Browse > Article
http://dx.doi.org/10.5483/BMBRep.2022.55.12.103

Dikkopf-1 promotes matrix mineralization of osteoblasts by regulating Ca+-CAMK2A- CREB1 pathway  

Hyosun, Park (Hanyang University Institute for Rheumatology Research)
Sungsin, Jo (Hanyang University Institute for Rheumatology Research)
Mi-Ae, Jang (Department of Laboratory Medicine and Genetics, Soonchunhyang University Bucheon Hospital, Soonchunhyang University College of Medicine)
Sung Hoon, Choi (Department of Orthopedic Surgery, Hanyang University Seoul Hospital)
Tae-Hwan, Kim (Hanyang University Institute for Rheumatology Research)
Publication Information
BMB Reports / v.55, no.12, 2022 , pp. 627-632 More about this Journal
Abstract
Dickkopf-1 (DKK1) is a secreted protein that acts as an antagonist of the canonical WNT/β-catenin pathway, which regulates osteoblast differentiation. However, the role of DKK1 on osteoblast differentiation has not yet been fully clarified. Here, we investigate the functional role of DKK1 on osteoblast differentiation. Primary osteoprogenitor cells were isolated from human spinal bone tissues. To examine the role of DKK1 in osteoblast differentiation, we manipulated the expression of DKK1, and the cells were differentiated into mature osteoblasts. DKK1 overexpression in osteoprogenitor cells promoted matrix mineralization of osteoblast differentiation but did not promote matrix maturation. DKK1 increased Ca+ influx and activation of the Ca+/calmodulin-dependent protein kinase II Alpha (CAMK2A)-cAMP response element-binding protein 1 (CREB1) and increased translocation of p-CREB1 into the nucleus. In contrast, stable DKK1 knockdown in human osteosarcoma cell line SaOS2 exhibited reduced nuclear translocation of p-CREB1 and matrix mineralization. Overall, we suggest that manipulating DKK1 regulates the matrix mineralization of osteoblasts by Ca+-CAMK2A-CREB1, and DKK1 is a crucial gene for bone mineralization of osteoblasts.
Keywords
$Ca^+$ influx; CAMK2A-CREB1; DKK1; Matrix mineralization; Osteoblast differentiation;
Citations & Related Records
Times Cited By KSCI : 2  (Citation Analysis)
연도 인용수 순위
1 Mao B, Wu W, Davidson G et al (2002) Kremen proteins are Dickkopf receptors that regulate Wnt/beta-catenin signalling. Nature 417, 664-667   DOI
2 Lin L, Qiu Q, Zhou N et al (2016) Dickkopf-1 is involved in BMP9-induced osteoblast differentiation of C3H10T1/2 mesenchymal stem cells. BMB Rep 49, 179-184   DOI
3 Jo S, Yoon S, Lee SY et al (2020) DKK1 induced by 1,25d3 is required for the mineralization of osteoblasts. Cells 9, 236-250   DOI
4 MacDonald BT, Joiner DM, Oyserman SM et al (2007) Bone mass is inversely proportional to Dkk1 levels in mice. Bone 41, 331-339   DOI
5 Li X, Liu P, Liu W et al (2005) Dkk2 has a role in terminal osteoblast differentiation and mineralized matrix formation. Nat Genet 37, 945-952   DOI
6 Nam B, Park H, Lee YL et al (2020) TGFbeta1 suppressed matrix mineralization of osteoblasts differentiation by regulating SMURF1-C/EBPbeta-DKK1 axis. Int J Mol Sci 21, 1-10
7 Komori T (2006) Regulation of osteoblast differentiation by transcription factors. J Cell Biochem 99, 1233-1239   DOI
8 Lee MH, Kim YJ, Kim HJ et al (2003) BMP-2-induced Runx2 expression is mediated by Dlx5, and TGF-beta 1 opposes the BMP-2-induced osteoblast differentiation by suppression of Dlx5 expression. J Biol Chem 278, 34387-34394   DOI
9 Bennett CN, Longo KA, Wright WS et al (2005) Regulation of osteoblastogenesis and bone mass by Wnt10b. Proc Natl Acad Sci U S A 102, 3324-3329   DOI
10 Day TF, Guo X, Garrett-Beal L and Yang Y (2005) Wnt/betacatenin signaling in mesenchymal progenitors controls osteoblast and chondrocyte differentiation during vertebrate skeletogenesis. Dev Cell 8, 739-750   DOI
11 Guo J, Liu M, Yang D et al (2010) Suppression of Wnt signaling by Dkk1 attenuates PTH-mediated stromal cell response and new bone formation. Cell Metab 11, 161-171   DOI
12 Butler JS, Murray DW, Hurson CJ, O'Brien J, Doran PP and O'Byrne JM (2011) The role of Dkk1 in bone mass regulation: correlating serum Dkk1 expression with bone mineral density. J Orthop Res 29, 414-418   DOI
13 Tian E, Zhan F, Walker R et al (2003) The role of the Wnt-signaling antagonist DKK1 in the development of osteolytic lesions in multiple myeloma. N Engl J Med 349, 2483-2494   DOI
14 Pawar NM and Rao P (2018) Secreted frizzled related protein 4 (sFRP4) update: a brief review. Cell Signal 45, 63-70   DOI
15 Nakanishi R, Akiyama H, Kimura H et al (2008) Osteoblast-targeted expression of Sfrp4 in mice results in low bone mass. J Bone Miner Res 23, 271-277   DOI
16 Haraguchi R, Kitazawa R, Mori K et al (2016) sFRP4-dependent Wnt signal modulation is critical for bone remodeling during postnatal development and age-related bone loss. Sci Rep 6, 25198
17 Guan H, Zhang Y, Gao S et al (2018) Differential patterns of secreted frizzled-related protein 4 (SFRP4) in adipocyte differentiation: adipose depot specificity. Cell Physiol Biochem 46, 2149-2164   DOI
18 Wang K, Zhang Y, Li X et al (2008) Characterization of the Kremen-binding site on Dkk1 and elucidation of the role of Kremen in Dkk-mediated Wnt antagonism. J Biol Chem 283, 23371-23375
19 Beresford JN, Bennett JH, Devlin C, Leboy PS and Owen ME (1992) Evidence for an inverse relationship between the differentiation of adipocytic and osteogenic cells in rat marrow stromal cell cultures. J Cell Sci 102(Pt 2), 341-351   DOI
20 Gallagher JA, Gundle R and Beresford JN (1996) Isolation and culture of bone-forming cells (osteoblasts) from human bone. Methods Mol Med 2, 233-262   DOI
21 Jo S, Won EJ, Kim MJ et al (2021) STAT3 phosphorylation inhibition for treating inflammation and new bone formation in ankylosing spondylitis. Rheumatology (Oxford) 60, 3923-3935   DOI
22 Jo S, Lee JK, Han J et al (2018) Identification and characterization of human bone-derived cells. Biochem Biophys Res Commun 495, 1257-1263   DOI
23 Jo S, Lee YY, Han J et al (2019) CCAAT/enhancer-binding protein beta (C/EBPbeta) is an important mediator of 1,25 dihydroxyvitamin D3 (1,25D3)-induced receptor activator of nuclear factor kappa-B ligand (RANKL) expression in osteoblasts. BMB Rep 52, 391-396   DOI
24 Eriksen EF (2010) Cellular mechanisms of bone remodeling. Rev Endocr Metab Disord 11, 219-227   DOI
25 Florencio-Silva R, Sasso GR, Sasso-Cerri E, Simoes MJ and Cerri PS (2015) Biology of bone tissue: structure, function, and factors that influence bone cells. Biomed Res Int 2015, 421746
26 Hashimoto A, Yamaguchi Y, Chiu LD et al (2015) Time-lapse Raman imaging of osteoblast differentiation. Sci Rep 5, 12529
27 Chae WJ and Bothwell ALM (2018) Canonical and non-canonical wnt signaling in immune cells. Trends Immunol 39, 830-847   DOI
28 Kulterer B, Friedl G, Jandrositz A et al (2007) Gene expression profiling of human mesenchymal stem cells derived from bone marrow during expansion and osteoblast differentiation. BMC Genomics 8, 70
29 Yang CM, Ji S, Li Y, Fu LY, Jiang T and Meng FD (2017) beta-Catenin promotes cell proliferation, migration, and invasion but induces apoptosis in renal cell carcinoma. Onco Targets Ther 10, 711-724   DOI
30 Tan SH, Senarath-Yapa K, Chung MT, Longaker MT, Wu JY and Nusse R (2014) Wnts produced by Osterix-expressing osteolineage cells regulate their proliferation and differentiation. Proc Natl Acad Sci U S A 111, E5262-5271
31 Harb J, Lin PJ and Hao J (2019) Recent development of wnt signaling pathway inhibitors for cancer therapeutics. Curr Oncol Rep 21, 12
32 Sheng M, Thompson MA and Greenberg ME (1991) CREB: a Ca(2+)-regulated transcription factor phosphorylated by calmodulin-dependent kinases. Science 252, 1427-1430   DOI
33 Ding N, Lu Y, Cui H et al (2020) Physalin D inhibits RANKL-induced osteoclastogenesis and bone loss via regulating calcium signaling. BMB Rep 53, 154-159   DOI
34 Mantamadiotis T, Papalexis N and Dworkin S (2012) CREB signalling in neural stem/progenitor cells: recent developments and the implications for brain tumour biology. Bioessays 34, 293-300   DOI
35 Wang H, Xu J, Lazarovici P, Quirion R and Zheng W (2018) cAMP Response Element-Binding Protein (CREB): a possible signaling molecule link in the pathophysiology of schizophrenia. Front Mol Neurosci 11, 255
36 Niehrs C (2006) Function and biological roles of the Dickkopf family of Wnt modulators. Oncogene 25, 7469-7481   DOI