. RESULTS: The Harris-Hip-Score improved from 49.1 ±â€¯14.3 to 92.0 ±â€¯8.9 (P < 0.001). In the Delta group there were one ceramic fracture and 2 dislocations. Two hips underwent revision. There were one revision in the Forte group for instability and one squeaking hip. CONCLUSIONS: The new ceramic bearings provides a safe bearing for THA, with rare complications.

The effectiveness of shoe modifications and orthotics in the conservative treatment of Civinini-Morton syndrome: state of art.

Civinini Morton's Syndrome (CMS), better known as Morton's Neuroma, is a benign enlargement that typically affects the third common digital branch of the plantar nerve. It is a common cause of metatarsalgia leading to debilitating pain. It prefers the female gender, with a female to male ratio of 5:1 and an average age of 50 years at time of surgery. Precise aetiology remains under debate, with four etiopathogenetic theories often cited in the literature. Clinical symptoms, physical exam and instrumental evidence are important in assessing and grading the disease. Biomechanics seem to play an important role, especially regarding the usefulness of correct footwear. The first approach in the early stages of this condition usually begins with shoe modifications and orthotics, designed to limit the nerve compression. In order to prevent or delay the development of CMS, shoes should be sufficiently long, comfortable, broad toe-boxed, should bear a flat heel and a sufficiently thick external sole which should not be excessively flexible. Most authors suggested that an insole with medial arch support and a retrocapital bar or pad, just proximal to the metatarsal heads, displaces the pressure sites and can be beneficial to relieve the pain from the pinched nerve. A threshold period of 4.5 months appears to emerge from the results of the analysed studies, indicating that, beyond this period and in neuromas larger than 5-6 mm, orthotics and/or shoes modifications do not seem to give convincing results, proving to be more a palliation for the clinical condition to allow an acceptable life with pain rather than a real treatment.

LIGHT/TNFSF14 Promotes Osteolytic Bone Metastases in Non-small Cell Lung Cancer Patients.

Tumor necrosis factor superfamily member 14 (TNFSF14), LIGHT, is a component of the cytokine network that regulates innate and adaptive immune responses, which promote homeostasis of lymphoid organs, liver, and bone. Metastatic tumors often disrupt the tissue microenvironment, thus altering the homeostasis of the invaded organ; however, the underlying mechanisms required further studies. We investigated the role of LIGHT in osteolytic bone disease induced by metastatic non-small cell lung cancer (NSCLC). Patients diagnosed with NSCLC bone metastasis show significantly higher levels of LIGHT expressed in monocytes compared with non-bone metastatic tumors and healthy controls. Serum LIGHT levels were also higher in patients with bone metastases than in controls, suggesting a role for LIGHT in stimulating osteoclast precursors. In bone metastatic patients, we also detected increased RNA expression and serum RANKL levels, thus by adding anti-LIGHT or RANK-fragment crystallizable region (RANK-Fc) in PBMC cultures, a significant inhibition of osteoclastogenesis was observed. To model this observation in mice, we used the mouse lung cancer cell line LLC-1. After intratibial implantation, wild-type mice showed an increased number of osteoclasts but reduced numbers of osteoblasts and decreased osteoid formation. In contrast, Tnfsf14-/- mice showed no significant bone loss or other changes in bone homeostasis associated with this model. These data indicate LIGHT is a key control mechanism for regulating bone homeostasis during metastatic invasion. Thus, LIGHT may be a novel therapeutic target in osteolytic bone metastases. © 2019 American Society for Bone and Mineral Research.

PMMA-Based Bone Cements and the Problem of Joint Arthroplasty Infections: Status and New Perspectives.

Polymethyl methacrylate (PMMA)-based bone cement is a biomaterial that has been used over the last 50 years to stabilize hip and knee implants or as a bone filler. Although PMMA-based bone cement is widely used and allows a fast-primary fixation to the bone, it does not guarantee a mechanically and biologically stable interface with bone, and most of all it is prone to bacteria adhesion and infection development. In the 1970s, antibiotic-loaded bone cements were introduced to reduce the infection rate in arthroplasty; however, the efficiency of antibiotic-containing bone cement is still a debated issue. For these reasons, in recent years, the scientific community has investigated new approaches to impart antibacterial properties to PMMA bone cement. The aim of this review is to summarize the current status regarding antibiotic-loaded PMMA-based bone cements, fill the gap regarding the lack of data on antibacterial bone cement, and explore the progress of antibacterial bone cement formulations, focusing attention on the new perspectives. In particular, this review highlights the innovative study of composite bone cements containing inorganic antibacterial and bioactive phases, which are a fascinating alternative that can impart both osteointegration and antibacterial properties to PMMA-based bone cement.

The Crosstalk Between Osteodifferentiating Stem Cells and Endothelial Cells Promotes Angiogenesis and Bone Formation.

The synergistic crosstalk between osteodifferentiating stem cells and endothelial cells (ECs) gained the deserved consideration, shedding light on the role of angiogenesis for bone formation and healing. A deep understanding of the molecular basis underlying the mutual influence of mesenchymal stem cells (MSCs) and ECs in the osteogenic process may help improve greatly bone regeneration. Here, the authors demonstrated that osteodifferentiating MSCs co-cultured with ECs promote angiogenesis and ECs recruitment. Moreover, through the use of 3D co-culture systems, we showed that ECs are in turn able to further stimulate the osteodifferentiation of MSCs, thus enhancing bone production. These findings highlighted the existence of a virtuous loop between MSCs and ECs that is central to the osteogenic process. Unraveling the molecular mechanisms governing the functional interaction MSCs and ECs holds great potential in the field of regenerative medicine.