title: In silico investigations of potential anabolic treatments in multiple myeloma-induced bone disease.
abstract: No anabolic drugs are currently approved to treat multiple myeloma (MM)-induced bone disease and the anti-MM agent bortezomib exhibits the anabolic effects in the clinic. In this study, we focus on investigating potential anabolic treatments of MM-induced bone disease using our previously proposed MM-bone model, with the goal for clarifying the underlying molecular/cellular mechanisms. Firstly, a variety of virtual drug treatments are explored by the parametric study to clarify the anabolic-related molecular/cellular mechanisms. The real drug (i.e., bortezomib) treatments are further examined by developing an integrated model with bortezomib to validate the clarified anabolic-related molecular/cellular mechanisms. The simulated responses to the bortezomib treatments that are validated by the clinical data are consistent with the simulated responses to the virtual drug treatments. Our study clarifies that the anabolic effects in the treatment of MM-induced bone disease are associated with promoting the differentiation of bone marrow stromal cells (BMSC) and inhibiting the apoptosis of active osteoblasts, while promoting the differentiation of osteoblast precursors is instead suggested to be associated with the anti-catabolic effects. Compared with the individual anabolic therapies, the anabolic therapies that promote the differentiation of BMSC in combination with the anti-MM/anti-catabolic therapies are found to induce a greater increase in the bone volume, while the anabolic therapies that inhibit the apoptosis of active osteoblasts in combination with the anti-MM/anti-catabolic therapies induce a lower increase in the bone volume. The simulations also suggest that the direct inhibition of bortezomib on the osteoclast activity is probably a redundant mechanism.
authors: Department of Infrastructure Engineering, School of Engineering, University of Melbourne, Melbourne, VIC 3010, Australia. wangyan00@tsinghua.org.cn
authors: Yan
authors: Y
authors: Wang
authors: Bo
authors: B
authors: Lin
mesh_terms: D045930:Anabolic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001847:Bone Diseases / Q000188:drug therapy* / Q000209:etiology*; D001897:Boronic Acids / Q000493:pharmacokinetics / Q000627:therapeutic use; D000069286:Bortezomib; D002138:Calibration; D002452:Cell Count; D003198:Computer Simulation; D004164:Diphosphonates / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D004359:Drug Therapy, Combination; D006801:Humans; D008954:Models, Biological; D009101:Multiple Myeloma / Q000150:complications*; D009929:Organ Size / Q000187:drug effects; D010006:Osteoblasts / Q000187:drug effects / Q000473:pathology; D010010:Osteoclasts / Q000187:drug effects / Q000473:pathology; D000077268:Pamidronate; D011719:Pyrazines / Q000493:pharmacokinetics / Q000627:therapeutic use; D015203:Reproducibility of Results; D014584:User-Computer Interface
chemical_list: D045930:Anabolic Agents; D001897:Boronic Acids; D004164:Diphosphonates; D011719:Pyrazines; D000069286:Bortezomib; D000077268:Pamidronate