Researchers at UC Davis Health and UC San Francisco have identified a brain-derived hormone called CCN3 that actively builds bone mass and accelerates fracture healing in mice, offering a potential new treatment path for osteoporosis that goes beyond simply slowing bone loss. The finding, published in Nature, caps two decades of investigation into how pregnancy hormones affect the skeleton. If the results translate to humans, CCN3 could fill a significant gap in osteoporosis care, where drugs that stimulate new bone formation remain limited.
How CCN3 Strengthens the Skeleton
Most osteoporosis drugs work by blocking the cells that break down bone. CCN3 takes the opposite approach. Described as a maternal brain hormone, the protein acts as a circulating factor that stimulates skeletal stem cells, the precursors responsible for generating new bone tissue. In mouse experiments, raising CCN3 levels in the bloodstream led to measurable gains in bone mass and strength over a period of weeks, according to a UC San Francisco summary of the work.
The hormone did not just add density. It also sped up fracture repair in young and old mice of both sexes, a detail that distinguishes it from therapies whose benefits taper in aging animals. When researchers added CCN3 directly to skeletal stem cells in the lab, the cells formed bone tissue in vitro, confirming that the hormone triggers an active building process rather than merely preventing breakdown. The collaboration between UC Davis and UC San Francisco, described in a UC Davis release, traces the discovery back to observations about how lactating mothers maintain skeletal integrity despite calcium demands from nursing.
Those early observations suggested that the brain might send a systemic signal to protect the skeleton during late pregnancy and breastfeeding, when the body channels large amounts of calcium into milk. By systematically screening hormones elevated in that period, the team homed in on CCN3 as a candidate that rose in the brain, entered the circulation, and appeared to act directly on bone-forming cells. The new study connects that maternal adaptation to a therapeutic concept: if CCN3 can be safely delivered as a drug, it might reproduce the same protective effect in older adults with fragile bones.
Why Current Treatments Fall Short
Three FDA-approved anabolic agents already exist for osteoporosis: teriparatide, abaloparatide, and romosozumab. Each stimulates bone formation to some degree, but all carry usage limits. Teriparatide and abaloparatide are restricted to roughly two years of treatment, and romosozumab carries cardiovascular warnings that narrow its eligible patient pool. The field has long recognized that major opportunities for new drug development remain, and the number of molecular targets has increased substantially as researchers learn more about how bones remodel themselves.
Recent advances in molecular biology and imaging have expanded understanding of the signaling pathways that govern bone turnover, accelerating the pipeline from preclinical research into clinical trials. Yet most patients still receive anti-resorptive medications like bisphosphonates, which slow bone loss without rebuilding what has already been lost. That gap between slowing destruction and actively restoring structure is exactly where CCN3 and a handful of other experimental strategies aim to land. A hormone that can recruit skeletal stem cells and push them toward bone formation could, in theory, both thicken weakened bones and help heal fractures more quickly.
Another practical limitation of current anabolic drugs is that they tend to be expensive, injectable, and time-limited, which makes clinicians cautious about when to start and stop therapy. Many patients cycle through years of anti-resorptives before they ever receive a bone-building agent, by which time significant structural deterioration has already occurred. A new class of therapies that more closely mimic physiological signals, such as CCN3’s role in pregnancy and lactation, could eventually offer more flexible or longer-term options, though that remains speculative until human data emerge.
Parallel Research Targets the Same Gap
CCN3 is not the only molecule drawing attention. A separate preclinical study tested teriparatide in a type 2 diabetes mouse model and reported reversal of what the authors call a multi-level “diabetic bone” signature, including improvements in bone structure, increased bone formation, and correction of cortical porosity. Published in Bone Research, the work suggests that an existing anabolic agent can counteract the skeletal damage that diabetes inflicts, a finding relevant to millions of people managing both conditions simultaneously.
On the gene-therapy side, a study in ovariectomized rat osteoporosis models found that boosting expression of a protein called Hmga1 through lentiviral overexpression partially reversed bone loss. The mechanism runs through the Wnt/beta-catenin signaling pathway, one of the central circuits that tells stem cells to become bone-forming osteoblasts rather than fat cells. By nudging this pathway, the researchers were able to restore some of the microarchitectural features that are lost after estrogen depletion, a common proxy for postmenopausal osteoporosis in animal studies.
A separate team at Osaka Metropolitan University has taken a regenerative approach, using adipose-derived stem cells shaped into osteogenic spheroids to treat vertebral fracture models analogous to osteoporotic compression fractures. In that work, clusters of fat-derived stem cells were coaxed into a bone-forming state and then implanted into damaged vertebrae, where they contributed to new bone formation and structural reinforcement. This strategy bypasses systemic signaling altogether, instead delivering cells that are already primed to rebuild skeletal tissue at the site of injury.
What connects these otherwise distinct experiments is a shared logic: instead of just slowing resorption, each tries to restart the body’s own bone-building machinery. CCN3 does it through a hormone signal. Hmga1 does it by reprogramming stem cell fate via a key developmental pathway. The spheroid approach physically transplants cells ready to form bone. All three remain preclinical, but together they represent a broader shift in how researchers think about treating fragile skeletons, moving from maintenance toward true regeneration.
Steroid-Induced Bone Loss Gets Its Own Lead
A separate UC Davis Health study published in September 2025 uncovered a key protein involved in steroid-induced bone damage. Researchers examined how skeletal stem cells, the cells responsible for building and maintaining bones, interact with glucocorticoids and noticed elevated levels of a protein called Basigin. That finding points to a promising strategy to prevent bone damage caused by long-term steroid use, a common clinical problem for patients with autoimmune diseases, asthma, and organ transplants.
The Basigin discovery matters because steroid medications are among the most common non-age-related causes of osteoporosis and fractures. Long-term glucocorticoid therapy can suppress bone formation, increase resorption, and impair the function of skeletal stem cells, leaving patients with thinner, more fragile bones even at relatively young ages. By identifying a protein that rises specifically in response to steroid exposure in bone-building cells, the UC Davis team has highlighted a potential molecular handle for intervention.
In their experiments, the researchers linked elevated Basigin to changes in how skeletal stem cells behave under steroid stress, suggesting that blocking or modulating this protein could help preserve bone-forming capacity. While this work is still at an early stage, it complements the CCN3 findings by focusing on a different but related problem: not just age-related bone loss, but medication-induced damage that current osteoporosis drugs only partially address. Together, these lines of research underscore how skeletal stem cells sit at the center of many forms of bone fragility.
From Mouse Models to Human Bones
Despite the excitement around CCN3 and related strategies, translating mouse and rat results into human therapies is a long and uncertain process. Animal models allow researchers to manipulate genes, hormones, and stem cells in ways that would be impossible in people, but they cannot fully capture the complexity of human aging, comorbidities, and long-term drug exposure. Safety is a particular concern for any treatment that stimulates cell growth or alters fundamental signaling pathways, given the theoretical risk of unwanted tissue changes.
For CCN3, key questions include how best to deliver the hormone, what dose would be effective yet safe, and whether chronic exposure might have off-target effects in organs beyond bone. Similar uncertainties surround gene-based approaches such as Hmga1 overexpression, which would require precise control to avoid disrupting other Wnt-dependent processes. Even cell therapies like osteogenic spheroids must clear hurdles related to manufacturing, immune compatibility, and durability of benefit before they can be widely adopted.
Still, the convergence of hormonal, genetic, and regenerative approaches signals a hopeful moment in osteoporosis research. By focusing on skeletal stem cells and the signals that guide them, scientists are building a more unified picture of how bones maintain themselves, and how that maintenance fails in aging, diabetes, steroid use, and other conditions. CCN3, Basigin, Hmga1, and adipose-derived cells represent different entry points into that shared biology. If even a few of these avenues lead to safe, effective therapies, future patients may have options that not only slow bone loss but actively rebuild the skeleton they have already lost.
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*This article was researched with the help of AI, with human editors creating the final content.
