TY  - JOUR
A1  - Benisch, Peggy
A1  - Schilling, Tatjana
A1  - Klein-Hitpass, Ludger
A1  - Frey, Sönke P.
A1  - Seefried, Lothar
A1  - Raaijmakers, Nadja
A1  - Krug, Melanie
A1  - Regensburger, Martina
A1  - Zeck, Sabine
A1  - Schinke, Thorsten
A1  - Amling, Michael
A1  - Ebert, Amling
A1  - Jakob, Franz
T1  - The Transcriptional Profile of Mesenchymal Stem Cell Populations in Primary Osteoporosis Is Distinct and Shows Overexpression of Osteogenic Inhibitors
JF  - PLoS One
N2  - Primary osteoporosis is an age-related disease characterized by an imbalance in bone homeostasis. While the resorptive aspect of the disease has been studied intensely, less is known about the anabolic part of the syndrome or presumptive deficiencies in bone regeneration. Multipotent mesenchymal stem cells (MSC) are the primary source of osteogenic regeneration. In the present study we aimed to unravel whether MSC biology is directly involved in the pathophysiology of the disease and therefore performed microarray analyses of hMSC of elderly patients (79-94 years old) suffering from osteoporosis (hMSC-OP). In comparison to age-matched controls we detected profound changes in the transcriptome in hMSC-OP, e.g. enhanced mRNA expression of known osteoporosis-associated genes (LRP5, RUNX2, COL1A1) and of genes involved in osteoclastogenesis (CSF1, PTH1R), but most notably of genes coding for inhibitors of WNT and BMP signaling, such as Sclerostin and MAB21L2. These candidate genes indicate intrinsic deficiencies in self-renewal and differentiation potential in osteoporotic stem cells. We also compared both hMSC-OP and non-osteoporotic hMSC-old of elderly donors to hMSC of similar to 30 years younger donors and found that the transcriptional changes acquired between the sixth and the ninth decade of life differed widely between osteoporotic and non-osteoporotic stem cells. In addition, we compared the osteoporotic transcriptome to long term-cultivated, senescent hMSC and detected some signs for pre-senescence in hMSC-OP. Our results suggest that in primary osteoporosis the transcriptomes of hMSC populations show distinct signatures and little overlap with non-osteoporotic aging, although we detected some hints for senescence-associated changes. While there are remarkable inter-individual variations as expected for polygenetic diseases, we could identify many susceptibility genes for osteoporosis known from genetic studies. We also found new candidates, e.g. MAB21L2, a novel repressor of BMP-induced transcription. Such transcriptional changes may reflect epigenetic changes, which are part of a specific osteoporosis-associated aging process.
KW  - alkaline-phosphatase
KW  - in vitro
KW  - bone-mineral density
KW  - age-related osteoporosis
KW  - WNT signaling pathway
KW  - replicative senescence
KW  - morphogenetic protein
KW  - parathyroid-hormone
KW  - growth factor
KW  - skeletal overexpression
Y1  - 2012
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-133379
VL  - 7
IS  - 9
ER  - 
TY  - JOUR
A1  - Ebert, Regina
A1  - Benisch, Peggy
A1  - Krug, Melanie
A1  - Zeck, Sabine
A1  - Meißner-Weigl, Jutta
A1  - Steinert, Andre
A1  - Rauner, Martina
A1  - Hofbauer, Lorenz
A1  - Jakob, Franz
T1  - Acute phase serum amyloid A induces proinflammatory cytokines and mineralization via toll-like receptor 4 in mesenchymal stem cells
JF  - Stem Cell Research
N2  - The role of serum amyloid A (SAA) proteins, which are ligands for toll-like receptors, was analyzed in human bone marrow-derived mesenchymal stem cells (hMSCs) and their osteogenic offspring with a focus on senescence, differentiation andmineralization. In vitro aged hMSC developed a senescence-associated secretory phenotype (SASP), resulting in enhanced SAA1/2, TLR2/4 and proinflammatory cytokine (IL6, IL8, IL1\(\beta\), CXCL1, CXCL2) expression before entering replicative senescence. Recombinant human SAA1 (rhSAA1) induced SASP-related genes and proteins in MSC, which could be abolished by cotreatment with the TLR4-inhibitor CLI-095. The same pattern of SASP-resembling genes was stimulated upon induction of osteogenic differentiation, which is accompanied by autocrine SAA1/2 expression. In this context additional rhSAA1 enhanced the SASP-like phenotype, accelerated the proinflammatory phase of osteogenic differentiation and enhanced mineralization. Autocrine/paracrine and rhSAA1 via TLR4 stimulate a proinflammatory phenotype that is both part of the early phase of osteogenic differentiation and the development of senescence. This signaling cascade is tightly involved in bone formation and mineralization, but may also propagate pathological extraosseous calcification conditions such as calcifying inflammation and atherosclerosis.
KW  - human atherosclerotic lesions
KW  - senescence
KW  - expression
KW  - toll-like receptor
KW  - mineralization
KW  - osteogenic differentiation
KW  - serum amyloid A
KW  - inflammation
KW  - mesenchymal stem cells
KW  - WNT5A
KW  - model
KW  - lines
KW  - stromal cells
KW  - RT-PCR
Y1  - 2015
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-148491
VL  - 15
ER  -