Bone loss resulting from trauma, fractures, or disease presents a major global health challenge, often leading to long-term disability. Bone Morphogenetic Proteins (BMPs) are well-known for their essential role in bone formation and healing, yet their clinical use is hampered by significant hurdles. High doses of BMPs are often required, posing risks of toxicity and potential oncogenesis, while their unregulated activity can lead to abnormal bone formation in soft tissues, known as heterotopic ossification. Addressing these challenges requires a deeper understanding of the factors modulating BMP signaling, underscoring the urgency of identifying mechanisms that can enhance bone regeneration while minimizing adverse effects.
On January 2, 2025, a study (DOI: 10.1038/s41413-024-00391-z) published in Bone Research unveiled the pivotal role of Discoidin Domain Receptor 2 (DDR2) in BMP signaling. Conducted by a team at the University of Michigan School of Dentistry, the research demonstrates that DDR2 is not only essential for effective bone regeneration but is also involved in heterotopic ossification. This discovery establishes DDR2 as a critical modulator of BMP activity, with profound implications for bone biology and therapeutic development.
The researchers utilized an integrative approach to examine DDR2's role in BMP signaling. By implanting subcutaneous BMP2 in mice, they observed significantly impaired bone formation in Ddr2-deficient mice. In a mouse model of fibrodysplasia ossificans progressiva (FOP)—a genetic condition causing abnormal bone growth in soft tissues—DDR2 deficiency markedly reduced heterotopic ossification. Intriguingly, DDR2 was found to co-express with GLI1, a marker of skeletal stem cells, in cells migrating to BMP2 implants. These DDR2/GLI1-positive cells significantly contributed to bone formation, influencing cartilage and bone lineages alike. Further experiments revealed that selectively removing DDR2 in Gli1-expressing cells produced bone formation deficits akin to those seen in globally Ddr2-deficient animals, primarily due to reduced proliferation of Gli1+ cells rather than apoptosis. Notably, DDR2 was shown to regulate YAP and TAZ, two key components of the Hippo pathway, highlighting its role in orchestrating BMP responses via the collagen matrix.
"Our findings highlight the importance of DDR2 in modulating BMP signaling," said Renny T. Franceschi, Ph.D., Professor at the University of Michigan School of Dentistry and senior author of the study. "This discovery not only deepens our understanding of bone biology but also opens exciting possibilities for therapeutic interventions to enhance bone regeneration and address conditions like heterotopic ossification."
The potential applications of this research are groundbreaking. By identifying DDR2 as a critical regulator of BMP activity, scientists can develop new therapies to improve bone regeneration in clinical contexts such as fracture healing and spinal fusions. Additionally, these findings offer hope for treating debilitating conditions like FOP, where abnormal bone formation severely impacts quality of life. This study represents a transformative step forward, ensuring the safer and more targeted use of BMPs in advancing bone repair and regeneration.
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References
DOI
10.1038/s41413-024-00391-z
Original Source URL
https://doi.org/10.1038/s41413-024-00391-z
Funding information
This work was supported by the Scientific Research Training Program for Young Talents of Union Hospital, Tongji Medical College, Huazhong University of Science and Technology (F.W.), NIH/NIDCR grants DE029012 and DE029465 and Department of Defense Grant PR190899 (R.T.F.) and the Michigan Musculoskeletal Health Core Center (NIH/NIAMS P30 AR069620).
About Bone Research
Bone Research was founded in 2013. As a new English-language periodical, Bone Research focuses on basic and clinical aspects of bone biology, pathophysiology and regeneration, and supports the foremost discoveries resulting from basic investigations and clinical research related to bone. The aim of the Journal is to foster the worldwide dissemination of research in bone-related physiology, pathology, diseases and treatment.