Monocytes Promote Osteogenic Differentiation of Mesenchymal Stem Cells

Bone loss is a characteristic of many chronic inflammatory and degenerative diseases such as rheumatoid arthritis and osteoporosis. A major challenge is how to replace bone once it is lost. It is known that the immune system strongly regulates bone and investigations into these interactions have demonstrated that osteoclasts, the bone resorbing cells, are strongly regulated by the immune system. However, less is known about the regulation of osteoblasts, the bone forming cells. Mesenchymal stem cells are multipotent progenitors that can be induced in culture to form osteoblasts. The aim of this study was to investigate whether immune cells also regulate OB differentiation. Using in vitro cell cultures of human bone marrow-derived MSCs it was shown that monocytes/Mφs potently induced MSC differentiation to OBs evidenced by increased alkaline phosphatase and mineralisation. However, the ability of monocyte/Mφs to promote osteogenesis differed between CD14++CD16- and CD14+CD16+ monocyte subset as well as M-CSF and GM-CSF Mφs when activated; the CD16- monocytes and M-CSF Mφs still promoted differentiation whereas the CD16+ monocytes and GM-CSF Mφs inhibited it. The monocyte osteogenic effect was mediated by monocyte-derived soluble factors and required STAT3 signalling as well as COX2 upregulation and the production of PGE2. Finally, gene profiling microarray identified Oncostatin M as the mediator of monocyte-induced osteogenesis. This study established a role for monocyte/Mφs as critical regulators of osteogenic differentiation via OSM and STAT3 signalling. It also provides an insight into the interactions between MSCs and monocyte/Mφs in an inflammatory setting where OB differentiation will depend on the balance between pro-inflammatory versus anti-inflammatory monocyte/Mφs

Monocytes induce STAT3 activation in human mesenchymal stem cells to promote osteoblast formation

A major therapeutic challenge is how to replace bone once it is lost. Bone loss is a characteristic of chronic inflammatory and degenerative diseases such as rheumatoid arthritis and osteoporosis. Cells and cytokines of the immune system are known to regulate bone turnover by controlling the differentiation and activity of osteoclasts, the bone resorbing cells. However, less is known about the regulation of osteoblasts (OB), the bone forming cells. This study aimed to investigate whether immune cells also regulate OB differentiation. Using in vitro cell cultures of human bone marrow-derived mesenchymal stem cells (MSC), it was shown that monocytes/macrophages potently induced MSC differentiation into OBs. This was evident by increased alkaline phosphatase (ALP) after 7 days and the formation of mineralised bone nodules at 21 days. This monocyte-induced osteogenic effect was mediated by cell contact with MSCs leading to the production of soluble factor(s) by the monocytes. As a consequence of these interactions we observed a rapid activation of STAT3 in the MSCs. Gene profiling of STAT3 constitutively active (STAT3C) infected MSCs using Illumina whole human genome arrays showed that Runx2 and ALP were up-regulated whilst DKK1 was down-regulated in response to STAT3 signalling. STAT3C also led to the up-regulation of the oncostatin M (OSM) and LIF receptors. In the co-cultures, OSM that was produced by monocytes activated STAT3 in MSCs, and neutralising antibodies to OSM reduced ALP by 50%. These data indicate that OSM, in conjunction with other mediators, can drive MSC differentiation into OB. This study establishes a role for monocyte/macrophages as critical regulators of osteogenic differentiation via OSM production and the induction of STAT3 signalling in MSCs. Inducing the local activation of STAT3 in bone cells may be a valuable tool to increase bone formation in osteoporosis and arthritis, and in localised bone remodelling during fracture repair

Alterations in Circulating miRNA Levels after Infection with SARS-CoV-2 Could Contribute to the Development of Cardiovascular Diseases: What We Know So Far

The novel coronavirus disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and poses significant complications for cardiovascular disease (CVD) patients. MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression and influence several physiological and pathological processes, including CVD. This critical review aims to expand upon the current literature concerning miRNA deregulation during the SARS-CoV-2 infection, focusing on cardio-specific miRNAs and their association with various CVDs, including cardiac remodeling, arrhythmias, and atherosclerosis after SARS-CoV-2 infection. Despite the scarcity of research in this area, our findings suggest that changes in the expression levels of particular COVID-19-related miRNAs, including miR-146a, miR-27/miR-27a-5p, miR-451, miR-486-5p, miR-21, miR-155, and miR-133a, may be linked to CVDs. While our analysis did not conclusively determine the impact of SARS-CoV-2 infection on the profile and/or expression levels of cardiac-specific miRNAs, we proposed a potential mechanism by which the miRNAs mentioned above may contribute to the development of these two pathologies. Further research on the relationship between SARS-CoV-2, CVDs, and microRNAs will significantly enhance our understanding of this connection and may lead to the use of these miRNAs as biomarkers or therapeutic targets for both pathologies

Combined effect of glutamine at position 70 of HLA-DRB1 and alanine at position 57 of HLA-DQB1 in type 1 diabetes: An epitope analysis

<div><p>The contribution of specific HLA Class II alleles in type 1 diabetes is determined by polymorphic amino acid epitopes that direct antigen binding therefore, along with conventional allele frequency analysis, epitope analysis can provide important insights into disease susceptibility. We analyzed the highly heterogeneous Cypriot population for the HLA class II loci of T1DM patients and controls and we report for the first time their allele frequencies. Within our patient cohort we identified a subgroup that did not carry the DRB1*03:01-DQA1*05:01-DQB1*02:01 and DRB1*04:xx-DQA1*03:01-DQB1*03:02 risk haplotypes but a novel recombinant one, DRB1*04:XX-DQA1*03:01-DQB1*02:01 designated DR4-DQ2.3. Through epitope analysis we identified established susceptibility (DQB1 A⁵⁷, DRB1 H¹³) and resistance (DQB1 D⁵⁷) residues as well as other novel susceptibility residues DRB1 Q⁷⁰, DQB1 L²⁶ and resistance residues DRB1 D⁷⁰, R⁷⁰ and DQB1 Y⁴⁷. Prevalence of susceptibility epitopes was higher in patients and was not exclusively a result of linkage disequilibrium. Residues DRB1 Q⁷⁰, DQB1 L²⁶ and A⁵⁷ and a 10 amino acid epitope of DQA1 were the most significant in discriminating risk alleles. An extended haplotype containing these epitopes was carried by 92% of our patient cohort. Sharing of susceptibility epitopes could also explain the absence of risk haplotypes in patients. Finally, many significantly associated epitopes were non-pocket residues suggesting that critical immune functions may exist spanning further from the binding pockets.</p></div

HLA class II genotypes of type 1 diabetes patients and control subjects.

<p>HLA class II genotypes of type 1 diabetes patients and control subjects.</p

Type 1 diabetes associated polymorphic residues of DQB1 alleles with a proposed function.

<p>Type 1 diabetes associated polymorphic residues of DQB1 alleles with a proposed function.</p

Homozygous and heterozygous inheritance of shared HLA class II epitopes associated with type 1 diabetes.

<p>Homozygous and heterozygous inheritance of shared HLA class II epitopes associated with type 1 diabetes.</p

Type 1 diabetes associated polymorphic residues of DRB1 alleles with a proposed function.

<p>Type 1 diabetes associated polymorphic residues of DRB1 alleles with a proposed function.</p