The guanine nucleotide exchange factor DOCK5 negatively regulates osteoblast differentiation and BMP2-induced bone regeneration via the MKK3/6 and p38 signaling pathways

Abstract

DOCK5 (dedicator of cytokinesis 5), a guanine nucleotide exchange factor for Rac1, has been implicated in BMP2-mediated osteoblast differentiation, but its specific role in osteogenesis and bone regeneration remained unclear. This study investigated the effect of DOCK5 on bone regeneration using C21, a DOCK5 chemical inhibitor, and Dock5-deficient mice. Osteoblast differentiation and bone regeneration were analyzed using bone marrow mesenchymal stem cells (BMSCs) and various animal models. C21 significantly enhanced osteoblast differentiation and mineral deposition in mouse MC3T3-E1 cells and in human and mouse BMSCs. Dock5 knockout (KO) mice exhibited increased bone mass and mineral apposition rate, with their BMSCs showing enhanced osteoblast differentiation. Calvarial defect and ectopic bone formation models demonstrated significant induction of bone regeneration in Dock5 KO mice compared to wild-type (WT) mice. Moreover, DOCK5 inhibition by C21 in WT mice enhanced BMP2-induced subcutaneous ectopic bone formation. The mechanism responsible for enhanced bone formation induced by DOCK5 inhibition may involve the suppression of Rac1 under TAK1, accompanied by the activation of MKK3/6 and p38 induced by BMP2. These findings strongly suggest that DOCK5 negatively regulates osteoblast differentiation and bone regeneration through signaling pathways involving TAK1, MKK3/6, and p38, providing new insights into potential therapeutic strategies for bone regeneration. Bone regeneration involves repairing damaged or lost bone by forming new tissue, supported by growth factors like BMP2 (bone morphogenetic protein 2). However, high doses of BMP2 can cause side effects. In this study, researchers found that blocking DOCK5, a protein involved in cell signaling, enhances BMP2’s ability to promote bone growth. They used chemical inhibitors and genetically modified mice to study DOCK5’s role in bone formation, growing bone cells in vitro and testing bone regeneration in vivo. Results showed that inhibiting DOCK5 increased bone growth and mineralization when BMP2 was present. The study suggests that targeting DOCK5 could enhance BMP2’s effects, allowing for lower doses in bone healing and offering a new approach for bone repair therapies. Future research may explore the use of DOCK5 inhibitors in clinical settings. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.