A Discovery Enabled by Federal Funding: Scientists Identify Hormones That May Offer Hope for Osteoporosis and Osteoarthritis Patients
Osteoarthritis and osteoporosis, two common degenerative musculoskeletal diseases affecting roughly 33 million adults in the United States, leave millions coping with fragile bones, fractures, and worn joints that often require replacement. Despite their impact, no therapies currently exist to slow or reverse osteoarthritis, and most osteoporosis treatments work primarily by reducing bone loss, with only a few options able to build new bone but their use is limited.
Now, there is new hope. Scientists at the University of California have identified a molecule that could open the door to treatments for conditions that weaken both bone and cartilage.
Researchers at UC Davis Health and UC San Francisco have identified a brain-derived hormone, CCN3 (also known as the Maternal Brain Hormone), that significantly increases bone density, bone strength, and bone regeneration. The study, published in Nature, reveals a previously unknown mechanism that protects women’s bones during breastfeeding and opens the door to new treatments for osteoporosis, fractures, and potentially cartilage‑related diseases.
Research impact
Most current osteoporosis drugs slow bone loss but do not rebuild bone. CCN3 directly activates skeletal stem cells to form new bone, offering a potential new class of therapies that could increase bone density, strengthen fragile bone and reduce fracture risk in aging populations.
Elderly patients often experience slow or incomplete fracture healing. In mouse models, CCN3 delivered through a hydrogel patch accelerated bone repair, suggesting future treatments that could reduce complications, improve mobility and independence and accelerate recovery after fractures in older adults. This could significantly improve outcomes for millions of people worldwide.
The breakthrough builds on two decades of UC Davis research into progesterone signaling and bone biology. Early mouse studies found that removing progesterone receptors activated the differentiation of osteoblasts to form new bone, thus hinting at a hormonal pathway that boosts bone formation. The amount of bone formed was nearly three times the amount in wild-type mice. A surprise telephone call from a research group at UCSF, came a few years later, reporting that blocking a specific estrogen receptor in the hypothalamus caused female mice to develop unusually strong bones, which later could be shown to be through the activation of bone- and cartilage-forming skeletal stem cells.
The UCSF research group of Holly Ingraham with expertise in neuroendocrine biology, led the multidisciplinary team to identify CCN3 as the key factor released by the hypothalamus to stimulate the new bone formation. Its physiological role is closely linked to protecting against lactation-induced bone loss, as the increased calcium demand during breastfeeding can weaken skeletal integrity. The discovery represents a significant step forward in understanding how the brain regulates skeletal health. In the future, CCN3‑based treatments could offer new hope for millions of people living with osteoporosis, fractures and joint disease.
The UC Davis research team includes Nancy E. Lane, distinguished professor of Rheumatology at UC Davis Health, as well as Thomas H. Ambrosi and Kent Leach, professors in the Department of Orthopaedic Surgery.
Role of federal funding
Federal funding played an important role in the research. A part of the funding came from the National Institute of Health. Specifically, efforts in the Ingraham lab were supported by R01s from the National Institute on Aging and National Institute of Diabetes and Digestive and Kidney Diseases. The NIH also funded the training and research of multiple young investigators involved with this study, including Ambrosi, enabling these discoveries.
The funding for the initial studies was funded with a P50 program project grant entitled “Sex Differences in musculoskeletal diseases across the lifespan” to Lane and the K12 Building Interdisciplinary research in women’s health or the BIRCWH. The K12 BIRCWH scholar who championed this work was Dr. Wei Yao, while at UC Davis. Both were from the Office of Research in Women’s Health and the endowment for healthy aging to Lane.
Future directions
Ongoing work is determining the signals within the brain that activate or suppress CCN3 and evaluating if CCN3 will be an effective “anabolic agent” to treat osteoporosis. The team has found that CCN3 may be harnessed both to prevent bone loss and to promote cartilage regeneration in women and men.
Ambrosi’s research has shown that skeletal stem cells can be directed toward bone or cartilage fates depending on specific environmental cues. Building on this insight, his group developed an approach that uses controlled microinjuries to activate local stem cells and guide them to form stable cartilage by leveraging CCN3 signaling. This strategy could ultimately help prevent osteoarthritis in younger athletes and middle-aged individuals with significant cartilage damage or enable regeneration of lost joint cartilage. Ambrosi and Lane have submitted NIH and National Institute on Aging grant applications to advance these studies.
Ingraham and Ambrosi have co-founded a company to accelerate the clinical translation of their findings. The patented technology is exclusively licensed through the University of California. The UC Davis Tech Transfer Office within the Office of Research is additionally supporting Lane and Ambrosi in their efforts to bring their discoveries around cartilage regeneration and bone loss to patients in need.
