TY - JOUR
T1 - DMP-1-mediated Ghr gene recombination compromises skeletal development and impairs skeletal response to intermittent PTH
AU - Liu, Zhongbo
AU - Kennedy, Oran D.
AU - Cardoso, Luis
AU - Basta-Pljakic, Jelena
AU - Partridge, Nicola C.
AU - Schaffler, Mitchell B.
AU - Rosen, Clifford J.
AU - Yakar, Shoshana
N1 - Funding Information:
This work was supported by U.S. National Institutes of Health (NIH), National Institute of Diabetes and Digestive and Kidney Diseases Grant DK100246 (to S.Y.); NIH National Institute of Arthritis and Musculoskeletal and Skin Diseases Grants AR041210 and AR057139 (to M.B.S.); and Binational Science Foundation Grant 2013282 (to S.Y.). The respective roles of the authors: Z.L. conducted all biochemical and gene expression studies, including serum hormone measurements and iPTH treatment; O.K. performed histomorphometry and micro-CT; L.C. and J.B.P. performed and analyzed micro-CT data; M.B.S. and C.J.R. consulted on study design, data analyses, and interpretation; and S.Y. was principle investigator, oversaw all experiments and data collection, and wrote the paper. All authors concurred with the contents of the manuscript. The material submitted for publication has not been reported and is not under consideration for publication elsewhere. The authors declare no conflicts of interest.
PY - 2016/2/1
Y1 - 2016/2/1
N2 - Bone minerals are acquired during growth and are key determinants of adult skeletal health. During puberty, the serumlevels of growth hormone (GH) and its downstream effector IGF-1 increase and play critical roles in bone acquisition. The goal of the current study was to determine how bone cells integrate signals from the GH/ IGF-1 to enhance skeletal mineralization and strength during pubertal growth. Osteocytes, the most abundant bone cells, were shown to orchestrate bone modeling during growth. We used dentin matrix protein (Dmp)-1- mediated Ghr knockout (DMP-GHRKO) mice to address the role of the GH/IGF axis in osteocytes. We found that DMP-GHRKO did not affect linear growth but compromised overall bone accrual.DMP-GHRKOmice exhibited reduced serum inorganic phosphate and parathyroid hormone (PTH) levels and decreased bone formation indices and were associated with an impaired response to intermittent PTH treatment. Using an osteocyte-like cell line along with in vivo studies, we found that PTH sensitized the response of bone to GH by increasing Janus kinase-2 and IGF-1R protein levels. We concluded that endogenously secreted PTH and GHR signaling in bone are necessary to establish radial bone growth and optimize mineral acquisition during growth.
AB - Bone minerals are acquired during growth and are key determinants of adult skeletal health. During puberty, the serumlevels of growth hormone (GH) and its downstream effector IGF-1 increase and play critical roles in bone acquisition. The goal of the current study was to determine how bone cells integrate signals from the GH/ IGF-1 to enhance skeletal mineralization and strength during pubertal growth. Osteocytes, the most abundant bone cells, were shown to orchestrate bone modeling during growth. We used dentin matrix protein (Dmp)-1- mediated Ghr knockout (DMP-GHRKO) mice to address the role of the GH/IGF axis in osteocytes. We found that DMP-GHRKO did not affect linear growth but compromised overall bone accrual.DMP-GHRKOmice exhibited reduced serum inorganic phosphate and parathyroid hormone (PTH) levels and decreased bone formation indices and were associated with an impaired response to intermittent PTH treatment. Using an osteocyte-like cell line along with in vivo studies, we found that PTH sensitized the response of bone to GH by increasing Janus kinase-2 and IGF-1R protein levels. We concluded that endogenously secreted PTH and GHR signaling in bone are necessary to establish radial bone growth and optimize mineral acquisition during growth.
KW - Fibroblast growth factor-23
KW - Growth hormone receptor
KW - Microcomputed tomography
KW - Osteocyte
KW - Parathyroid hormone
UR - http://www.scopus.com/inward/record.url?scp=84958767726&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84958767726&partnerID=8YFLogxK
U2 - 10.1096/fj.15-275859
DO - 10.1096/fj.15-275859
M3 - Article
C2 - 26481310
AN - SCOPUS:84958767726
VL - 30
SP - 635
EP - 652
JO - FASEB Journal
JF - FASEB Journal
SN - 0892-6638
IS - 2
ER -