title: Effects of age on bone mRNA levels of sclerostin and other genes relevant to bone metabolism in humans.
abstract: Although aging is associated with a decline in bone formation in humans, the molecular pathways contributing to this decline remain unclear. Several previous clinical studies have shown that circulating sclerostin levels increase with age, raising the possibility that increased production of sclerostin by osteocytes leads to the age-related impairment in bone formation. Thus, in the present study, we examined circulating sclerostin levels as well as bone mRNA levels of sclerostin using quantitative polymerase chain reaction (QPCR) analyses in needle bone biopsies from young (mean age, 30.0years) versus old (mean age, 72.9years) women. In addition, we analyzed the expression of genes in a number of pathways known to be altered with skeletal aging, based largely on studies in mice. While serum sclerostin levels were 46% higher (p<0.01) in the old as compared to the young women, bone sclerostin mRNA levels were no different between the two groups (p=0.845). However, genes related to notch signaling were significantly upregulated (p=0.003 when analyzed as a group) in the biopsies from the old women. In an additional analysis of 118 genes including those from genome-wide association studies related to bone density and/or fracture, BMP/TGFβ family genes, selected growth factors and nuclear receptors, and Wnt/Wnt-related genes, we found that mRNA levels of the Wnt inhibitor, SFRP1, were significantly increased (by 1.6-fold, p=0.0004, false discovery rate [q]=0.04) in the biopsies from the old as compared to the young women. Our findings thus indicate that despite increases in circulating sclerostin levels, bone sclerostin mRNA levels do not increase in elderly women. However, aging is associated with alterations in several key pathways and genes in humans that may contribute to the observed impairment in bone formation. These include notch signaling, which represents a potential therapeutic target for increasing bone formation in humans. Our studies further identified mRNA levels of SFRP1 as being increased in aging bone in humans, suggesting that this may also represent a viable target for the development of anabolic therapies for age-related bone loss and osteoporosis.
authors.affiliation: Endocrine Research Unit and Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA. Electronic address: roforth.matthew@mayo.edu.
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Roforth
authors.affiliation: Endocrine Research Unit and Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA. Electronic address: fujita.koji@mayo.edu.
authors.forename: Koji
authors.initials: K
authors.lastname: Fujita
authors.affiliation: Endocrine Research Unit and Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA. Electronic address: ulrikemcgregor@gmail.com.
authors.forename: Ulrike I
authors.initials: UI
authors.lastname: McGregor
authors.affiliation: Endocrine Research Unit and Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA. Electronic address: kirmani.salman@mayo.edu.
authors.forename: Salman
authors.initials: S
authors.lastname: Kirmani
authors.affiliation: Endocrine Research Unit and Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA. Electronic address: mccready.louise@mayo.edu.
authors.forename: Louise K
authors.initials: LK
authors.lastname: McCready
authors.affiliation: Endocrine Research Unit and Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA. Electronic address: Peterson.james18@mayo.edu.
authors.forename: James M
authors.initials: JM
authors.lastname: Peterson
authors.affiliation: Endocrine Research Unit and Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA. Electronic address: drake.matthew@mayo.edu.
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Drake
authors.affiliation: Endocrine Research Unit and Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA. Electronic address: monroe.david@mayo.edu.
authors.forename: David G
authors.initials: DG
authors.lastname: Monroe
authors.affiliation: Endocrine Research Unit and Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA. Electronic address: khosla.sundeep@mayo.edu.
authors.forename: Sundeep
authors.initials: S
authors.lastname: Khosla
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D050156:Adipogenesis / Q000235:genetics; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000235:genetics*; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D019485:Bone Morphogenetic Proteins / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D001842:Bone and Bones / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D005819:Genetic Markers / Q000235:genetics*; D055106:Genome-Wide Association Study; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D008875:Middle Aged; D010011:Osteocytes / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D013234:Stem Cells / Q000378:metabolism; D055815:Young Adult; D000099274:Frizzled-Related Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015415:Biomarkers; D019485:Bone Morphogenetic Proteins; D005819:Genetic Markers; D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; D012333:RNA, Messenger; D000099274:Frizzled-Related Proteins; C422903:SOST protein, human
keywords: Aging; Bone biopsy; Postmenopausal