Recombinant Human Bone Morphogenetic Proteins-4 Enhanced the Tendon-to-bone Attachment Healing in a Murine Model of Rotator Cuff Tear: A Randomized Controlled Trial

Abstract Background: Injuries on tendon-to-bone attachment (TBA) are common clinical dilemmas. Bone Morphogenetic Proteins-4 (BMP-4) has been found the potency in chondrogenesis. But there is rare studies focusing the influence of BMP-4 on the TBA healing. Thus, the objective of this study was to explore the effect of BMP-4 on the healing of TBA in murine model of rotator cuff tear.Methods: 120 mature C57BL/6 mice (12 weeks old) were randomly divided into BMP-4 group, noggin (an inhibitor of all BMP activities) group and control group after being established an injury model of supraspinatus tendon insertion. At week 2 and 4 after surgery, the supraspinatus tendon- humerus complex (SSTHC) were harvested for microradiographic, histologic, immunofluorescent and biomechanical evaluations.Results: Radiographic data showed that BMP-4 was able to improve the quality of subchondral bone, manifested as higher BV/TV, Tb.N, TB.Th, and lower Tb.Sp. Histologically, the BMP-4 group at week-2 and -4 showed better BTA healing interface, characterized by better organizational integration and remodeling, thicker fibrocartilage layer and more fibrocartilage cells. Immunoflorescence evaluation demonstrated the number of SOX 9 positive cells in the BMP-4 group was significantly more than that in the control or noggin group at postoperative weeks 2 and 4 (p<0.05 for all). Mechanical testing results 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 lower (p<0.05 for both), compared to the control group at postoperative weeks 4.Conclusion: BMP-4 might enhance the TBA healing by promoting the regeneration of fibrocartilaginous enthesis and mineralization, while noggin inhibited this process.Clinical Relevance: BMP-4 may be a potential therapy to augment TBA healing, and finally lead to more rapid rehabilitation and reduce risk of recurrent repair.