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...
Saved in:
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2025-01-01
|
| Series: | Experimental and Molecular Medicine |
| Online Access: | https://doi.org/10.1038/s12276-024-01372-2 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1825197607541014528 |
|---|---|
| author | Ju Ang Kim Soomin Im Jiwon Lim Jung Min Hong Hye Jung Ihn Jong-Sup Bae Jung-Eun Kim Yong Chul Bae Eui Kyun Park |
| author_facet | Ju Ang Kim Soomin Im Jiwon Lim Jung Min Hong Hye Jung Ihn Jong-Sup Bae Jung-Eun Kim Yong Chul Bae Eui Kyun Park |
| author_sort | Ju Ang Kim |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-56cb716366624f349e87645673fd822a |
| institution | Kabale University |
| issn | 2092-6413 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Experimental and Molecular Medicine |
| spelling | doaj-art-56cb716366624f349e87645673fd822a2025-02-09T12:14:16ZengNature Publishing GroupExperimental and Molecular Medicine2092-64132025-01-015718610310.1038/s12276-024-01372-2The guanine nucleotide exchange factor DOCK5 negatively regulates osteoblast differentiation and BMP2-induced bone regeneration via the MKK3/6 and p38 signaling pathwaysJu Ang Kim0Soomin Im1Jiwon Lim2Jung Min Hong3Hye Jung Ihn4Jong-Sup Bae5Jung-Eun Kim6Yong Chul Bae7Eui Kyun Park8Department of Pathology and Regenerative Medicine, School of Dentistry, IHBR, Kyungpook National UniversityDepartment of Pathology and Regenerative Medicine, School of Dentistry, IHBR, Kyungpook National UniversityDepartment of Pathology and Regenerative Medicine, School of Dentistry, IHBR, Kyungpook National UniversityDepartment of Pathology and Regenerative Medicine, School of Dentistry, IHBR, Kyungpook National UniversityCell and Matrix Research Institute, Kyungpook National UniversityResearch Institute of Pharmaceutical Sciences, College of Pharmacy, Kyungpook National UniversityDepartment of Molecular Medicine, Cell and Matrix Research Institute, School of Medicine, Kyungpook National UniversityDepartment of Anatomy and Neurobiology, School of Dentistry, Kyungpook National UniversityDepartment of Pathology and Regenerative Medicine, School of Dentistry, IHBR, Kyungpook National UniversityAbstract 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.https://doi.org/10.1038/s12276-024-01372-2 |
| spellingShingle | Ju Ang Kim Soomin Im Jiwon Lim Jung Min Hong Hye Jung Ihn Jong-Sup Bae Jung-Eun Kim Yong Chul Bae Eui Kyun Park The guanine nucleotide exchange factor DOCK5 negatively regulates osteoblast differentiation and BMP2-induced bone regeneration via the MKK3/6 and p38 signaling pathways Experimental and Molecular Medicine |
| title | The guanine nucleotide exchange factor DOCK5 negatively regulates osteoblast differentiation and BMP2-induced bone regeneration via the MKK3/6 and p38 signaling pathways |
| title_full | The guanine nucleotide exchange factor DOCK5 negatively regulates osteoblast differentiation and BMP2-induced bone regeneration via the MKK3/6 and p38 signaling pathways |
| title_fullStr | The guanine nucleotide exchange factor DOCK5 negatively regulates osteoblast differentiation and BMP2-induced bone regeneration via the MKK3/6 and p38 signaling pathways |
| title_full_unstemmed | The guanine nucleotide exchange factor DOCK5 negatively regulates osteoblast differentiation and BMP2-induced bone regeneration via the MKK3/6 and p38 signaling pathways |
| title_short | The guanine nucleotide exchange factor DOCK5 negatively regulates osteoblast differentiation and BMP2-induced bone regeneration via the MKK3/6 and p38 signaling pathways |
| title_sort | guanine nucleotide exchange factor dock5 negatively regulates osteoblast differentiation and bmp2 induced bone regeneration via the mkk3 6 and p38 signaling pathways |
| url | https://doi.org/10.1038/s12276-024-01372-2 |
| work_keys_str_mv | AT juangkim theguaninenucleotideexchangefactordock5negativelyregulatesosteoblastdifferentiationandbmp2inducedboneregenerationviathemkk36andp38signalingpathways AT soominim theguaninenucleotideexchangefactordock5negativelyregulatesosteoblastdifferentiationandbmp2inducedboneregenerationviathemkk36andp38signalingpathways AT jiwonlim theguaninenucleotideexchangefactordock5negativelyregulatesosteoblastdifferentiationandbmp2inducedboneregenerationviathemkk36andp38signalingpathways AT jungminhong theguaninenucleotideexchangefactordock5negativelyregulatesosteoblastdifferentiationandbmp2inducedboneregenerationviathemkk36andp38signalingpathways AT hyejungihn theguaninenucleotideexchangefactordock5negativelyregulatesosteoblastdifferentiationandbmp2inducedboneregenerationviathemkk36andp38signalingpathways AT jongsupbae theguaninenucleotideexchangefactordock5negativelyregulatesosteoblastdifferentiationandbmp2inducedboneregenerationviathemkk36andp38signalingpathways AT jungeunkim theguaninenucleotideexchangefactordock5negativelyregulatesosteoblastdifferentiationandbmp2inducedboneregenerationviathemkk36andp38signalingpathways AT yongchulbae theguaninenucleotideexchangefactordock5negativelyregulatesosteoblastdifferentiationandbmp2inducedboneregenerationviathemkk36andp38signalingpathways AT euikyunpark theguaninenucleotideexchangefactordock5negativelyregulatesosteoblastdifferentiationandbmp2inducedboneregenerationviathemkk36andp38signalingpathways AT juangkim guaninenucleotideexchangefactordock5negativelyregulatesosteoblastdifferentiationandbmp2inducedboneregenerationviathemkk36andp38signalingpathways AT soominim guaninenucleotideexchangefactordock5negativelyregulatesosteoblastdifferentiationandbmp2inducedboneregenerationviathemkk36andp38signalingpathways AT jiwonlim guaninenucleotideexchangefactordock5negativelyregulatesosteoblastdifferentiationandbmp2inducedboneregenerationviathemkk36andp38signalingpathways AT jungminhong guaninenucleotideexchangefactordock5negativelyregulatesosteoblastdifferentiationandbmp2inducedboneregenerationviathemkk36andp38signalingpathways AT hyejungihn guaninenucleotideexchangefactordock5negativelyregulatesosteoblastdifferentiationandbmp2inducedboneregenerationviathemkk36andp38signalingpathways AT jongsupbae guaninenucleotideexchangefactordock5negativelyregulatesosteoblastdifferentiationandbmp2inducedboneregenerationviathemkk36andp38signalingpathways AT jungeunkim guaninenucleotideexchangefactordock5negativelyregulatesosteoblastdifferentiationandbmp2inducedboneregenerationviathemkk36andp38signalingpathways AT yongchulbae guaninenucleotideexchangefactordock5negativelyregulatesosteoblastdifferentiationandbmp2inducedboneregenerationviathemkk36andp38signalingpathways AT euikyunpark guaninenucleotideexchangefactordock5negativelyregulatesosteoblastdifferentiationandbmp2inducedboneregenerationviathemkk36andp38signalingpathways |