The similarities between exosomes and liposomes, together with the high organotropism of several types of exosomes, have recently prompted the development of engineered-exosomes or exosome-mimetics, which may be artificial (liposomal) or cell-derived vesicles, as advanced platforms for targeted drug delivery. Here, we provide the current state-of-the-art of using exosome or exosome-inspired systems for drug delivery. We review the various approaches investigated and the shortcomings of each approach. Finally the challenges which have been identified to date in this field are summarized.

https://www.mdpi.com/1999-4923/10/4/218/pdf

Exosomes and Exosome-Inspired Vesicles for Targeted Drug Delivery

Articular hyaline cartilage is extensively hydrated, but it is neither innervated nor vascularized, and its low cell density allows only extremely limited self-renewal. Most clinical and research efforts currently focus on the restoration of cartilage damaged in connection with osteoarthritis or trauma. Here, we discuss current clinical approaches for repairing cartilage, as well as research approaches which are currently developing, and those under translation into clinical practice. We also describe potential future directions in this area, including tissue engineering based on scaffolding and/or stem cells as well as a combination of gene and cell therapy. Particular focus is placed on cell-based approaches and the potential of recently characterized chondro-progenitors; progress with induced pluripotent stem cells is also discussed. In this context, we also consider the ability of different types of stem cell to restore hyaline cartilage and the importance of mimicking the environment in vivo during cell expansion and differentiation into mature chondrocytes.

https://www.mdpi.com/1422-0067/19/8/2366/pdf

Repair of Damaged Articular Cartilage: Current Approaches and Future Directions.

Osteoporosis is a common metabolic bone disease, influenced by genetic and environmental factors, that increases bone fragility and fracture risk and, therefore, has a serious adverse effect on the quality of life of patients. However, epigenetic mechanisms involved in the development of osteoporosis remain unclear. There is accumulating evidence that epigenetic modifications may represent mechanisms underlying the links of genetic and environmental factors with increased risk of osteoporosis and bone fracture. Some RNAs, such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), have been shown to be epigenetic regulators with significant involvement in the control of gene expression, affecting multiple biological processes, including bone metabolism. This review summarizes the results of recent studies on the mechanisms of miRNA-, lncRNA-, and circRNA-mediated osteoporosis associated with osteoblasts and osteoclasts. Deeper insights into the roles of these three classes of RNA in osteoporosis could provide unique opportunities for developing novel diagnostic and therapeutic approaches to this disease.

/pdf/the-roles-of-mirna-lncrna-and-circrna-in-the-development-of-3d2qz7h0rj.pdf

The roles of miRNA, lncRNA and circRNA in the development of osteoporosis

Circular RNA FOXO3 (CircFOXO3, also termed as Hsa_circ_0006404) is derived from exon 2 of forkhead box O3 (FOXO3) gene, and abnormal expression is shown in different diseases. However, whether circFOXO3 plays important roles in tumorigenesis and progression of prostate cancer (PCa) remains unclear. In this study, we found that circFOXO3 was up-regulated in both PCa tissues and serum samples. Moreover, circFOXO3 was positively correlated with the Gleason score in PCa samples. CircFOXO3 was observed to be up-regulated in Gleason score > 6 PCa samples compared with Gleason score = 6 PCa samples. Knock-down circFOXO3 could remarkably inhibit PCa cell cycle, proliferation and promote cell apoptosis in vitro. Furthermore, we demonstrated circFOXO3 could act as miR-29a-3p sponge to up-regulate SLC25A15 expression by bioinformatics analysis, dual-luciferase reporter assays and biotinylated RNA pull-down assays. SLC25A15 could reverse the tumour suppressing roles of knock-down circFOXO3 in PCa. Of note, we found that miR-29a-3p was down-regulated; however, SLC25A15 was overexpressed in PCa samples compared with normal tissues. In conclusion, circFOXO3 acts as a miR-29a-3p sponge to exhibit oncogenic activity that affects the cell cycle and cell apoptosis in PCa through transcriptional up-regulation of SLC25A15. Our analysis suggests circFOXO3 could act as promising prostate cancer biomarkers.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/jcmm.14791

Circular RNA circFOXO3 promotes prostate cancer progression through sponging miR-29a-3p.

Advanced biomaterial-guided delivery of gene vectors is an emerging and highly attractive therapeutic solution for targeted articular cartilage repair, allowing for a controlled and minimally invasive delivery of gene vectors in a spatiotemporally precise manner, reducing intra-articular vector spread and possible loss of the therapeutic gene product. As far as it is known, the very first successful in vivo application of such a biomaterial-guided delivery of a potent gene vector in an orthotopic large animal model of cartilage damage is reported here. In detail, an injectable and thermosensitive hydrogel based on poly(ethylene oxide) (PEO)-poly(propylene oxide) (PPO)-PEO poloxamers, capable of controlled release of a therapeutic recombinant adeno-associated virus (rAAV) vector overexpressing the chondrogenic sox9 transcription factor in full-thickness chondral defects, is applied in a clinically relevant minipig model in vivo. These comprehensive analyses of the entire osteochondral unit with multiple standardized evaluation methods indicate that rAAV-FLAG-hsox9/PEO-PPO-PEO hydrogel-augmented microfracture significantly improves cartilage repair with a collagen fiber orientation more similar to the normal cartilage and protects the subchondral bone plate from early bone loss.

/pdf/thermosensitive-hydrogel-based-on-peo-ppo-peo-poloxamers-for-42mkofe1vc.pdf

Thermosensitive Hydrogel Based on PEO-PPO-PEO Poloxamers for a Controlled In Situ Release of Recombinant Adeno-Associated Viral Vectors for Effective Gene Therapy of Cartilage Defects

Deregulated miRNAs in bone health: Epigenetic roles in osteoporosis.

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.

Gene therapy for chondral and osteochondral regeneration: is the future now?

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.

Deregulated miRNAs in osteoporosis: effects in bone metastasis

https://iris.unipa.it/bitstream/10447/295631/1/Bellavia%20et%20al.pdf

A. De Luca

Papers

Deregulated miRNAs in bone health: Epigenetic roles in osteoporosis.

Gene therapy for chondral and osteochondral regeneration: is the future now?

Deregulated miRNAs in osteoporosis: effects in bone metastasis

Engineered exosomes: A new promise for the management of musculoskeletal diseases