The transcriptional profile of mesenchymal stem cell populations in primary osteoporosis is distinct and shows overexpression of osteogenic inhibitors.
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The transcriptional profile of mesenchymal stem cell populations in primary osteoporosis is distinct and shows overexpression of osteogenic inhibitors. / Benisch, Peggy; Schilling, Tatjana; Klein-Hitpass, Ludger; Frey, Sönke P; Seefried, Lothar; Raaijmakers, Nadja; Krug, Melanie; Regensburger, Martina; Zeck, Sabine; Schinke, Thorsten; Amling, Michael; Ebert, Regina; Jakob, Franz.
In: PLOS ONE, Vol. 7, No. 9, 9, 2012, p. 45142.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - The transcriptional profile of mesenchymal stem cell populations in primary osteoporosis is distinct and shows overexpression of osteogenic inhibitors.
AU - Benisch, Peggy
AU - Schilling, Tatjana
AU - Klein-Hitpass, Ludger
AU - Frey, Sönke P
AU - Seefried, Lothar
AU - Raaijmakers, Nadja
AU - Krug, Melanie
AU - Regensburger, Martina
AU - Zeck, Sabine
AU - Schinke, Thorsten
AU - Amling, Michael
AU - Ebert, Regina
AU - Jakob, Franz
PY - 2012
Y1 - 2012
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 ?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.
AB - 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 ?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 - Humans
KW - Male
KW - Aged
KW - Female
KW - Middle Aged
KW - Aged, 80 and over
KW - Risk Factors
KW - Genetic Predisposition to Disease
KW - Oligonucleotide Array Sequence Analysis
KW - Cluster Analysis
KW - Gene Expression Regulation
KW - Gene Expression Profiling
KW - Bone Density/genetics
KW - Aging/genetics
KW - Cell Aging/genetics
KW - Mesenchymal Stromal Cells/metabolism
KW - Osteogenesis/genetics
KW - Osteoporosis/genetics/pathology
KW - Osteoporotic Fractures/genetics
KW - Humans
KW - Male
KW - Aged
KW - Female
KW - Middle Aged
KW - Aged, 80 and over
KW - Risk Factors
KW - Genetic Predisposition to Disease
KW - Oligonucleotide Array Sequence Analysis
KW - Cluster Analysis
KW - Gene Expression Regulation
KW - Gene Expression Profiling
KW - Bone Density/genetics
KW - Aging/genetics
KW - Cell Aging/genetics
KW - Mesenchymal Stromal Cells/metabolism
KW - Osteogenesis/genetics
KW - Osteoporosis/genetics/pathology
KW - Osteoporotic Fractures/genetics
U2 - 10.1371/journal.pone.0045142
DO - 10.1371/journal.pone.0045142
M3 - SCORING: Journal article
VL - 7
SP - 45142
JO - PLOS ONE
JF - PLOS ONE
SN - 1932-6203
IS - 9
M1 - 9
ER -
