MicroRNA (miRNA) has shown to enhance or inhibit cell proliferation, differentiation and activity of different cell types in bone tissue. The discovery of miRNA actions and their targets has helped ...to identify them as novel regulations actors in bone. Various studies have shown that miRNA deregulation mediates the progression of bone-related pathologies, such as osteoporosis.
The present review intends to give an exhaustive overview of miRNAs with experimentally validated targets involved in bone homeostasis and highlight their possible role in osteoporosis development. Moreover, the review analyzes miRNAs identified in clinical trials and involved in osteoporosis.
•Review of miRNAs in osteogenic pathways•Review of miRNAs in osteoclastogenic pathways•Review of circulating miRNAs implicated in osteoporosis•Identification of circulating miRNAs as possible markers of osteoporosis
Starting from their role exerted on osteoblast and osteoclast differentiation and activity pathways, microRNAs (miRNAs) have been recently identified as regulators of different processes in bone ...homeostasis. For this purpose, in a recent review, we highlighted, as deregulated miRNAs could be involved in different bone diseases such as osteoporosis. In addition, recent studies supported the concept that osteoporosis-induced bone alterations might offer a receptive site for cancer cells to form bone metastases, However, to date, no data on specific-shared miRNAs between osteoporosis and bone metastases have been considered and described to clarify the evidence of this link. The main goal of this review is to underline as deregulated miRNAs in osteoporosis may have specific roles in the development of bone metastases. The review showed that several circulating osteoporotic miRNAs could facilitate tumor progression and bone-metastasis formation in several tumor types, i.e., breast cancer, prostate cancer, non-small-cell lung cancer, esophageal squamous cell carcinoma, and multiple myeloma. In detail, serum up-regulation of pro-osteoporotic miRNAs, as well as serum down-regulation of anti-osteoporotic miRNAs are common features of all these tumors and are able to promote bone metastasis. These results are of key importance and could help researcher and clinicians to establish new therapeutic strategies connected with deregulation of circulating miRNAs and able to interfere with pathogenic processes of osteoporosis, tumor progressions, and bone-metastasis formation.
Gene therapy might represent a promising strategy for chondral and osteochondral defects repair by balancing the management of temporary joint mechanical incompetence with altered metabolic and ...inflammatory homeostasis. This review analysed preclinical and clinical studies on gene therapy for the repair of articular cartilage defects performed over the last 10 years, focussing on expression vectors (non-viral and viral), type of genes delivered and gene therapy procedures (direct or indirect). Plasmids (non-viral expression vectors) and adenovirus (viral vectors) were the most employed vectors in preclinical studies. Genes delivered encoded mainly for growth factors, followed by transcription factors, anti-inflammatory cytokines and, less frequently, by cell signalling proteins, matrix proteins and receptors. Direct injection of the expression vector was used less than indirect injection of cells, with or without scaffolds, transduced with genes of interest and then implanted into the lesion site. Clinical trials (phases I, II or III) on safety, biological activity, efficacy, toxicity or bio-distribution employed adenovirus viral vectors to deliver growth factors or anti-inflammatory cytokines, for the treatment of osteoarthritis or degenerative arthritis, and tumour necrosis factor receptor or interferon for the treatment of inflammatory arthritis.
Bone marrow adipocytes (BMAs) are the most plentiful cells in the bone marrow and function as an endocrine organ by producing fatty acids, cytokines, and adipokines. Consequently, BMAs can interact ...with tumor cells, influencing both tumor growth and the onset and progression of bone metastasis. This review aims to systematically evaluate the role of BMAs in the development and progression of bone metastasis.
A comprehensive search was conducted on PubMed, Web of Science, and Scopus electronic databases, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement standards, to identify studies published from March 2013 to June 2023. Two independent reviewers assessed and screened the literature, extracted the data, and evaluated the quality of the studies. The body of evidence was evaluated and graded using the ROBINS-I tool for non-randomized studies of interventions and the Systematic Review Centre for Laboratory Animal Experimentation (SYRCLE) tool for
studies. The results were synthesized using descriptive methods.
The search yielded a total of 463 studies, of which 17 studies were included in the final analysis, including 15 preclinical studies and two non-randomized clinical studies. Analysis of preclinical studies revealed that BMAs play a significant role in bone metastasis, particularly in prostate cancer followed by breast and malignant melanoma cancers. BMAs primarily influence cancer cells by inducing a glycolytic phenotype and releasing or upregulating soluble factors, chemokines, cytokines, adipokines, tumor-derived fatty acid-binding protein (FABP), and members of the nuclear receptor superfamily, such as chemokine (C-C motif) ligand 7 (CCL7), C-X-C Motif Chemokine Ligand (CXCL)1, CXCL2, interleukin (IL)-1β, IL-6, FABP4, and peroxisome proliferator-activated receptor γ (PPARγ). These factors also contribute to adipocyte lipolysis and regulate a pro-inflammatory phenotype in BMAs. However, the number of clinical studies is limited, and definitive conclusions cannot be drawn.
The preclinical studies reviewed indicate that BMAs may play a crucial role in bone metastasis in prostate, breast, and malignant melanoma cancers. Nevertheless, further preclinical and clinical studies are needed to better understand the complex role and relationship between BMAs and cancer cells in the bone microenvironment. Targeting BMAs in combination with standard treatments holds promise as a potential therapeutic strategy for bone metastasis.
The growing incidence of degenerative musculoskeletal disorders as well as lifestyle changes has led to an increase in the surgical procedures involving implanted medical devices in orthopedics. When ...studying implant/tissue interface in hard materials (i.e., metals or dense plastics) and/or in large bone segments, the hard plastic embedding of the intact undecalcified tissue envelope with the implant in situ is needed. The aim of this work is to describe the advances and the possibilities of high-temperature methyl methacrylate (MMA) embedding for the histological, histomorphometrical, and biomechanical assessment of bone-implanted medical devices. Unlike routine techniques, undecalcified bone processing histology, using high-temperature MMA, requires a complex and precise sample processing methodology and the availability of sophisticated equipment and software for both sample preparation and analyses. MMA embedding permits the evaluation of biological responses to the presence of implanted medical devices without implant removal, allowing simultaneous qualitative and quantitative histological evaluation, both static and dynamic histomorphometry, and biomechanical analyses not possible with tissue decalcification. MMA embedding, despite being a demanding procedure, is still preferred to other kinds of resin-based embedding because of its peculiar characteristics, which allow the study of samples of big dimensions also implanted with hard materials without reducing the sample or removing the material. Dynamic measurements are allowed together with biomechanical investigations at the bone-biomaterial interface, obtaining a comprehensive and precise evaluation of the safety and effectiveness of medical devices for orthopedic regenerative, reconstructive, and reparative surgery.
Exosomes are nanovesicles actively secreted by potentially all cell types, including tumour cells, with the primary role of extracellular systemic communication mediators, both at autocrine and ...paracrine levels, at short and long distances. Recently, different studies have used exosomes as a delivery system for a plethora of different molecules, such as drugs, microRNAs and proteins. This has been made possible thanks to the simplicity in exosomes engineering, their great stability and versatility for applications in oncology as well as in regenerative medicine.
The aim of this review is to provide information on the state-of-the-art and possible applications of engineered exosomes, both for cargo and specific cell-targeting, in different pathologies related to the musculoskeletal system.
The use of exosomes as therapeutic agents is rapidly evolving, different studies explore drug delivery with exosomes using different molecules, showing an enormous potential in various research fields such as oncology and regenerative medicine.
However, despite the significant progress made by the different studies carried out, currently, the use of exosomes is not a therapeutic reality for the considerable difficulties to overcome.
•State-of-the-art of engineered exosomes in different musculoskeletal pathologies.•Exosome applications in regenerative medicine for muscular-skeletal pathologies•Possible applications of engineered exosomes as drug delivery in bone tumours.•Exosome applications in musculoskeletal diseases related to immune system.
Osteochondral lesions (OCs) are typically of traumatic origins but are also caused by degenerative conditions, in primis osteoarthritis (OA). On the other side, OC lesions themselves, getting worse ...over time, can lead to OA, indicating that chondral and OC defects represent a risk factor for the onset of the pathology. Many animal models have been set up for years for the study of OC regeneration, being successfully employed to test different treatment strategies, from biomaterials and cells to physical and biological adjuvant therapies. These studies rely on a plethora of post-explant investigations ranging from histological and histomorphometric analyses to biomechanical ones. The present review aims to analyze the methods employed for the evaluation of OC treatments in each animal model by screening literature data within the last 10 years. According to the selected research criteria performed in two databases, 60 works were included. Data revealed that lapine (50% of studies) and ovine (23% of studies) models are predominant, and knee joints are the most used anatomical locations for creating OC defects. Analyses are mostly conducted on paraffin-embedded samples in order to perform histological/histomorphometric analyses by applying semiquantitative scoring systems and on fresh samples in order to perform biomechanical investigations by indentation tests on articular cartilage. Instead, a great heterogeneity is pointed out in terms of OC defect dimensions and animal’s age. The choice of experimental times is generally adequate for the animal models adopted, although few studies adopt very long experimental times. Improvements in data reporting and in standardization of protocols would be desirable for a better comparison of results and for ethical reasons related to appropriate and successful animal experimentation.
Purpose
Inadequate subscapularis repair has been advocated as one of the contributing factors for dislocation in reverse total shoulder arthroplasty; nonetheless the need to restore the subscapularis ...tendon integrity is under debate. The aim of this systematic review was to answer the question: does subscapularis reattachment following reverse total shoulder arthroplasty improve joint stability, range of motion and functional scores?
Methods
The literature was systematically screened in accordance with PRISMA guidelines looking for papers evaluating clinical outcomes of reverse total shoulder arthroplasty in relation to the management of subscapularis tendon. Studies comparing clinical outcomes, complications and dislocation rate with or without subscapularis repair were included. Studies in which reverse total shoulder arthroplasty was performed for trauma or tumors were excluded. The methodology of included articles was scored with MINORS scale and the Risk of Bias was assessed adopting the ROBINS-I (Risk Of Bias In Non-randomized Studies of Interventions) developed by the Cochrane Group. A meta-analysis was also performed combining the studies to increase the sample size and hence the power to obtain meaningful data.
Results
The database search identified 1062 records, and 6 full-text articles were finally included. A total number of 1085 reverse total shoulder arthroplasty were assessed on. Except for one study, lateralized prosthetic designs have been used. Dislocation occurred in 0.8% (5/599 patients) of the patient with repaired subscapularis and in 1.6% (8/486 patients) of the tenotomized patients, and subscapularis repair was not associated with a higher risk of dislocation (pooled Peto OR: 0.496, 95% CI: 0.163 to 1.510,
p
= 0.217). Qualitative assessment revealed no differences in the range of motion and clinical scores.
Conclusion
Subscapularis repair after reverse total shoulder arthroplasty produces no clinically meaningful benefits, particularly using lateralized prosthetic designs. Subscapularis re-attachment does not improve implant stability, nor increases range of motion or clinical scores. Given these results, keeping in mind the antagonistic effect of the repaired subscapularis on external rotation, no evidence lead to suggest subscapularis reattachment following reverse total shoulder arthroplasty with lateralized prosthetic designs.
In vitro and in vivo behaviour of an injectable silk fibroin (SF) hydrogel was studied through osteoblast cultures and after implantation in critical-size defects of rabbit distal femurs. A ...commercial synthetic poly(
d,
l lactide-glycolide) copolymer was used as control material. In vitro biocompatibility was evaluated by measuring LDH release, cell proliferation (WST1), differentiation (ALP, OC), and synthetic activity (collagen I, TGF ß1, IL-6). Bone defect healing rate and quality of the newly formed bone inside the defects were determined in vivo by measuring trabecular bone volume
(BV/TV), trabecular thickness (Tb.Th), trabecular number (Tb.N), trabecular separation (Tb.Sp), mineral apposition rate (MAR) and bone formation rate (BFR/B.Pm). In vitro tests indicated that both materials significantly increased cell proliferation in comparison with the negative control. A significant increase in the TGF-
β1 level was found for SF hydrogel in comparison with the control material and negative control. Both materials promoted bone healing when used to fill critical size defects in rabbit femurs. The new-formed bone of the SF hydrogel treated defects showed significantly higher BV/TV, Tb.Th, MAR and BFR/B.Pm and lower Tb.Sp values in comparison with the control gel. At 12 weeks the re-grown bone of the SF hydrogel-treated defects appeared more similar to normal bone than that of the control synthetic polymeric material-treated defects, except for the Tb.N value that differed significantly from that of normal bone (
p<0.05). MAR and BFR/B.Pm presented significantly (
p<0.05) higher values for SF hydrogel-treated defects in comparison with controls treated with a synthetic polymeric material, confirming that SF hydrogel accelerated remodelling processes.
Vertebral body bone marrow aspirate (V-BMA), easily accessible simultaneously with the preparation of the site for pedicle screw insertion during spinal procedures, is becoming an increasingly used ...cell therapy approach in spinal surgery. However, the main drawbacks for V-BMA use are the lack of a standardized procedure and of a structural texture with the possibility of diffusion away from the implant site. The aim of this study was to evaluate, characterize and compare the biological characteristics of MSCs from clotted V-BMA and MSCs from whole and concentrate V-BMAs. MSCs from clotted V-BMA showed the highest cell viability and growth factors expression (TGF-β, VEGF-A, FGF2), the greatest colony forming unit (CFU) potency, cellular homogeneity, ability to differentiate towards the osteogenic (COL1AI, TNFRSF11B, BGLAP) and chondrogenic phenotype (SOX9) and the lowest ability to differentiate toward the adipogenic lineage (ADIPOQ) in comparison to all the other culture conditions. Additionally, results revealed that MSCs, differently isolated, expressed different level of HOX and TALE signatures and that PBX1 and MEIS3 were down-regulated in MSCs from clotted V-BMA in comparison to concentrated one. The study demonstrated for the first time that the cellular source inside the clotted V-BMA showed the best biological properties, representing an alternative and advanced cell therapy approach for patients undergoing spinal surgery.
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