DDR2 increases BMP-dependent bone regeneration and reduces heterotopic ossification

Research into bone regeneration has taken a significant step forward with the discovery of a key mechanism that could transform treatments for bone diseases. Scientists have identified how discoidin domain receptor 2 (DDR2) enhances bone morphogenetic protein (BMP)-dependent bone regeneration while reducing the risk of heterotopic ossification (HO), offering promising therapeutic opportunities. This breakthrough sheds light on how DDR2 regulates BMP activity, paving the way for safer and more effective interventions in bone repair and related conditions.

Bone loss resulting from injury, fracture or disease is 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, but their clinical application is hampered by significant obstacles. High doses of BMPs are often required, posing a risk 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 that modulate BMP signaling, highlighting the urgent need to identify mechanisms that can improve bone regeneration while minimizing adverse effects.

On January 2, 2025, a study (DOI: 10.1038/s41413-024-00391-z) published in the journal revealed a key role for discoidin domain receptor 2 (DDR2) in BMP signaling. Research conducted by a team from the University of Michigan School of Dentistry has shown that DDR2 is not only necessary for effective bone regeneration, but also participates in heterotopic ossification. This discovery establishes DDR2 as a critical modulator of BMP activity, which has profound implications for bone biology and therapeutic development.

Scientists used an integrative approach to investigate the role of DDR2 in BMP signaling. By implanting BMP2 subcutaneously into mice, they observed significantly impaired bone formation in Ddr2-deficient mice. In a mouse model of progressive fibrodysplasia ossificans (FOP), a genetic disease that causes abnormal bone growth in soft tissues, DDR2 deficiency significantly reduced heterotopic ossification. Interestingly, DDR2 was found to be coexpressed with GLI1, a marker of skeletal stem cells, in cells migrating to BMP2 implants. These DDR2/GLI1-positive cells contributed significantly to bone formation, affecting both cartilage and bone lineages. Further experiments showed that selective removal of DDR2 from Gli1-expressing cells results in deficits in bone formation similar to those observed in DDR2-deficient animals worldwide, primarily due to reduced Gli1+ cell proliferation rather than apoptosis. Notably, DDR2 has been shown to regulate YAP and TAZ, two key components of the Hippo pathway, highlighting its role in coordinating BMP responses via the collagen matrix.

Our findings highlight the importance of DDR2 in modulating BMP signaling. This discovery not only advances our understanding of bone biology, but also opens up exciting opportunities for therapeutic interventions to improve bone regeneration and treat conditions such as heterotopic ossification.”

Renny T. Franceschi, PhD, professor, University of Michigan School of Dentistry and lead author of the study

The potential applications of this research are groundbreaking. By identifying DDR2 as a critical regulator of BMP activity, scientists can develop new therapies to enhance bone regeneration in clinical contexts such as fracture healing and spinal fusions. Additionally, these findings offer hope for the treatment of debilitating conditions such as FOP, where abnormal bone formation severely impacts quality of life. This study represents a groundbreaking step forward, providing a safer and more targeted use of BMPs in accelerating bone repair and regeneration.