首页 | 官方网站   微博 | 高级检索  
     


Autocrine and Paracrine Regulation of the Murine Skeleton by Osteocyte‐Derived Parathyroid Hormone‐Related Protein
Authors:Blessing Crimeen‐Irwin  Ingrid J Poulton  Athena R Brunt  Mark R Forwood  Paola Divieti Pajevic  Jonathan H Gooi  T John Martin  Natalie A Sims
Affiliation:1. St. Vincent's Institute of Medical Research, Fitzroy, Victoria, Australia;2. School of Medical Science and Menzies Health Institute Queensland, Griffith University, Gold Coast, Queensland, Australia;3. Department of Molecular and Cell Biology, Boston University Goldman School of Dental Medicine, Boston, MA, USA;4. The University of Melbourne, Department of Medicine at St. Vincent's Hospital, Fitzroy, Victoria, Australia
Abstract:Parathyroid hormone–related protein (PTHrP) and parathyroid hormone (PTH) have N‐terminal domains that bind a common receptor, PTHR1. N‐terminal PTH (teriparatide) and now a modified N‐terminal PTHrP (abaloparatide) are US Food and Drug Administration (FDA)‐approved therapies for osteoporosis. In physiology, PTHrP does not normally circulate at significant levels, but acts locally, and osteocytes, cells residing within the bone matrix, express both PTHrP and the PTHR1. Because PTHR1 in osteocytes is required for normal bone resorption, we determined how osteocyte‐derived PTHrP influences the skeleton. We observed that adult mice with low PTHrP in osteocytes (targeted with the Dmp1(10kb)‐Cre) have low trabecular bone volume and osteoblast numbers, but osteoclast numbers were unaffected. In addition, bone size was normal, but cortical bone strength was impaired. Osteocyte‐derived PTHrP therefore stimulates bone formation and bone matrix strength, but is not required for normal osteoclastogenesis. PTHrP knockdown and overexpression studies in cultured osteocytes indicate that osteocyte‐secreted PTHrP regulates their expression of genes involved in matrix mineralization. We determined that osteocytes secrete full‐length PTHrP with no evidence for secretion of lower molecular weight forms containing the N‐terminus. We conclude that osteocyte‐derived full‐length PTHrP acts through both PTHR1 receptor‐mediated and receptor‐independent actions in a paracrine/autocrine manner to stimulate bone formation and to modify adult cortical bone strength. © 2017 American Society for Bone and Mineral Research.
Keywords:OSTEOCYTES  GENETIC ANIMAL MODELS  PTHrP  ANABOLICS  CELL/TISSUE SIGNALING  PARACRINE PATHWAYS
设为首页 | 免责声明 | 关于勤云 | 加入收藏

Copyright©北京勤云科技发展有限公司    京ICP备09084417号-23

京公网安备 11010802026262号