Skip to main content

Lund University Publications

LUND UNIVERSITY LIBRARIES

Perturbed bone composition and integrity with disorganized osteoblast function in zinc receptor/Gpr39-deficient mice

Jovanovic, Milena ; Schmidt, Felix N. ; Guterman-Ram, Gali ; Khayyeri, Hanifeh LU ; Hiram-Bab, Sahar ; Orenbuch, Ayelet ; Katchkovsky, Svetlana ; Aflalo, Anastasia ; Isaksson, Hanna LU orcid and Busse, Björn , et al. (2018) In FASEB Journal 32(5). p.2507-2518
Abstract

Changes in bone matrix composition are frequently found with bone diseases and may be associated with increased fracture risk. Bone is rich in the trace element zinc. Zinc was established to play a significant role in the growth, development, and maintenance of healthy bones; however, the mechanisms underlying zinc effects on the integrity of the skeleton are poorly understood. Here, we show that the zinc receptor (ZnR)/Gpr39 is required for normal bone matrix deposition by osteoblasts. Initial analysis showed that Gpr39-deficient (Gpr39-/-) mice had weaker bones as a result of altered bone composition. Fourier transform infrared spectroscopy analysis showed high mineral-to-matrix ratios in the bones of Gpr39-/-... (More)

Changes in bone matrix composition are frequently found with bone diseases and may be associated with increased fracture risk. Bone is rich in the trace element zinc. Zinc was established to play a significant role in the growth, development, and maintenance of healthy bones; however, the mechanisms underlying zinc effects on the integrity of the skeleton are poorly understood. Here, we show that the zinc receptor (ZnR)/Gpr39 is required for normal bone matrix deposition by osteoblasts. Initial analysis showed that Gpr39-deficient (Gpr39-/-) mice had weaker bones as a result of altered bone composition. Fourier transform infrared spectroscopy analysis showed high mineral-to-matrix ratios in the bones of Gpr39-/- mice. Histologic analysis showed abnormally high numbers of active osteoblasts but normal osteoclast numbers on the surfaces of bones from Gpr39-/- mice. Furthermore, Gpr39-/- osteoblasts had disorganized matrix deposition in vitro with cultures exhibiting abnormally low collagen and high mineral contents, findings that demonstrateacell-intrinsic role for ZnR/Gpr39 in these cells. We show that both collagen synthesis and deposition by Gpr39-/- osteoblasts are perturbed. Finally, the expression of the zinc transporter Zip13 and a disintegrin and metalloproteinase with thrombospondin motifs family of zinc-dependent metalloproteases that regulate collagen processing was downregulated in Gpr39-/- osteoblasts. Altogether, our results suggest that zinc sensing by ZnR/Gpr39 affects the expression levels of zinc-dependent enzymes in osteo-blasts and regulates collagen processing and deposition.

(Less)
Please use this url to cite or link to this publication:
author
; ; ; ; ; ; ; ; and , et al. (More)
; ; ; ; ; ; ; ; ; ; and (Less)
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Bone, Collagen deposition, GPCR, Osteoblast, Zinc
in
FASEB Journal
volume
32
issue
5
pages
12 pages
publisher
Wiley
external identifiers
  • scopus:85041729242
  • pmid:29295862
ISSN
0892-6638
DOI
10.1096/fj.201700661RR
language
English
LU publication?
yes
id
eb3c1593-32d5-4642-9575-2e0470358f50
date added to LUP
2020-04-22 14:45:48
date last changed
2024-02-16 14:47:39
@article{eb3c1593-32d5-4642-9575-2e0470358f50,
  abstract     = {{<p>Changes in bone matrix composition are frequently found with bone diseases and may be associated with increased fracture risk. Bone is rich in the trace element zinc. Zinc was established to play a significant role in the growth, development, and maintenance of healthy bones; however, the mechanisms underlying zinc effects on the integrity of the skeleton are poorly understood. Here, we show that the zinc receptor (ZnR)/Gpr39 is required for normal bone matrix deposition by osteoblasts. Initial analysis showed that Gpr39-deficient (Gpr39<sup>-/-</sup>) mice had weaker bones as a result of altered bone composition. Fourier transform infrared spectroscopy analysis showed high mineral-to-matrix ratios in the bones of Gpr39<sup>-/-</sup> mice. Histologic analysis showed abnormally high numbers of active osteoblasts but normal osteoclast numbers on the surfaces of bones from Gpr39<sup>-/-</sup> mice. Furthermore, Gpr39<sup>-/-</sup> osteoblasts had disorganized matrix deposition in vitro with cultures exhibiting abnormally low collagen and high mineral contents, findings that demonstrateacell-intrinsic role for ZnR/Gpr39 in these cells. We show that both collagen synthesis and deposition by Gpr39<sup>-/-</sup> osteoblasts are perturbed. Finally, the expression of the zinc transporter Zip13 and a disintegrin and metalloproteinase with thrombospondin motifs family of zinc-dependent metalloproteases that regulate collagen processing was downregulated in Gpr39<sup>-/-</sup> osteoblasts. Altogether, our results suggest that zinc sensing by ZnR/Gpr39 affects the expression levels of zinc-dependent enzymes in osteo-blasts and regulates collagen processing and deposition.</p>}},
  author       = {{Jovanovic, Milena and Schmidt, Felix N. and Guterman-Ram, Gali and Khayyeri, Hanifeh and Hiram-Bab, Sahar and Orenbuch, Ayelet and Katchkovsky, Svetlana and Aflalo, Anastasia and Isaksson, Hanna and Busse, Björn and Jähn, Katharina and Levaot, Noam}},
  issn         = {{0892-6638}},
  keywords     = {{Bone; Collagen deposition; GPCR; Osteoblast; Zinc}},
  language     = {{eng}},
  number       = {{5}},
  pages        = {{2507--2518}},
  publisher    = {{Wiley}},
  series       = {{FASEB Journal}},
  title        = {{Perturbed bone composition and integrity with disorganized osteoblast function in zinc receptor/Gpr39-deficient mice}},
  url          = {{http://dx.doi.org/10.1096/fj.201700661RR}},
  doi          = {{10.1096/fj.201700661RR}},
  volume       = {{32}},
  year         = {{2018}},
}