Effects of age on parathyroid hormone signaling in human marrow stromal cells

Aging Cell

Shuanhu Zhou²  Ericka M. Bueno²  Sung Won Kim²  Ilaria Amato²  Longxiang Shen²  Jochen Hahne²  Ilan Bleiberg²  Paul Morley¹ 

[1] Zelos Therapeutics, Inc., West Conshohocken, PA 19428, USA;Department of Orthopedic Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA

关键词: parathyroid hormone;    age;    signaling;    osteoblast;    proliferation;    differentiation;    β‐catenin;    CREB;    human marrow stromal cells;   

DOI  :  10.1111/j.1474-9726.2011.00717.x

来源: Wiley

【 摘 要 】

Summary

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, Leu²⁷, Cyclo[Glu²²-Lys²⁶]-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.

【 授权许可】

Unknown   
© 2011 The Authors. Aging Cell © 2011 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland