title: The transcriptional profile of mesenchymal stem cell populations in primary osteoporosis is distinct and shows overexpression of osteogenic inhibitors.
abstract: 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.
authors.affiliation: Orthopedic Center for Musculoskeletal Research, University of Wuerzburg, Wuerzburg, Germany.
authors.forename: Peggy
authors.initials: P
authors.lastname: Benisch
authors.forename: Tatjana
authors.initials: T
authors.lastname: Schilling
authors.forename: Ludger
authors.initials: L
authors.lastname: Klein-Hitpass
authors.forename: Sönke P
authors.initials: SP
authors.lastname: Frey
authors.forename: Lothar
authors.initials: L
authors.lastname: Seefried
authors.forename: Nadja
authors.initials: N
authors.lastname: Raaijmakers
authors.forename: Melanie
authors.initials: M
authors.lastname: Krug
authors.forename: Martina
authors.initials: M
authors.lastname: Regensburger
authors.forename: Sabine
authors.initials: S
authors.lastname: Zeck
authors.forename: Thorsten
authors.initials: T
authors.lastname: Schinke
authors.forename: Michael
authors.initials: M
authors.lastname: Amling
authors.forename: Regina
authors.initials: R
authors.lastname: Ebert
authors.forename: Franz
authors.initials: F
authors.lastname: Jakob
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000235:genetics; D015519:Bone Density / Q000235:genetics; D016922:Cellular Senescence / Q000235:genetics; D016000:Cluster Analysis; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D010012:Osteogenesis / Q000235:genetics*; D010024:Osteoporosis / Q000235:genetics* / Q000473:pathology*; D058866:Osteoporotic Fractures / Q000235:genetics; D012307:Risk Factors