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

Coupling Sequence-specific Recognition to DNA Modification*

Enzymes that modify DNA are faced with significant challenges in specificity for both substrate binding and catalysis. We describe how single hydrogen bonds between M.HhaI, a DNA cytosine methyltransferase, and its DNA substrate regulate the positioning of a peptide loop which is ∼28 Å away. Stopped-flow fluorescence measurements of a tryptophan inserted into the loop provide real-time observations of conformational rearrangements. These long-range interactions that correlate with substrate binding and critically, enzyme turnover, will have broad application to enzyme specificity and drug design for this medically relevant class of enzymes

Statistical coevolution analysis and molecular dynamics: Identification of amino acid pairs essential for catalysis

Molecular dynamics (MD) simulations of HhaI DNA methyltransferase and statistical coupling analysis (SCA) data on the DNA cytosine methyltransferase family were combined to identify residues that are coupled by coevolution and motion. The highest ranking correlated pairs from the data matrix product (SCA·MD) are colocalized and form stabilizing interactions; the anticorrelated pairs are separated on average by 30 Å and form a clear focal point centered near the active site. We suggest that these distal anti-correlated pairs are involved in mediating active-site compressions that may be important for catalysis. Mutants that disrupt the implicated interactions support the validity of our combined SCA·MD approach

FULLSPECTRUM: a new PV wave making more efficient use of the solar spectrum

The project FULLSPECTRUM — an Integrated Project (IP) in the terminology of the European Commission — pursues a better exploitation of the FULL solar SPECTRUM by (1) further developing concepts already scientifically proven but not yet developed and (2) by trying to prove new ones in the search for a breakthrough in photovoltaic (PV) technology. More specific objectives are the development of: (a) III–V multijunction cells (MJC), (b) solar thermo-photovoltaic (TPV) converters, (c) intermediate band (IB) materials and cells (IBC), (d) molecular-based concepts (MBC) for full PV utilisation of the solar spectrum and (e) manufacturing technologies (MFG) for novel concepts including assembling. MJC technology towards 40% efficiency will be developed using lower cost substrates and high light concentration (up or above 1000 suns). TPV is a concept with a theoretically high efficiency limit because the entire energy of all the photons is used in the heating process and because the non-used photons can be fed back to the emitter, therefore helping in keeping it hot. In the IBC approach, sub-bandgap photons are exploited by means of an IB. Specific IB materials will be sought by direct synthesis suggested by material-band calculations and using nanotechnology in quantum dot (QD) IBCs. In the development of the MBC, topics such as the development of two-photon dye cells and the development of a static global (direct and diffuse) light concentrator by means of luminescent multicolour dyes and QDs, with the radiation confined by photonic crystals, will be particularly addressed. MFG include optoelectronic assembling techniques and coupling of light to cells with new-optic miniconcentrators

FULLSPECTRUM, a New PV Wave of more Efficient Use of the Solar Spectrum.

Abstract not availableJRC.H-Institute for environment and sustainability (Ispra