TGFβ Inhibition Stimulates Collagen Maturation to Enhance Bone Repair and Fracture Resistance in a Murine Myeloma Model

Abstract

Multiple myeloma is a plasma cell malignancy that causes debilitating bone disease and fractures, in which TGFβ plays a central role. Current treatments do not repair existing damage and fractures remain a common occurrence. We developed a novel low tumor phase murine model mimicking the plateau phase in patients as we hypothesized this would be an ideal time to treat with a bone anabolic. Using in vivo μCT we show substantial and rapid bone lesion repair (and prevention) driven by SD‐208 (TGFβ receptor I kinase inhibitor) and chemotherapy (bortezomib and lenalidomide) in mice with human U266‐GFP‐luc myeloma. We discovered that lesion repair occurred via an intramembranous fracture repair‐like mechanism and that SD‐208 enhanced collagen matrix maturation to significantly improve fracture resistance. Lesion healing was associated with VEGFA expression in woven bone, reduced osteocyte‐derived PTHrP, increased osteoblasts, decreased osteoclasts, and lower serum tartrate‐resistant acid phosphatase 5b (TRACP‐5b). SD‐208 also completely prevented bone lesion development in mice with aggressive JJN3 tumors, and was more effective than an anti‐TGFβ neutralizing antibody (1D11). We also discovered that SD‐208 promoted osteoblastic differentiation (and overcame the TGFβ‐induced block in osteoblastogenesis) in myeloma patient bone marrow stromal cells in vitro, comparable to normal donors. The improved bone quality and fracture‐resistance with SD‐208 provides incentive for clinical translation to improve myeloma patient quality of life by reducing fracture risk and fatality. © 2019 American Society for Bone and Mineral Research.

Myeloma Bone Disease: The Osteoblast in the Spotlight

“…Subsequently, the group developed a low-tumour MBD mouse model (NSG mice inoculated with human U266-GFP-luc myeloma) and treated established lytic disease with chemotherapy with or without SD208. Treatment with SD208 improved bone structure, lesion repair, and fracture resistance when compared to chemotherapy alone in this established MBD model [89]. In vitro treatment of human myeloma BMSC samples with SD208 also enhanced OB differentiations [89].…”

“…Treatment with SD208 improved bone structure, lesion repair, and fracture resistance when compared to chemotherapy alone in this established MBD model [89]. In vitro treatment of human myeloma BMSC samples with SD208 also enhanced OB differentiations [89]. Some TGFβ antagonists have also shown preclinical evidence of antitumour effects, in addition to their bone anabolic effects [36,90].…”

Advances in murine models of breast cancer bone disease

“…In addition to tumour growth, researchers are often interested in the effects that tumours and/or treatments are having on the bone microenvironment. Osteolytic lesion area and abnormal bone remodelling can be visualised and assessed weekly in vivo using a cabinet X-ray machine or by live µCT imaging of the affected bone(s) [Figure 3B] [18,42,43,64] . Using in vivo µCT scanning, percentage changes in trabecular bone parameters and the size or number of osteolytic lesions can be measured over time as bone disease develops [Figure 4A-C].…”

Machine Learning Approaches for Cancer Bone Segmentation from Micro Computed Tomography Images

“…Micro Computed Tomography (µCT) datasets were used by scanning the proximal end of mouse tibiae with or without tumour [14]. The µCT datasets contain 2D transverse slices that can be rendered into a 3D dataset.…”