Attenuation of Transforming Growth Factor-β Signaling Promotes Complete Recovery of Trabecular Bone Structure...

Marked trabecular bone loss of the distal femoral and proximal tibial regions is one of the most common and devastating complications of spinal cord injury (SCI) with highest incidence of fracture and no efficacious treatment to date. Osteocytes exhibit increased transforming growth factor-β (TGF-β) signaling 5 weeks after SCI. Whether reducing TGF-β signaling will restore trabecular bone structure after development of bone loss with SCI has not been tested. To address this, male mice underwent laminectomy (sham) or thoracic (T10) contusion SCI resulting in complete hindlimb paralysis. Five weeks later, sham and SCI mice received either control (IgG) or anti-TGF-β neutralizing (ID11) antibody (10 mg/kg/day, twice weekly) for 5 weeks before sacrifice. Micro-computed tomography (micro-CT) analysis of the distal femoral region showed that, compared to sham-IgG animals, treatment with ID11 significantly (p < 0.05) restored trabecular fractional bone volume (107% SCI-ID11 vs. 65% SCI-IgG), thickness (109% SCI-ID11 vs. 88% SCI-IgG), connectivity (99% SCI-ID11 vs. 78% SCI-IgG), and structure model index (101% SCI-ID11 vs. 118% SCI-IgG). In contrast, analysis of femoral mid-shaft regions showed that both SCI-1D11 and SCI-IgG mice exhibited reduced cortical thickness (91% vs. 84%). Histomorphometric analysis revealed no differences in indices of osteoblast or osteoclast numbers or surfaces between SCI-IgG, SCI-1D11, and sham-IgG groups. Similarly, analysis of femoral bone marrow supernatants demonstrated no significant difference in levels of procollagen type 1 intact N-terminal propeptide (P1NP) or tartrate-resistant acid phosphatase 5b (TRAcP-5b). Thus, TGF-β signaling may be a promising therapeutic target to regain trabecular bone architecture and prevent fractures after SCI.