title: Combined treatment with a transforming growth factor beta inhibitor (1D11) and bortezomib improves bone architecture in a mouse model of myeloma-induced bone disease.
abstract: Multiple myeloma (MM) patients frequently develop tumor-induced bone destruction, yet no therapy completely eliminates the tumor or fully reverses bone loss. Transforming growth factor-β (TGF-β) activity often contributes to tumor-induced bone disease, and pre-clinical studies have indicated that TGF-β inhibition improves bone volume and reduces tumor growth in bone metastatic breast cancer. We hypothesized that inhibition of TGF-β signaling also reduces tumor growth, increases bone volume, and improves vertebral body strength in MM-bearing mice. We treated myeloma tumor-bearing (immunocompetent KaLwRij and immunocompromised Rag2-/-) mice with a TGF-β inhibitory (1D11) or control (13C4) antibody, with or without the anti-myeloma drug bortezomib, for 4weeks after inoculation of murine 5TGM1 MM cells. TGF-β inhibition increased trabecular bone volume, improved trabecular architecture, increased tissue mineral density of the trabeculae as assessed by ex vivo micro-computed tomography, and was associated with significantly greater vertebral body strength in biomechanical compression tests. Serum monoclonal paraprotein titers and spleen weights showed that 1D11 monotherapy did not reduce overall MM tumor burden. Combination therapy with 1D11 and bortezomib increased vertebral body strength, reduced tumor burden, and reduced cortical lesions in the femoral metaphysis, although it did not significantly improve cortical bone strength in three-point bending tests of the mid-shaft femur. Overall, our data provides rationale for evaluating inhibition of TGF-β signaling in combination with existing anti-myeloma agents as a potential therapeutic strategy to improve outcomes in patients with myeloma bone disease.
authors.affiliation: Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN 27212, USA; Department of Orthopaedic Surgery & Rehabilitation, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Center for Bone Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Biomedical Engineering, Vanderbilt University, Nashville, TN 37232, USA. Electronic address: jeffry.s.nyman@vanderbilt.edu.
authors.forename: Jeffry S
authors.initials: JS
authors.lastname: Nyman
authors.affiliation: Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN 27212, USA; Center for Bone Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: Alyssa R
authors.initials: AR
authors.lastname: Merkel
authors.affiliation: Department of Orthopaedic Surgery & Rehabilitation, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: Sasidhar
authors.initials: S
authors.lastname: Uppuganti
authors.affiliation: Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
authors.forename: Bijaya
authors.initials: B
authors.lastname: Nayak
authors.affiliation: Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN 27212, USA.
authors.forename: Barbara
authors.initials: B
authors.lastname: Rowland
authors.affiliation: Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN 27212, USA; Center for Bone Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Biomedical Engineering, Vanderbilt University, Nashville, TN 37232, USA.
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Makowski
authors.affiliation: Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA; The Cancer Therapy & Research Center, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
authors.forename: Babatunde O
authors.initials: BO
authors.lastname: Oyajobi
authors.affiliation: Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN 27212, USA; Center for Bone Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Biomedical Engineering, Vanderbilt University, Nashville, TN 37232, USA; Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Cancer Biology, Vanderbilt University, Nashville, TN 37232, USA. Electronic address: julie.sterling@vanderbilt.edu.
authors.forename: Julie A
authors.initials: JA
authors.lastname: Sterling
mesh_terms: D000818:Animals; D001847:Bone Diseases / Q000188:drug therapy* / Q000209:etiology* / Q000473:pathology; D001842:Bone and Bones / Q000187:drug effects / Q000473:pathology*; D000069286:Bortezomib / Q000494:pharmacology / Q000627:therapeutic use*; D000071556:Cancellous Bone / Q000473:pathology / Q000503:physiopathology; D002452:Cell Count; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D008810:Mice, Inbred C57BL; D009101:Multiple Myeloma / Q000150:complications* / Q000473:pathology; D010006:Osteoblasts / Q000473:pathology; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D000069286:Bortezomib
keywords: 1D11; Bone architecture; Bortezomib; Myeloma bone disease; Osteolysis