Abstract

Disuse osteoporosis, caused by mechanical unloading, is linked to dysregulated TGFβ and BMP signaling. This study explores their roles and evaluates BMP9 as a potential therapy. A hindlimb unloading (HLU) mouse model was used to assess bone changes and signaling alterations. In vitro, a Rotary Cell Culture System (RCCS) with 3D printing simulated microgravity. BMP9 was overexpressed in bone marrow stromal cells (BMSCs) and osteocytes treated with TGFβ1. HLU mice showed reduced bone density, microstructural integrity, and dysregulated signaling (increased p-Smad2/3, decreased p-Smad1/5/8). BMP9 overexpression restored osteogenic differentiation in vitro and improved bone properties in vivo. However, RCCS failed to replicate osteogenic inhibition, likely due to shear stress. Despite challenges, BMP9 shows promise for treating disuse osteoporosis. Future research will refine vector specificity and reduce immunogenicity for clinical application.