Three-dimensional in vitro modeling of malignant bone disease recapitulates experimentally accessible mechanisms of osteoinhibition

• DOI: 10.1038/s41419-018-1203-8
• Publication Date: 2018-11-26T10:52:37Z
• Authors: Eoin P. McNeill; Robert W. Reese; Abishek Tondon; Bret H. Clough; Simin Pan; Jeremiah Froese; Daniel Palmer; Ulf Krause; David M. Loeb; Roland Kaunas; Carl A. Gregory
• Keywords: DKK1; Bone cell

Abstract Malignant bone disease (MBD) occurs when tumors establish in bone, causing catastrophic tissue damage as a result of accelerated destruction and inhibition repair. The resultant so-called osteolytic lesions (OL) take the form tumor-filled cavities that cause pain, fractures, associated morbidity. Furthermore, OL microenvironment can support survival tumor cells resistance to chemotherapy. Therefore, deeper understanding formation MBD progression is imperative for development future therapeutic strategies. Herein, we describe novel vitro platform study bone–tumor interactions based on three-dimensional co-culture osteogenically enhanced human mesenchymal stem (OEhMSCs) rotating wall vessel bioreactor (RWV) while attached micro-carrier beads coated with extracellular matrix (ECM) composed factors found anabolic tissue. Osteoinhibition was recapitulated this model by co-culturing OEhMSCs cell line (MOSJ-Dkk1) secretes canonical Wnt (cWnt) inhibitor Dkk-1, tumor-borne osteoinhibitory factor widely several forms MBD, or intact fragments from Dkk-1 positive patient-derived xenografts (PDX). Using model, observed depending conditions growth, biochemically inhibit osteogenesis disrupting cWnt activity OEhMSCs, simultaneously co-engrafting displacing them niche, perturbing their activity, promoting death. In absence detectable co-engraftment PDX had capacity enhance OEhMSC proliferation inhibiting osteogenic differentiation. described has provide new quantifiable insights into multiple pathological mechanisms are not readily measured using monolayer culture animal models.