title: Effects of age on parathyroid hormone signaling in human marrow stromal cells.
abstract: Human bone marrow stromal cells (hMSCs) have the potential to differentiate into osteoblasts; there are age-related decreases in their proliferation and differentiation to osteoblasts. Parathyroid hormone (PTH), when applied intermittently in vivo, has osteoanabolic effects in a variety of systems. In this study, we compared PTH signaling and osteoanabolic effects in hMSCs from young and old subjects. There were age-related decreases in expression of PTH/PTHrP receptor type 1 (PTHR1) gene (P = 0.049, n = 19) and in PTH activation of CREB (P = 0.029, n = 7) and PTH stabilization of β-catenin (P = 0.018, n = 7). Three human PTH peptides, PTH1-34, PTH1-31C (Ostabolin-C, Leu(27) , Cyclo[Glu(22) -Lys(26) ]-hPTH1-31), and PTH1-84 (10 nm), stimulated osteoblast differentiation with hMSCs. Treatment with PTH1-34 resulted in a significant 67% increase in alkaline phosphatase activity in hMSCs obtained from younger subjects (<50 years old, n = 5), compared with an 18% increase in hMSCs from elders (>55 years old, n = 7). Both knockdown of CREB and treatment with a protein kinase A inhibitor H-89 blocked PTH stimulation of osteoblast differentiation in hMSCs from young subjects. The PTH peptides significantly stimulated proliferation of hMSCs. Treatment with PTH1-34 resulted in an average of twice as many cells in cultures of hMSCs from young subjects (n = 4), but had no effect with hMSCs from elders (n = 7). Upregulation of PTHR1 by 24-h pretreatment with 100 nm dexamethasone rescued PTH stimulation of proliferation in hMSCS from elders. In conclusion, age-related intrinsic alterations in signaling responses to osteoanabolic agents like PTH may contribute to cellular and tissue aging of the human skeleton.
authors.affiliation: Department of Orthopedic Surgery, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA.
authors.forename: Shuanhu
authors.initials: S
authors.lastname: Zhou
authors.forename: Ericka M
authors.initials: EM
authors.lastname: Bueno
authors.forename: Sung Won
authors.initials: SW
authors.lastname: Kim
authors.forename: Ilaria
authors.initials: I
authors.lastname: Amato
authors.forename: Longxiang
authors.initials: L
authors.lastname: Shen
authors.forename: Jochen
authors.initials: J
authors.lastname: Hahne
authors.forename: Ilan
authors.initials: I
authors.lastname: Bleiberg
authors.forename: Paul
authors.initials: P
authors.lastname: Morley
authors.forename: Julie
authors.initials: J
authors.lastname: Glowacki
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D000375:Aging / Q000187:drug effects / Q000502:physiology; D000469:Alkaline Phosphatase / Q000378:metabolism; D015153:Blotting, Western; D001854:Bone Marrow Cells / Q000166:cytology; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D003907:Dexamethasone / Q000494:pharmacology; D018274:Electroporation; D005260:Female; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D008875:Middle Aged; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D010281:Parathyroid Hormone / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D044168:Receptor, Parathyroid Hormone, Type 1 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D017154:Stromal Cells / Q000166:cytology; D013449:Sulfonamides / Q000494:pharmacology; D014162:Transfection; D051176:beta Catenin / Q000378:metabolism
chemical_list: C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D007546:Isoquinolines; C470125:PTH protein, human; C473449:PTH1R protein, human; D010281:Parathyroid Hormone; D034741:RNA, Small Interfering; D044168:Receptor, Parathyroid Hormone, Type 1; D013449:Sulfonamides; D051176:beta Catenin; D003907:Dexamethasone; D017868:Cyclic AMP-Dependent Protein Kinases; D000469:Alkaline Phosphatase; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide