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Concerted stimuli regulating osteo-chondral differentiation from stem cells: phenotype acquisition regulated by microRNAs.

Gordeladze JO, Djouad F, Brondello JM, Noël D, Duroux-Richard I, Apparailly F, Jorgensen C - Acta Pharmacol. Sin. (2009)

Bottom Line: These act on stem cells (SCs) recruited for lineage-specific differentiation, with cellular phenotypes representing various functions throughout their life span.The signals are rendered by hormones and growth factors (GFs) and mechanical forces ensuring proper modelling and remodelling of bone and cartilage, due to indigenous and programmed metabolism in SCs, osteoblasts, chondrocytes, as well as osteoclasts and other cell types (eg T helper cells).This review focuses on the concerted action of such signals, as well as the regulatory and/or stabilizing control circuits rendered by a class of small RNAs, designated microRNAs.The present approach to cell differentiation in vitro may vastly influence cell engineering for in vivo tissue repair.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, Institute for Basal Medical Sciences, Medical Faculty, University of Oslo, Norway. j.o.gordeladze@medisin.uio.no

ABSTRACT
Bone and cartilage are being generated de novo through concerted actions of a plethora of signals. These act on stem cells (SCs) recruited for lineage-specific differentiation, with cellular phenotypes representing various functions throughout their life span. The signals are rendered by hormones and growth factors (GFs) and mechanical forces ensuring proper modelling and remodelling of bone and cartilage, due to indigenous and programmed metabolism in SCs, osteoblasts, chondrocytes, as well as osteoclasts and other cell types (eg T helper cells).This review focuses on the concerted action of such signals, as well as the regulatory and/or stabilizing control circuits rendered by a class of small RNAs, designated microRNAs. The impact on cell functions evoked by transcription factors (TFs) via various signalling molecules, also encompassing mechanical stimulation, will be discussed featuring microRNAs as important members of an integrative system. The present approach to cell differentiation in vitro may vastly influence cell engineering for in vivo tissue repair.

Show MeSH
Mechano-stimulation of osteoblasts (and chondrocytes). Signalling molecules like BMPs, FGFs, G-protein activating hormones, the extracellular matrix (ECM), and Ca2+-channels are impinging on intracellular signalling mediators converging towards transcription factors (TFs) and TF-modulating proteins determining gene transcriptional activities, here exemplified by TF-binding elements in osteoblasts associating with Smads, Runx2, CREBP, and β-catenin.
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fig4: Mechano-stimulation of osteoblasts (and chondrocytes). Signalling molecules like BMPs, FGFs, G-protein activating hormones, the extracellular matrix (ECM), and Ca2+-channels are impinging on intracellular signalling mediators converging towards transcription factors (TFs) and TF-modulating proteins determining gene transcriptional activities, here exemplified by TF-binding elements in osteoblasts associating with Smads, Runx2, CREBP, and β-catenin.

Mentions: In general, mechano-stimulation will activate many of the same signalling systems like, for example, VEGF-mediated MAPK-enhancement and cAMP/cGMP- and DAG/IP3-mediated signalling118, 144, 145, 146(Figure 4). In osteoblasts, mechano-stimulation increases both cAMP and IP3 levels. Cyclic AMP may be stimulated by PGE2-release, however, many G-proteins like Gαq and Gβγ may activate GTP-ases like Ras and Rho GTP-ases. The PGE2-mediated cAMP increase leads to enhancement of connexin-43 expression through CREBP-activation111, 139, 145, 146, 147. Calcium spikes in osteoblasts can be obtained from mechano-sensitive ion channels, but also from IP3-stimulated opening of calcisomes, leading to increased COX2 activity and c-fos activation148. MAPK is involved through stimulation of the cascade ERK1/2, p38 MAPK, BMK-1, and JNK. Following the up-regulation of MAPKs activities is a down-regulation of RANK-L secretion and an increase in the expression of eNOS. As a result, eNOS-induced NO-synthesis ensues, which eventually leads to reduced RANK-L expression through activation of the guanylate cyclase, yielding the cells low in RANK-L/OPG-ratio111, 119, 126, 149.


Concerted stimuli regulating osteo-chondral differentiation from stem cells: phenotype acquisition regulated by microRNAs.

Gordeladze JO, Djouad F, Brondello JM, Noël D, Duroux-Richard I, Apparailly F, Jorgensen C - Acta Pharmacol. Sin. (2009)

Mechano-stimulation of osteoblasts (and chondrocytes). Signalling molecules like BMPs, FGFs, G-protein activating hormones, the extracellular matrix (ECM), and Ca2+-channels are impinging on intracellular signalling mediators converging towards transcription factors (TFs) and TF-modulating proteins determining gene transcriptional activities, here exemplified by TF-binding elements in osteoblasts associating with Smads, Runx2, CREBP, and β-catenin.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4007326&req=5

fig4: Mechano-stimulation of osteoblasts (and chondrocytes). Signalling molecules like BMPs, FGFs, G-protein activating hormones, the extracellular matrix (ECM), and Ca2+-channels are impinging on intracellular signalling mediators converging towards transcription factors (TFs) and TF-modulating proteins determining gene transcriptional activities, here exemplified by TF-binding elements in osteoblasts associating with Smads, Runx2, CREBP, and β-catenin.
Mentions: In general, mechano-stimulation will activate many of the same signalling systems like, for example, VEGF-mediated MAPK-enhancement and cAMP/cGMP- and DAG/IP3-mediated signalling118, 144, 145, 146(Figure 4). In osteoblasts, mechano-stimulation increases both cAMP and IP3 levels. Cyclic AMP may be stimulated by PGE2-release, however, many G-proteins like Gαq and Gβγ may activate GTP-ases like Ras and Rho GTP-ases. The PGE2-mediated cAMP increase leads to enhancement of connexin-43 expression through CREBP-activation111, 139, 145, 146, 147. Calcium spikes in osteoblasts can be obtained from mechano-sensitive ion channels, but also from IP3-stimulated opening of calcisomes, leading to increased COX2 activity and c-fos activation148. MAPK is involved through stimulation of the cascade ERK1/2, p38 MAPK, BMK-1, and JNK. Following the up-regulation of MAPKs activities is a down-regulation of RANK-L secretion and an increase in the expression of eNOS. As a result, eNOS-induced NO-synthesis ensues, which eventually leads to reduced RANK-L expression through activation of the guanylate cyclase, yielding the cells low in RANK-L/OPG-ratio111, 119, 126, 149.

Bottom Line: These act on stem cells (SCs) recruited for lineage-specific differentiation, with cellular phenotypes representing various functions throughout their life span.The signals are rendered by hormones and growth factors (GFs) and mechanical forces ensuring proper modelling and remodelling of bone and cartilage, due to indigenous and programmed metabolism in SCs, osteoblasts, chondrocytes, as well as osteoclasts and other cell types (eg T helper cells).This review focuses on the concerted action of such signals, as well as the regulatory and/or stabilizing control circuits rendered by a class of small RNAs, designated microRNAs.The present approach to cell differentiation in vitro may vastly influence cell engineering for in vivo tissue repair.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, Institute for Basal Medical Sciences, Medical Faculty, University of Oslo, Norway. j.o.gordeladze@medisin.uio.no

ABSTRACT
Bone and cartilage are being generated de novo through concerted actions of a plethora of signals. These act on stem cells (SCs) recruited for lineage-specific differentiation, with cellular phenotypes representing various functions throughout their life span. The signals are rendered by hormones and growth factors (GFs) and mechanical forces ensuring proper modelling and remodelling of bone and cartilage, due to indigenous and programmed metabolism in SCs, osteoblasts, chondrocytes, as well as osteoclasts and other cell types (eg T helper cells).This review focuses on the concerted action of such signals, as well as the regulatory and/or stabilizing control circuits rendered by a class of small RNAs, designated microRNAs. The impact on cell functions evoked by transcription factors (TFs) via various signalling molecules, also encompassing mechanical stimulation, will be discussed featuring microRNAs as important members of an integrative system. The present approach to cell differentiation in vitro may vastly influence cell engineering for in vivo tissue repair.

Show MeSH