How it all began: the search for molecular drivers of osteoarthritis
Like many research projects, this study began with a question: what are the molecular mechanisms driving joint damage in osteoarthritis (OA)? Our team was active for many years in researching the role of Wnt signaling in the joint. Excessive Wnt signaling accelerates joint degeneration in many of our laboratory models. But how?
Previous studies similarly pointed to Wnt as a key player in OA, but still, the effectors exerting the damage in the joint upon Wnt activation remained unknown. We set out to find such factors, using both molecular biology experiments and animal models of OA. We figured that if we could better understand the key events that occur after Wnt activation, we could identify new therapeutic approaches.
The IGF1 connection
Our journey led us to IGF1, or insulin-like growth factor 1, a protein best known for its role in growth and development. Using transcriptome analysis on human chondrocytes (cartilage cells) with increased Wnt signaling activation, we consistently found IGF1 among the most highly increased genes. This was intriguing because, despite IGF1's well-established role in skeletal growth, its role in OA was not established.
We wondered: could IGF1 be one of the key mediators of cartilage damage in OA? To test this, we developed mouse models with cartilage-specific Igf1 deletion and analyzed the progression of OA in these mice when Wnt signaling was activated.
Surprising results: protection from joint damage
The results validated our hypothesis — mice lacking IGF1 in their cartilage were protected from the joint damage that is associated with excessive Wnt activation.
This finding was exciting because it directly linked IGF1 to OA progression. Specifically, we found that IGF1 was responsible for inducing chondrocyte hypertrophy—a process where cartilage cells lose their normal identity and produce a different type of matrix and tissue-destructive enzymes, thereby leading to cartilage breakdown.
By blocking IGF1, we did not only reduce chondrocyte hypertrophy but also prevented the formation of osteophytes—bony outgrowths that are characteristic of OA. In addition, markers of cartilage degradation, such as the enzymes MMP13 and ADAMTS5, were significantly lower in Igf1-deficient mice. Combined, these data provided compelling evidence that IGF1 plays a central role in joint degeneration when Wnt signaling is overly active.
Behind the scenes: a collaborative effort
This study was a collaborative journey for a group of scientists that applied bioinformatics, molecular biology, and in vivo experiments. Working with our team of early and advanced career researchers, we developed a multifaceted approach to investigate the Wnt-IGF1 link. These experiments involved experimental techniques such as luciferase reporter assaysand chromatin immunoprecipitation (ChIP), to confirm that Wnt signaling directly controls IGF1 expression in cartilage.
What’s next?
The identification of IGF1 as a key mediator of OA progression may present a new target for therapeutic intervention. By targeting the Wnt-induced IGF1 axis, we may be able to slow or halt the progression of OA, offering hope to patients for whom joint replacement may be the only long-term option. Our next steps are focused on testing this idea further. We are already working on developing approaches to effectively block IGF1 that could be tested in preclinical models of OA. Additionally, we are exploring whether selectively modulating Wnt signaling in joint tissues could offer a more precise approach to maintaining joint health without triggering destructive branches.
Broader Implications: Rethinking OA Treatment
The broader implications of this study go beyond OA. Wnt signaling and IGF1 are involved in multiple tissues and disease contexts, including cancer and fibrosis. The insights from this research could inform new strategies to balance the beneficial and harmful aspects of Wnt signaling in various diseases.
For OA specifically, we hope that our findings will inspire more research into how other downstream targets of Wnt may contribute to disease progression. By expanding our understanding of these molecular pathways, we can move closer to developing treatments that do more than just alleviate symptoms—they can fundamentally alter the disease course.
By writing this blog post, I hope to make our research more accessible to a wider audience, from experts in the field to the general public. If you are interested in learning more about the study or the science behind it, please check out the full paper here: https://rdcu.be/dXYc6