Recombinant human bone morphogenetic protein-4 enhances tendon-to-bone attachment healing in a murine model of rotator cuff tear

Injuries of tendon-to-bone attachments (TBA) are common clinical challenges. Bone morphogenetic protein-4 (BMP-4) is potent in chondrogenesis. However, studies focusing on the influence of BMP-4 on the healing of TBA are scarce. Thus, this study's objective was to explore the effect of BMP-4 on the healing of TBA in a murine model of rotator cuff tear.An injury model of the supraspinatus tendon (SST) insertion was established on a total of 120 mature C57 black (BL)/6 mice (12 weeks old), who were then randomly allocated into 3 groups: BMP-4, noggin (an inhibitor of all BMP activities), and control, At weeks 2 and 4 after surgery, the supraspinatus tendon-humerus complexes (SSTHC) were harvested for microradiographic, histologic, immunofluorescent, and biomechanical evaluations.Radiographic data showed that BMP-4 was able to improve the quality of subchondral bone, manifested as higher bone volume fraction (BV/TV), trabecular number (Tb.N), trabecular thickness (Tb.Th), and lower trabecular spacing (Tb.Sp). Histologically, the BMP-4 group at week-2 and -4 showed a better TBA healing interface, characterized by better organizational integration and remodeling, thicker fibrocartilage layer, and more fibrocartilage cells. Immunofluorescence evaluation demonstrated that the number of SOX 9 positive cells in the BMP-4 group was significantly more than that in the control or noggin groups at postoperative weeks 2 and 4 (P<0.05 for all). Mechanical testing results at postoperative weeks 4 demonstrated the failure load, and stiffness in the BMP-4 group were significantly higher (P<0.05 for both), while in the noggin group were significantly lower (P<0.05 for both), compared to the control group.The BMP-4 might enhance TBA healing by promoting the regeneration of fibrocartilaginous enthesis and mineralization, while this process was inhibited by noggin. Thus, BMP-4 may be a potential therapy to augment TBA healing and finally lead to more rapid rehabilitation and reduce recurrent injury risk.