This review focuses on the osteogenic differentiation of mesenchymal stem cells (MSC), bone formation and turn-over in good and ill skeletal fates. The interacting molecular pathways which control ...bone remodeling in physiological conditions during a lifelong process are described. Then, alterations of the molecular pathways regulating osteogenesis are addressed. In the aging process, as well as in glucocorticoid-induced osteoporosis, bone loss is caused not only by an unbalanced bone resorption activity, but also by an impairment of MSCs' commitment towards the osteogenic lineage, in favour of adipogenesis. Mutations affecting the expression of key genes involved in the control of bone development occur in several heritable bone disorders. A few examples are described in order to illustrate the pathological consequences of perturbation in different steps of osteogenic commitment, osteoblast maturation, and matrix mineralization, respectively. The involvement of abnormal MSC differentiation in cancer is then discussed. Finally, a brief overview of clinical applications of MSCs in bone regeneration and repair is presented.
Autophagy is involved in different degenerative diseases and it may control epigenetic modifications, metabolic processes, stem cells differentiation as well as apoptosis. Autophagy plays a key role ...in maintaining the homeostasis of cartilage, the tissue produced by chondrocytes; its impairment has been associated to cartilage dysfunctions such as osteoarthritis (OA). Due to their location in a reduced oxygen context, both differentiating and mature chondrocytes are at risk of premature apoptosis, which can be prevented by autophagy. AutophagomiRNAs, which regulate the autophagic process, have been found differentially expressed in OA. AutophagomiRNAs, as well as other regulatory molecules, may also be useful as therapeutic targets. In this review, we describe and discuss the role of autophagy in OA, focusing mainly on the control of autophagomiRNAs in OA pathogenesis and their potential therapeutic applications.
The ubiquitin‐proteasome system (UPS) plays an important role in maintaining cellular homeostasis by degrading a multitude of key regulatory proteins. FBXW11, also known as b‐TrCP2, belongs to the ...F‐box family, which targets the proteins to be degraded by UPS. Transcription factors or proteins associated with cell cycle can be modulated by FBXW11, which may stimulate or inhibit cellular proliferation. Although FBXW11 has been investigated in embryogenesis and cancer, its expression has not been evaluated in osteogenic cells. With the aim to explore FBXW11gene expression modulation in the osteogenic lineage we performed molecular investigations in mesenchymal stem cells (MSCs) and osteogenic cells in normal and pathological conditions. In vitro experiments as well as ex vivo investigations have been performed. In particular, we explored the FBXW11 expression in normal osteogenic cells as well as in cells of cleidocranial dysplasia (CCD) patients or osteosarcoma cells. Our data showed that FBXW11 expression is modulated during osteogenesis and overexpressed in circulating MSCs and in osteogenically stimulated cells of CCD patients. In addition, FBXW11 is post‐transcriptionally regulated in osteosarcoma cells leading to increased levels of beta‐catenin. In conclusion, our findings show the modulation of FBXW11 in osteogenic lineage and its dysregulation in impaired osteogenic cells.
Runx2 is a transcription factor involved in melanoma cell migration and proliferation. Here, we extended the analysis of Runt domain of Runx2 in melanoma cells to deepen understanding of the ...underlying mechanisms. By the CRISPR/Cas9 system we generated the Runt KO melanoma cells 3G8. Interestingly, the proteome analysis showed a specific protein signature of 3G8 cells related to apoptosis and migration, and pointed out the involvement of Runt domain in the neoangiogenesis process. Among the proteins implicated in angiogenesis we identified fatty acid synthase, chloride intracellular channel protein-4, heat shock protein beta-1, Rho guanine nucleotide exchange factor 1, D-3-phosphoglycerate dehydrogenase, myosin-1c and caveolin-1. Upon querying the TCGA provisional database for melanoma, the genes related to these proteins were found altered in 51.36% of total patients. In addition, VEGF gene expression was reduced in 3G8 as compared to A375 cells; and HUVEC co-cultured with 3G8 cells expressed lower levels of CD105 and CD31 neoangiogenetic markers. Furthermore, the tube formation assay revealed down-regulation of capillary-like structures in HUVEC co-cultured with 3G8 in comparison to those with A375 cells. These findings provide new insight into Runx2 molecular details which can be crucial to possibly propose it as an oncotarget of melanoma.
Cbfa1/Runx2 is a bone transcription factor homologous to the Drosophila protein, Runt. Runx2 is a master gene that encodes for a protein involved in the osteogenic differentiation process from ...mesenchymal precursors. It is known that in Cbfa1 deficient mice (Cbfa1
−/−
) the lack of mature osteoblasts is associated to incomplete bone mineralization. An important aim of modern biology is the development of new molecular tools for identification of therapeutic approaches. Recent discoveries in cell and molecular biology enabled researchers in the bone tissue-engineering field to develop new strategies for gene and cell-based therapies. This review summarizes the process of osteogenic differentiation from mesenchymal stem cells and the importance of bone regeneration is discussed. In particular, given the increasing interest in the study of the transcription factor Runx2, this review highlights the role of this target gene and addresses recent strategies using Runx2 for bone regeneration.
Vitamin D deficiency is highly prevalent among children and adults worldwide. Agreement exists that vitamin D deficiency should be corrected. However, the definitions of vitamin deficiency and ...effective vitamin D replacement therapy are inconsistent in the literature. Not only is the dosing regimen still under debate, but also the time and period of administration (i.e., daily vs. monthly dose). In pediatric as well as elderly subjects, dosing regimens with high vitamin D doses at less frequent intervals were proposed to help increase compliance to treatment: these became widespread in clinical practice, despite mounting evidence that such therapies are not only ineffective but potentially harmful, particularly in elderly subjects. Moreover, in the elderly, high doses of vitamin D seem to increase the risk of functional decline and are associated with a higher risk of falls and fractures. Achieving good adherence to recommended prophylactic regimens is definitely one of the obstacles currently being faced in view of the wide segment of the population liable to the treatment and the very long duration of prophylaxis. The daily intake for extended periods is in fact one of the frequent causes of therapeutic drop-outs, while monthly doses of vitamin D may effectively and safely improve patient compliance to the therapy. The aim of our paper is a quasi-literature review on dosing regimens among children and elderly. These two populations showed a particularly significant beneficial effect on bone metabolism, and there could be different outcomes with different dosing regimens.
Fibromyalgia syndrome (FMS) is a chronic clinical condition characterized by pain, fatigue, altered sleep, and cognitive disturbances. The purpose of this study was to compare two alternative ...treatments (nutraceutical and acupuncture) in FMS patients through a randomized clinical trial.
A total of 60 FMS female patients were randomized for treatment with a nutritional combination containing coenzyme Q10, vitamin D, alpha-lipoic acid, magnesium, and tryptophan (Migratens
Group) or acupuncture treatment (Acupuncture Group) performed according the principles of traditional Chinese medicine (TCM), both for 3 months. Changes in pain and in quality of life (QoL) measured with a Fibromyalgia Impact Questionnaire Score-Revised (FIQ-R) and the Fibromyalgia Severity Scale (FSS) were performed at 1, 3, and 6 months after the start of treatments.
A total of 55 patient completed the study (21 in the Migratens
Group and 34 in the Acupuncture Group). Migratens
treatment shows a statistically significant reduction of pain 1 month after the start of therapy (T1, p = 0.025), strengthened after 3 months with maintenance of treatment (p = 0.012). The efficacy in reducing pain was apparent in the Acupuncture Group at all post-treatment determinations and at follow-up (T1 and T2 p = <0.001). Regarding QoL, improvement in FIQ-R and FSS values was revealed in both groups.
The nutraceutical approach with Migratens
seems to be an effective option to for patients with FMS. Our experience confirmed also the validity of acupuncture in these patients. Considering the complexity of the management of FMS patients, our results suggest a cyclical and sequential, or even concurrent treatment with different approaches, to improve the efficacy and the compliance of patients to long-term treatment.
Purpose: The aim of the study was to compare bone mineral density (BMD) in the lumbar spine (LS
BMD
) and the femoral neck (F
BMD
) in male road cyclists (RC n = 39), mountain cyclists (MC n = 30) ...and controls (C n = 27) and to determine the factors associated with BMD in the same group of participants. Methods: BMD, fat mass (FM) and fat-free mass (FFM) were measured using DXA. Calcium intake (Cal), exercise energy expenditure (EEE) and energy availability (EA) were assessed using self-reported questionnaires. Samples for circulating hormones were also obtained. VO
2max
was estimated by a cycloergometric test. Results: After adjustment for body mass, in cyclists LS
BMD
(RC 0.98 ± 0.12; MC 0.98 ± 0.10 g/cm
2
) was significantly lower than in C (1.11 ± 0.10; p < .001), while F
BMD
resulted in no significant difference in cyclists compared to C (p = 0.213). EA (kcal/FFM/day) was different in cyclists and in C (p < .05). In C, EEE and EA were positively associated with LS
BMD
(R = 0.561, R = 0.656, respectively, p < .01), whereas only EA was associated with F
BMD
(R = 0.554, p < .05); a positive association between EA and F
BMD
was found in MC (R = 0.464, p < .05). A negative relationship between VO
2max
and LS
BMD
in RC (R = -0.418, p < .05) and a positive one between EEE and LS
BMD
in MC were found (R = 0.605, p < .001). CaI, free testosterone and cortisol were unrelated to BMD. Conclusion: Both the RC and MC had lower LS
BMD
than C, whereas no difference was found between the two groups of cyclists. The factors associated with BMD are manifold, vary in relation to the measurement site and are likely different in RC, MC and C.
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