Association of Klotho with physical performance and frailty in middle-aged and older adults: A systematic review

Abstract Ageing is an inevitable process of physical deterioration that impairs functional autonomy and quality of life, becoming a public health issue. Since the percentage of people over 60 years is increasing worldwide, the use of easily detectable biomarkers of ageing is a relevant tool for monitoring of the ageing process and treatment. Among them, Klotho, an ageing suppressor gene because its deficiency leads to ageing like phenotype, seems particularly promising. This systematic review includes the last 10 years clinical studies that evaluated the association between plasma Klotho and body composition, physical performance and frailty in both sedentary and active middle-aged and older adults. Sixteen studies have been found: nine regarding the association between Klotho and body composition, two the association of Klotho and frailty and finally five concerning the effects of physical activity on Klotho. The results of these studies, albeit with some exceptions, point out that Klotho is positively associated with muscle strength and negatively with osteoporosis, frailty, disability and mortality while physical activity generally increases Klotho levels. Moreover, even if there are still few clinical studies, Klotho might be positively associated with bone mineral density, muscle strength, longevity, mobility and robustness during ageing

Sex Specific Determinants in Osteoarthritis: A Systematic Review of Preclinical Studies

Osteoarthritis (OA) is a highly prevalent joint disease that primarily affects about 10% of the world's population over 60 years old. The purpose of this study is to systematically review the preclinical studies regarding sex differences in OA, with particular attention to the molecular aspect and gene expression, but also to the histopathological aspects. Three databases (PubMed, Scopus, and Web of Knowledge) were screened for eligible studies. In vitro and in vivo papers written in English, published in the last 11 years (2009-2020) were eligible. Participants were preclinical studies, including cell cultures and animal models of OA, evaluating sex differences. Independent extraction of articles and quality assessments were performed by two authors using predefined data fields and specific tools (Animals in Research Reporting In Vivo Experiments (ARRIVE) guideline and Systematic Review Centre for Laboratory animal Experimentation (SYRCLE) tool). Twenty-three studies were included in the review: 4 in vitro studies, 18 in vivo studies, and 1 both in vitro and in vivo study. From in vitro works, sex differences were found in the gene expression of inflammatory molecules, hormonal receptors, and in responsiveness to hormonal stimulation. In vivo research showed a great heterogeneity of animal models mainly focused on the histopathological aspects rather than on the analysis of sex-related molecular mechanisms. This review highlights that many gaps in knowledge still exist; improvementsin the selection and reporting of animal models, the use of advanced in vitro models, and multiomics analyses might contribute to developing a personalized gender-based medicine

The interplay of reactive oxygen species, hypoxia, inflammation, and sirtuins in cancer initiation and progression

The presence of ROS is a constant feature in living cells metabolizing O2. ROS concentration and compartmentation determine their physiological or pathological effects. ROS overproduction is a feature of cancer cells and plays several roles during the natural history of malignant tumor. ROS continuously contribute to each step of cancerogenesis, from the initiation to the malignant progression, acting directly or indirectly. In this review, we will (a) underline the role of ROS in the pathway leading a normal cell to tumor transformation and progression, (b) define the multiple roles of ROS during the natural history of a tumor, (c) conciliate many conflicting data about harmful or beneficial effects of ROS, (d) rethink the importance of oncogene and tumor suppressor gene mutations in relation to the malignant progression, and (e) collocate all the cancer hallmarks in a mechanistic sequence which could represent a "physiological" response to the initial growth of a transformed stem/pluripotent cell, defining also the role of ROS in each hallmark. We will provide a simplified sketch about the relationships between ROS and cancer. The attention will be focused on the contribution of ROS to the signaling of HIF, NFκB, and Sirtuins as a leitmotif of cancer initiation and progressi

Biofabrication and Bone Tissue Regeneration: Cell Source, Approaches, and Challenges

The growing occurrence of bone disorders and the increase in aging population have resulted in the need for more effective therapies to meet this request. Bone tissue engineering strategies, by combining biomaterials, cells, and signaling factors, are seen as alternatives to conventional bone grafts for repairing or rebuilding bone defects. Indeed, skeletal tissue engineering has not yet achieved full translation into clinical practice because of several challenges. Bone biofabrication by additive manufacturing techniques may represent a possible solution, with its intrinsic capability for accuracy, reproducibility, and customization of scaffolds as well as cell and signaling molecule delivery. This review examines the existing research in bone biofabrication and the appropriate cells and factors selection for successful bone regeneration as well as limitations affecting these approaches. Challenges that need to be tackled with the highest priority are the obtainment of appropriate vascularized scaffolds with an accurate spatiotemporal biochemical and mechanical stimuli release, in order to improve osseointegration as well as osteogenesis

The role of detraining in tendon mechanobiology

INTRODUCTION: Several conditions such as training, aging, estrogen deficiency and drugs could affect the biological and anatomo-physiological characteristics of the tendon. Additionally, recent preclinical and clinical studies examined the effect of detraining on tendon, showing alterations in its structure and morphology and in tenocyte mechanobiology. However, few data evaluated the importance that cessation of training might have on tendon. Basically, we do not fully understand how tendons react to a phase of training followed by sudden detraining. Therefore, within this review, we summarize the studies where tendon detraining was examined. MATERIALS AND METHODS: A descriptive systematic literature review was carried out by searching three databases (PubMed, Scopus and Web of Knowledge) on tendon detraining. Original articles in English from 2000 to 2015 were included. In addition, the search was extended to the reference lists of the selected articles. A public reference manager (www.mendeley.com) was adopted to remove duplicate articles. RESULTS: An initial literature search yielded 134 references (www.pubmed.org: 53; www.scopus.com: 11; www.webofknowledge.com: 70). Fifteen publications were extracted based on the title for further analysis by two independent reviewers. Abstracts and complete articles were after that reviewed to evaluate if they met inclusion criteria. CONCLUSIONS: The revised literature comprised four clinical studies and an in vitro and three in vivo reports. Overall, the results showed that tendon structure and properties after detraining are compromised, with an alteration in the tissue structural organization and mechanical properties. Clinical studies usually showed a lesser extent of tendon alterations, probably because preclinical studies permit an in-depth evaluation of tendon modifications, which is hard to perform in human subjects. In conclusion, after a period of sudden detraining (e.g., after an injury), physical activity should be taken with caution, following a targeted rehabilitation program. However, further research should be performed to fully understand the effect of sudden detraining on tendons

MiR-33a Controls hMSCS Osteoblast Commitment Modulating the Yap/Taz Expression Through EGFR Signaling Regulation

Mesenchymal stromal cells (hMSCs) display a pleiotropic function in bone regeneration. The signaling involved in osteoblast commitment is still not completely understood, and that determines the failure of current therapies being used. In our recent studies, we identified two miRNAs as regulators of hMSCs osteoblast differentiation driving hypoxia signaling and cytoskeletal reorganization. Other signalings involved in this process are epithelial to mesenchymal transition (EMT) and epidermal growth factor receptor (EGFR) signalings through the regulation of Yes-associated protein (YAP)/PDZ-binding motif (TAZ) expression. In the current study, we investigated the role of miR-33a family as a (i) modulator of YAP/TAZ expression and (ii) a regulator of EGFR signaling during osteoblast commitments. Starting from the observation on hMSCs and primary osteoblast cell lines (Nh-Ost) in which EMT genes and miR-33a displayed a specific expression, we performed a gain and loss of function study with miR-33a-5p and 3p on hMSCs cells and Nh-Ost. After 24 h of transfections, we evaluated the modulation of EMT and osteoblast genes expression by qRT-PCR, Western blot, and Osteoimage assays. Through bioinformatic analysis, we identified YAP as the putative target of miR-33a-3p. Its role was investigated by gain and loss of function studies with miR-33a-3p on hMSCs; qRT-PCR and Western blot analyses were also carried out. Finally, the possible role of EGFR signaling in YAP/TAZ modulation by miR-33a-3p expression was evaluated. Human MSCs were treated with EGF-2 and EGFR inhibitor for different time points, and qRT-PCR and Western blot analyses were performed. The above-mentioned methods revealed a balance between miR-33a-5p and miR-33a-3p expression during hMSCs osteoblast differentiation. The human MSCs phenotype was maintained by miR-33a-5p, while the maintenance of the osteoblast phenotype in the Nh-Ost cell model was permitted by miR-33a-3p expression, which regulated YAP/TAZ through the modulation of EGFR signaling. The inhibition of EGFR blocked the effects of miR-33a-3p on YAP/TAZ modulation, favoring the maintenance of hMSCs in a committed phenotype. A new possible personalized therapeutic approach to bone regeneration was discussed, which might be mediated by customizing delivery of miR-33a in simultaneously targeting EGFR and YAP signaling with combined use of drugs

Nanomechanical Mapping of Hard Tissues by Atomic Force Microscopy: An Application to Cortical Bone

Force mapping of biological tissues via atomic force microscopy (AFM) probes the mechanical properties of samples within a given topography, revealing the interplay between tissue organization and nanometer-level composition. Despite considerable attention to soft biological samples, constructing elasticity maps on hard tissues is not routine for standard AFM equipment due to the difficulty of interpreting nanoindentation data in light of the available models of surface deformation. To tackle this issue, we proposed a protocol to construct elasticity maps of surfaces up to several GPa in moduli by AFM nanoindentation using standard experimental conditions (air operation, nanometrically sharp spherical tips, and cantilever stiffness below 30 N/m). We showed how to process both elastic and inelastic sample deformations simultaneously and independently and quantify the degree of elasticity of the sample to decide which regime is more suitable for moduli calculation. Afterwards, we used the frequency distributions of Young’s moduli to quantitatively assess differences between sample regions different for structure and composition, and to evaluate the presence of mechanical inhomogeneities. We tested our method on histological sections of sheep cortical bone, measuring the mechanical response of different osseous districts, and mapped the surface down to the single collagen fibril level

In Vivo Model of Osteoarthritis to Compare Allogenic Amniotic Epithelial Stem Cells and Autologous Adipose Derived Cells

SIMPLE SUMMARY: An early resolution of osteoarthritis (OA), through minimally invasive orthobiological solutions, would be important to enable a return to daily and sport activities, and delay prosthesis solutions. No study has yet evaluated amniotic epithelial stem cells (AECs) in OA. They could be considered a valid alternative to adipose derived cells, expanded or concentrated, because they differentiate into three lineages and express mesenchymal and embryonic markers, without a tumorigenic phenotype. The innovative aspects of this study are the comparison of three injective orthobiological treatments, the in vivo use of AECs in OA, and the evaluation of structural and inflammatory fronts of OA for up to six months. ABSTRACT: The challenge of osteoarthritis (OA) is to find a minimally invasive orthobiological therapy to contrast OA progression, on inflammatory and structural fronts. The aim of the present study is to compare the effects of an intra-articular injection of three orthobiological treatments, autologous culture expanded adipose-derived mesenchymal stromal cells (ADSCs), autologous stromal vascular fraction (SVF) and allogenic culture expanded amniotic epithelial stem cells (AECs), in an animal model of OA. OA was induced in 24 sheep by bilateral lateral meniscectomy and, at 3 and 6 months post-treatment, the results were analyzed with macroscopy, histology, histomorphometry, and biochemistry. All the three treatments showed better results than control (injection of NaCl), but SVF and AECs showed superiority over ADSCs, because they induced higher cartilage regeneration and lower inflammation. SVF showed better results than AECs at 3 and 6 months. To conclude, SVF seems to be more favorable than the other biological options, because it is easily obtained and rapidly used after harvesting, with good healing potential. AECs cause no discomfort and could be also considered for the treatment of OA joints

Multifunctionalization Modulates Hydroxyapatite Surface Interaction with Bisphosphonate: Antiosteoporotic and Antioxidative Stress Materials

Multifunctionalized biomaterials with enhanced bone antiresorptive properties were obtained through adsorption of a bisphosphonate, risedronate, on hydroxyapatite (HA) nanocrystals functionalized with zinc ions and polyethylenimine (PEI). Zn incorporation into the HA structure amounts to about 8 atom %, whereas the PEI content of the bifunctionalized material ZnHAPEIBP is about 5.9 wt %. The mechanism of adsorption and release of the bisphosphonate on ZnHAPEI is compared with that on ZnHA: risedronate adsorption isotherm on ZnHA is a Langmuir type, whereas the isotherm of adsorption on ZnHAPEI is better fitted with a Freundlich model and involved a higher amount of adsorbed risedronate. In vitro cell tests were carried out with a coculture model of osteoblasts and osteoclasts using a model simulating oxidative stress and consequent cellular senescence and osteoporosis by the addition of H2O2. The conditions utilized in the coculture model strongly affect osteoblast behavior. The results show that the composite materials allow an increase in osteoblast viability and recover impairment, revealing a novel characteristic of risedronate that is able to counteract the negative effects of oxidative stress when associated with differently functionalized samples. Both PEI and the bisphosphonate reduce osteoclast viability. Moreover, PEI, and even more risedronate, exerts an inhibitory effect on osteoclast activity