Effects of continuous activation of vitamin D and Wnt response pathways on osteoblastic proliferation and differentiation

Shi. Yan-chuan, Worton, Leah, Esteban, Luis, Baldock, Paul, Fong, Colette, Eisman, John A. and Gardiner, Edith M. (2007) Effects of continuous activation of vitamin D and Wnt response pathways on osteoblastic proliferation and differentiation. Bone, 41 1: 87-96. doi:10.1016/j.bone.2007.04.174

Author Shi. Yan-chuan
Worton, Leah
Esteban, Luis
Baldock, Paul
Fong, Colette
Eisman, John A.
Gardiner, Edith M.
Title Effects of continuous activation of vitamin D and Wnt response pathways on osteoblastic proliferation and differentiation
Journal name Bone   Check publisher's open access policy
ISSN 8756-3282
Publication date 2007-04-19
Year available 2007
Sub-type Article (original research)
DOI 10.1016/j.bone.2007.04.174
Open Access Status
Volume 41
Issue 1
Start page 87
End page 96
Total pages 10
Editor R. Baron
Place of publication Philadelphia, PA, United States
Publisher Elsevier
Language eng
Subject 730114 Skeletal system and disorders (incl. arthritis)
270102 Cell Metabolism
Abstract The Wnt pathway regulates cell proliferation and differentiation in development and disease, with a number of recent reports linking Wnt to control of osteoblast differentiation and bone mass. There is also accumulating evidence for interaction between the Wnt and nuclear receptor (NR)-mediated control pathways in non-osseous tissues. Calcitriol (1,25D3), which is the active hormonal ligand for the vitamin D receptor (VDR), a member of the NR superfamily, induces osteoblastic cell cycle arrest and expression of genes involved in matrix mineralization in vitro, with over-expression of VDR in mature osteoblasts increasing bone mass in mice. To determine whether the vitamin D and Wnt control pathways interact in osteoblastic regulation, we investigated the treatment effects of 1,25D3 and/or lithium chloride (LiCl), which mimics canonical Wnt pathway activation, on osteoblast proliferation and differentiation. Treatments were initiated at various stages in differentiating cultures of the MC3T3-E1 osteoprogenitor cell line. Treatment of subconfluent cultures (day 1) with either agent transiently increased cell proliferation but decreased viable cell number, with additive inhibition after combined treatment. Interestingly, although early response patterns of alkaline phosphatase activity to 1,25D3 and LiCl were opposite, mineralized nodule formation was virtually abolished by either treatment initiated at day 1 and remained very low after initiating treatments at matrix-formation stage (day 6). By contrast, mineralized nodule formation was substantial but reduced if 1,25D3 and/or LiCl treatment was initiated at mineralization onset (day 13). Osteocalcin production was reduced by all treatments at all time points. Thus, vitamin D and/or canonical Wnt pathway activation markedly reduced mineralization, with additive inhibitory effects on viable cell number. The strength of the response was dependent on the stage of differentiation at treatment initiation. Importantly, the inhibitory effect of LiCl in this committed osteoblastic cell line contrasts with the stimulatory effects of genetic Wnt pathway activation in human and mouse bone tissue. This is consistent with the anabolic Wnt response occurring at a stage prior to the mature osteoprogenitor in the intact skeleton and suggests that prolonged or repeated activation of the canonical Wnt response in committed cells may have an inhibitory effect on osteoblast differentiation and function.
Keyword 1,25D3;
Proliferation and differentiation
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

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Created: Tue, 22 Apr 2008, 20:07:19 EST by Kylie Hengst on behalf of UQ Diamantina Institute