Myeloma cells inhibit non-canonical wnt co-receptor ror2 expression in human bone marrow osteoprogenitor cells: effect of wnt5a/ror2 pathway activation on the osteogenic differentiation impairment induced by myeloma cells

被引：43

作者：

Bolzoni, M. ^{[1
]}

Donofrio, G. ^{[2
]}

Storti, P. ^{[1
]}

Guasco, D. ^{[1
]}

Toscani, D. ^{[1
]}

Lazzaretti, M. ^{[3
]}

Bonomini, S. ^{[1
]}

Agnelli, L. ^{[4
,5
]}

Capocefalo, A. ^{[2
]}

Dalla Palma, B. ^{[1
]}

Neri, A. ^{[4
,5
]}

Nicolini, F. ^{[6
]}

Lisignoli, G. ^{[7
]}

Russo, F. ^{[1
]}

Colla, S. ^{[8
]}

Aversa, F. ^{[1
]}

Giuliani, N. ^{[1
]}

机构：

[1] Univ Parma, Hematol & BMT Ctr, I-43126 Parma, Italy

[2] Univ Parma, Dept Anim Hlth, Infect Dis Sect, I-43126 Parma, Italy

[3] Univ Parma, Dept Genet Microorganism Biol Anthropol & Evolut, I-43126 Parma, Italy

[4] Univ Milan, Dept Clin Sci & Community Hlth, Milan, Italy

[5] Fdn IRCCS Ca Granda Osped Maggiore Policlin, Milan, Italy

[6] Univ Parma, Dept Heart, I-43126 Parma, Italy

[7] Ist Ortoped Rizzoli, Lab Immunoreumatol & Rigeneraz Tissutale, Bologna, Italy

[8] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA

来源：

LEUKEMIA | 2013年 / 27卷 / 02期

关键词：

multiple myeloma; microenvironment; mesenchymal cells; non-canonical Wnt signaling; PROMOTES OSTEOBLAST DIFFERENTIATION; MESENCHYMAL STEM-CELLS; OSTEOLYTIC LESIONS; STROMAL CELLS; DISEASE; HOMODIMERIZATION; BIOLOGY; DKK1;

D O I：

10.1038/leu.2012.190

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Multiple nnyeloma (MM) is characterized by the impaired osteogenic differentiation of human nnesenchymal stromal cells (hMSCs). Canonical Wnt signaling is critical for the regulation of bone formation, however, recent evidence suggests that the non-canonical Wnt agonist Wnt5a stimulates human osteoblastogenesis through its co-receptor Ror2. The effects of MM cells on non-canonical Wnt signaling and the effect of the activation of this pathway on MM-induced osteoblast exhaustion are not known and were investigated in this study. We found that the osteogenic differentiation of bone marrow hMSCs toward osteoprogenitor cells (PreOB) significantly increased Ror2 expression, and that MM cells inhibit Ror2 expression by PreOB in co-culture by inhibiting the non-canonical Wnt5a signaling. The activation of the non-canonical Wnt pathway in hMSCs by means of Wnt5a treatment and the overexpression of Wnt5 or Ror2 by lentiviral vectors increased the osteogenic differentiation of hMSCs and blunted the inhibitory effect of MM in co-culture. Consistently, Wnt5a inhibition by specific small interfering RNA reduced the hMSC expression of osteogenic markers. Our findings demonstrate that the Wnt5a/Ror2 pathway is involved in the pathophysiology of MM-induced bone disease and that the activation of the non-canonical Wnt5a/Ror2 pathway in hMSCs increases osteogenic differentiation and may counterbalance the inhibitory effect of MM cells. Leukemia (2013) 27, 451-463; doi:10.1038/leu.2012.190

引用

页码：451 / 463

页数：13

共 38 条

[1] Cross-talk between Wnt signaling pathways in human mesenchymal stem cells leads to functional antagonism during osteogenic differentiation [J].