Adipose-derived stem cells: a review of osteogenesis differentiation

Second part of manuscript based on osteogenesis differentiation of stem cells. Bones are highly regenerative organs but there are still many problems with therapy of large bone defects. Sometimes there is necessary to make a replacement or expansion new bone tissue. Stem cells might be a good solution for this especially ADSCs which manage differentiate into osteoblast in in vitro and in vivo conditions

Wnt10b Deficiency Results in Age-Dependent Loss of Bone Mass and Progressive Reduction of Mesenchymal Progenitor Cells

Wnt10b is a canonical Wnt ligand expressed in developing bone and has been linked to mesenchymal progenitor functions in mice and humans. Because Wnt signaling has been shown to play an important role in progenitor maintenance in a variety of adult tissues, we examined bone deposition and growth rates throughout postnatal development in Wnt10b-null mice. Using bone histomorphometry and micro–computed tomographic (µCT) studies, we demonstrate that trabecular bone deposition is slightly enhanced in Wnt10b-null mice at 1 month of age, followed by progressive loss with age. Importantly, we find that Wnt10b is required for maintenance of adult bone density in multiple backgrounds of inbred mice and that both copies of the Wnt10b gene are required to maintain normal bone density in 6-month-old animals. We go on to show that the loss in trabecular bone in Wnt10b-null mice is associated with a reduction in the number of bone marrow–derived mesenchymal progenitors (MPCs) using in vitro colony-forming unit assays and marker analysis. Analysis of osteogenic gene expression in primary bone marrow stromal cells demonstrated reductions in expression of several osteoblast differentiation markers. Taken together, our results indicate that Wnt10b is uniquely required for maintenance of mesenchymal progenitor activity in adult bone. The results show the significance of studying individual Wnt ligands and their potentially unique contribution in the context of aging and disease. © 2010 American Society for Bone and Mineral Research

Coronectomy of deeply impacted lower third molar : incidence of outcomes and complications after one year follow-up

Objectives: The purpose of present study was to assess the surgical management of impacted third molar with proximity to the inferior alveolar nerve and complications associated with coronectomy in a series of patients undergoing third molar surgery. Material and Methods: The position of the mandibular canal in relation to the mandibular third molar region and mandibular foramen in the front part of the mandible (i.e., third molar in close proximity to the inferior alveolar nerve [IAN] or not) was identified on panoramic radiographs of patients scheduled for third molar extraction. Results: Close proximity to the IAN was observed in 64 patients (35 females, 29 males) with an impacted mandibular third molar. Coronectomy was performed in these patients. The most common complication was tooth migration away from the mandibular canal (n = 14), followed by root exposure (n = 5). Re-operation to remove the root was performed in cases with periapical infection and root exposure. Conclusions: The results indicate that coronectomy can be considered a reasonable and safe treatment alternative for patients who demonstrate elevated risk for injury to the inferior alveolar nerve with removal of the third molars. Coronectomy did not increase the incidence of damage to the inferior alveolar nerve and would be safer than complete extraction in situations in which the root of the mandibular third molar overlaps or is in close proximity to the mandibular canal

Osteogenetic differentiation: a novel role of Slug protein

The regeneration of bone tissue depends on the concerted actions of a plethora of signals that recruit mesenchymal stem cells for lineage-specific differentiation. The signals are conveyed in hormones, growth factors and transcription factors. These molecules are crucial for the osteoblast commitment, differentiation, functions and, consequently, ensure the proper bone modelling and remodelling. Among these factors, Wnt proteins have a critical role in bone development and homeostasis. Accumulated evidences have shown that lymphocyte enhancer binding factor 1/T cell factor (Lef1/Tcf) transcription factors, the nuclear effectors of the Wnt/β-catenin signaling pathway, influence osteoblast proliferation, function, and regeneration. Nevertheless, most downstream bone-specific target genes of this pathway are only partially known. Among these, Slug has been recently implicated in osteosarcoma progression as a Wnt-responsive molecule strongly correlated with a loss of tumor suppressors such as E-cadherin. Slug, also named Snail2, belongs to the Snail family of genes encoding zinc-finger transcription factors. It is expressed at different stages of development in different tissues, mediates epithelial–mesenchymal transition and directs cell motility during embriogenesis. Slug is also expressed in most normal adult human tissues, but little is known about its potential functions. In order to identify new potential osteoblast-specific proteins, in this study we analysed the expression, regulation and role of Slug in human normal primary osteoblasts (hOBs) and in their mesenchymal precursors (hMSCs), in relation to the expression of Wnt/β-catenin signalling mediators and genes which are required in the control of osteochondroprogenitors differentiation. The experiments were performed on hOBs and hMSCs, obtained from bone marrow iliac crest, bone marrow tibial plateau and Wharton’s jelly umbilical cord. Using several molecular analysis including siRNA strategy and Chromatin Immunoprecipitation (ChIP) assay, we demonstrated that: - Slug is expressed in hOBs as well as their mesenchymal precursors; - In hOBs, Slug is regulated by β-catenin and Lef1 that, together with Tcf-1, Tcf-4 and Runx2 are recruited to the Slug gene promoter in vivo; - In hOBs, Slug is positively correlated with osteoblastic markers, such as Runx2, osteopontin, osteocalcin, collagen type I, CXCL12, Wnt/β-catenin signalling and mineral deposition. At the same time, it negatively correlated with Sox9, a factor indispensable for chondrogenic development; - In hMSCs, Slug acts as a negative regulator of Sox9 and Sox5 expression and a positive regulator of Sox6 and STAT1 genes. Regarding Runx2, the role of Slug seems influenced by cell type; - Slug interacts in vivo with Runx2 and Sox9 promoters in hOBs and hMSCs. Our results support the hypothesis that Slug functions as a novel regulator of osteoblast activity, even if with a different role in mature committed osteoblasts and in their undifferentiated progenitors. Furthermore, these findings suggest Slug as a new potential therapeutic target for bone tissue repair and regeneration

Is obesity in women protective against osteoporosis?

The belief that obesity is protective against osteoporosis has recently come into question. The latest epidemiologic and clinical studies have shown that a high level of fat mass might be a risk factor for osteoporosis and fragility fractures. Further, increasing evidence seems to indicate that different components of the metabolic syndrome, ie, hypertension, increased triglycerides, reduced high-density lipoprotein cholesterol, are also potential risk factors for the development of low bone mineral density and osteoporosis. This review considers both the older and more recent data in the literature in order to evaluate further the relationship between fat tissue and bone tissue

Sclerostin: an Emerging Target for the Treatment of Cancer-Induced Bone Disease

Purpose of Review This review provides a summary of the current knowledge on Sost/sclerostin in cancers targeting the bone, discusses novel observations regarding its potential as a therapeutic approach to treat cancer-induced bone loss, and proposes future research needed to fully understand the potential of therapeutic approaches that modulate sclerostin function. Recent Findings Accumulating evidence shows that sclerostin expression is dysregulated in a number of cancers that target the bone. Further, new findings demonstrate that pharmacological inhibition of sclerostin in preclinical models of multiple myeloma results in a robust prevention of bone loss and preservation of bone strength, without apparent effects on tumor growth. These data raise the possibility of targeting sclerostin for the treatment of cancer patients with bone metastasis. Summary Sclerostin is emerging as a valuable target to prevent the bone destruction that accompanies the growth of cancer cells in the bone. Further studies will focus on combining anti-sclerostin therapy with tumor-targeted agents to achieve both beneficial skeletal outcomes and inhibition of tumor progression

The Effects of Ageing on Differentiation and Characterisation of Human Mesenchymal Stem Cells.

BACKGROUND: Mesenchymal stem cells (MSC) are unique in their ability to self-renew and differentiate into one of many lineage possibilities. It is therefore integral to preserve these qualities to prevent the far reaching effects of a defective stem cell. Human mesenchymal stem cells (hMSC) are precursors for and can differentiate into osteoblasts, adipocytes and chondrocytes. They were originally found in the bone marrow, but have also been located in the umbilical cord, adipose tissue and muscle. Few studies have been conducted into the in vivo effects of age on these cells. This contribution reviews current knowledge surrounding the effects of age on the characteriation and differentiation of human mesenchymal stem cells. METHOD: 471 articles were found using a combination of Online published articles from January 1983 to January 2016 were searched using the Cochrane Library, PubMed, Medline, Scopus, Web of Science and Science Direct databases. There were no existing systematic reviews on this research topic. RESULTS: Nine studies were identified that met the predefined selection criteria. Three studies were used to assess the effects of ageing on characterisation of hMSC with no conclusive results. The cumulative results of these studies show that the effect of ageing on characterisation of hMSC remains inconclusive. Seven studies were used to assess the differentiation potentials of hMSC showing that age either decreased or altered lineage preference in hMSC differentiation. CONCLUSION: There is indication that ageing affects hMSC characterisation and differentiation, however it is not conclusive. There are not enough high quality controlled clinical trials to make reliable conclusions.This is the author accepted manuscript. The final version is available from Bentham Science via http://dx.doi.org/10.2174/1574888X1166616042912252

The Wnt/\u3b2-catenin Signaling: A Microenvironmental Support To Chemoresistance In Acute Myeloid Leukemia

The Wnt/\u3b2-catenin signaling is an evolutionarily conserved pathway that plays a pivotal role in the regulation of cell differentiation and self-renewal. It is considered one of the main components of the hematopoiesis and its impairment can lead to the development of acute myeloid leukemia (AML). In the last years, it was reported that human bone marrow mesenchymal stromal cells (hBM-MSCs) support the growth and chemoresistance of leukemia cells, but their contribution to Wnt/\u3b2-catenin signaling in AML cells is still unclear. In this study, we first analyzed the expression pattern of Wnt/\u3b2-catenin components and their correlation with the clinical outcome of AML patients, observing high expression levels of \u3b2-catenin and its active form (phospho-Ser675) in intermediate and poor-risk groups of patients. Accordingly, patients with a lower activation of Wnt/\u3b2-catenin signaling showed longer progression-free survival. Then, we demonstrated that hBM-MSCs increase the activity of nuclear \u3b2-catenin in blast cells, suggesting that Wnt signaling could be involved in the crosstalk between bone marrow stroma and leukemia cells. Therefore, we investigated the anti-leukemia effects of pharmacological Wnt (Niclosamide and PNU-74654) or GSK-3 (LiCl and AR-A014418) inhibitors in combination or not with classic anti-leukemia drugs (Ara-C and Idarubicin). In vitro, Wnt/GSK-3 inhibitors significantly reduced cell proliferation and cell viability, improving drug sensitivity of AML cells cultured alone or in presence of hMB-MSCs. In vivo, PNU-74654, Niclosamide, and LiCl, acting synergistically with Ara-C, dramatically reduced the engraftment of human CD45+ leukemic cells, thus improving animal survival. In conclusion, our results suggest that \u3b2-catenin could be useful as a prognostic marker for AML patients and its inhibition could represent a new potential therapeutic strategy to improve patient outcome and to overcome the chemoresistance mediated by tumor microenvironment