For over two decades, scientists at UC Davis Health and UC San Francisco have been working to uncover the secrets of bone strength and regeneration. Their persistence has culminated in a breakthrough discovery: a molecule known as Maternal Brain Hormone (CCN3), which has the potential to transform the treatment of bone-related conditions, including osteoporosis. This exciting advancement, recently published in *Nature*, sheds light on the intricate processes that maintain bone density and strength, particularly in women during breastfeeding.

A New Frontier in Bone Health

Bones are remarkable living tissues that constantly renew themselves. However, as we age, this renewal process can slow down, leading to conditions like osteoporosis, where bones become brittle and prone to fractures. Scientists have long sought therapies to not just slow bone loss but actively regenerate bone tissue. 

The discovery of CCN3 could be the game-changer the medical community has been waiting for. This molecule plays a key role in increasing bone density and strength, offering new hope for patients with bone-weakening diseases. Additionally, CCN3’s potential applications extend beyond bone health, with promising implications for cartilage regeneration and degenerative diseases like osteoarthritis.

From Mice to Molecules: The Journey to Discovery

The foundation for this groundbreaking research began two decades ago at UC Davis. Nancy E. Lane, a distinguished professor of rheumatology at UC Davis Health, recalls the unlikely beginnings of their work. 

“Interestingly, this all started with mice we got from Kamala Harris’ mother’s lab at the Lawrence Berkeley National Laboratory,” Lane shared. The team noticed something unusual in their experiments with mice lacking nuclear progesterone receptors — a specific protein that binds to the hormone progesterone. These mice had both denser and stronger bones compared to normal mice. 

While this initial research pointed to a link between progesterone signaling and bone formation, the project took a new direction when Lane received a call from the Ingraham Lab at UC San Francisco years later.

A Collaborative Breakthrough

The researchers at UC San Francisco had been studying estrogen receptors in a specific part of the brain, the arcuate nucleus (ARC) of the hypothalamus. Their findings suggested that blocking these receptors led to increased bone density in female mice but had little effect in males. Recognizing the potential significance of this discovery, they reached out to Lane’s team for their expertise in bone research.

Together, the multidisciplinary team embarked on a mission to uncover why blocking the estrogen receptor had such a profound impact on bone density. Their work eventually zeroed in on CCN3, a hormone linked to several biological processes, including cell growth and migration.

The Role of CCN3 in Bone Formation

The researchers discovered that the estrogen receptor in question was involved in nutrient sensing in the brain. Blocking this receptor caused female mice to develop extraordinarily dense bones. However, when these mice were placed on a high-fat diet, their bone density returned to normal. This finding prompted the team to search for the factors responsible for the bone-strengthening effect, ultimately identifying CCN3 as the key molecule.

Further experiments revealed CCN3’s remarkable properties:

1. Stimulating Bone Growth in the Lab: When the team added CCN3 to mouse skeletal stem cells in a petri dish, tiny bits of bone began to form.

2. Healing Fractures in Elderly Mice: Applying a hydrogel patch infused with CCN3 to fractured bones in elderly mice promoted bone growth, demonstrating its therapeutic potential.

“This is incredibly exciting because we have therapies to prevent bone loss, but we are still limited in terms of the drugs that stimulate bone formation,” Lane explained. “Discovering this molecule, which acts through the skeletal stem cell, could pave the way for therapies to regenerate bone and treat conditions like osteoporosis.”

Potential Applications Beyond Bone Health

The implications of CCN3 extend beyond its ability to strengthen bones. Lane and her colleagues are now exploring whether this molecule could help regenerate cartilage, offering hope for patients with osteoarthritis. This degenerative condition affects millions worldwide, leading to joint pain and reduced mobility as cartilage breaks down.

The team is investigating whether injecting CCN3 into damaged cartilage could stimulate regeneration in environments where oxygen and blood supply are limited. If successful, this approach could revolutionize the treatment of osteoarthritis and other joint disorders.

What’s Next for CCN3 Research?

The discovery of CCN3 marks the beginning of an exciting new chapter in bone and cartilage health research. The team plans to delve deeper into the molecular mechanisms of CCN3 to better understand its role in bone and cartilage regeneration. Key questions include:

- How does CCN3 interact with skeletal stem cells to promote bone growth?

- Can CCN3 therapy be optimized for human applications?

- What are the long-term effects of using CCN3 in treating degenerative conditions?

Lane and her collaborators at UC Davis Health, including Thomas H. Ambrosi and Kent Leach, are committed to answering these questions. Their work could lead to new therapies that not only prevent bone loss but actively rebuild damaged tissue.

A Legacy of Innovation

This discovery is a testament to the power of collaboration and persistence in scientific research. It underscores the importance of building on previous findings, no matter how unexpected or unrelated they may initially seem. From studying progesterone receptors in mice to uncovering the potential of CCN3, the journey to this breakthrough has been anything but linear.

It also highlights the contributions of Vice President Kamala Harris’ late mother, Shyamala Gopalan, a respected scientist whose work laid the groundwork for these advancements. Her legacy continues to inspire researchers like Lane and her team to push the boundaries of what’s possible.

A Brighter Future for Patients

For the millions of people affected by osteoporosis, osteoarthritis, and other bone and joint conditions, the discovery of CCN3 offers a glimmer of hope. Current treatments focus primarily on preventing bone loss, but CCN3 could open the door to therapies that actively regenerate bone and cartilage. 

As research progresses, the possibility of reversing the effects of degenerative diseases and improving patients’ quality of life becomes increasingly tangible. Whether through bone-strengthening treatments, fracture-healing patches, or cartilage-regenerating injections, the potential applications of CCN3 are vast and transformative.

Conclusion

The discovery of CCN3 represents a monumental step forward in the quest to understand and treat bone and cartilage disorders. Backed by two decades of meticulous research, this breakthrough has the potential to redefine how we approach conditions like osteoporosis and osteoarthritis. 

As scientists continue to explore the capabilities of this remarkable molecule, one thing is certain: the future of bone health has never looked brighter. With continued collaboration, innovation, and dedication, CCN3 could one day transform the lives of millions around the world.