Stephanie Bryant, a researcher in the BioFrontiers Institute at the University of Colorado Boulder, will be receiving a substantial grant to find a possible cure for osteoarthritis works with Graduate Research Assistant Laurel Stefani, a Biomedical Engineering PhD major from Richardson, TX. (Photo by Casey A. Cass/University of Colorado)

Imagine a day when joints could heal themselves.

At the first sign of a creaky knee, patients could get a single shot in the joint that would not only stop their cartilage and bone from eroding but also kick-start their regrowth. In more advanced cases, that shot might also deliver a biomaterial repair kit to patch holes in tissue. If multiple joints ached, an annual IV infusion could ferry regenerating therapies to all of them at once.

This may seem like a dream to the 32.5 million people who suffer from osteoarthritis. This week, the Advanced Research Projects Agency for Health (ARPA-H) awarded up to $39 million to a University of Colorado Boulder-led team of scientists to work toward making it a reality. 

The Novel Innovations for Tissue Regeneration in Osteoarthritis (NITRO) program was the first created under ARPA-H, a new federal agency to support “high-impact solutions to society’s most challenging health problems.” 

With the cash infusion, a dream team of engineers, medical scientists, and veterinarians from CU Boulder, the CU Anschutz Medical Campus, and Colorado State University can aggressively make the final push toward a goal many have spent their entire careers pursuing. 

“Our goal is to develop a suite of noninvasive therapies that can end osteoarthritis within five years,” said project leader and Principal Investigator Stephanie Bryant, PhD, a professor in the Department of Chemical and Biological Engineering, Materials Science and Engineering, and the BioFrontiers Institute at CU Boulder. “It could be an absolute game-changer for patients.”

An epidemic without a cure

Osteoarthritis is the third most common disease in the U.S. and affects roughly one in six people over age 30 worldwide.
 
The disease causes cartilage—the buffering tissue that keeps bones from grinding together—to decay. Over time, bone is damaged, too, reshaping the joint and making movement painful. 
 
Age and obesity increase risk, and rates are on the rise as the U.S. population ages and grows more sedentary. At present, patients are generally limited to two options: Treat the pain and, when that is no longer adequate, surgically replace the joint. There is no cure.

“To truly address osteoarthritis, you have to address both the biology and the structural problem,” said co-principal Investigator Michael Zuscik, PhD, a professor and research vice chair in the Department of Orthopedics at the Anschutz Medical Campus. “This unique Colorado dream team we have put together has the multidisciplinary expertise and now the resources to tackle both at once. We can approach curing the disease like never before.”

Zuscik spent 15 years developing and testing a drug that addresses the biology, nudging cartilage and bone cells to produce proteins needed to rebuild. While promising, it must be injected every day.

Meanwhile, Bryant, a materials scientist, has worked for 26 years to develop three-dimensional gel-like biomaterials that can slip into the cracks of torn cartilage or worn bone. These materials provide supportive scaffolding — like the joists of a new building—for the body’s own cells to migrate to.

CSU scientists have been working for years to perfect gene therapy techniques that control inflammation and hasten cartilage healing.

The team now faces an engineering challenge – to devise methods to deliver these technologies to the body together, in a way that provides lasting benefit and treats multiple joints at once if needed.

A one-shot medical breakthrough

To that end, the team is developing nanoparticles that could be administered intravenously, serving as Trojan horses that migrate to inflamed sites and deliver a regenerative medicine cocktail that enables joints to heal.

The team hopes to ultimately commercialize three innovations: a healing shot; an injury-patching hydrogel; and an annual infusion for systemically treating osteoarthritis. 

When it’s time for trials, co-Principal Investigator Laurie Goodrich, DVM PhD, a veterinary clinician scientist and director of the Orthopaedic Research Center at CSU’s Translational Medicine Institute, will lead the charge in animals. 

“CSU’s expertise in veterinary medicine will play a crucial role in helping to move this science to the next step,” said Goodrich. “It’s humbling to be a part of it.”

Within 3.5 years, the team hopes to begin conducting trials in human patients. 

However, it’s not enough to simply develop such treatments, said Co-Principal Investigator Karin Payne, PhD, associate professor of orthopedics at CU Anschutz.

“At the core of this, the goal is to develop a therapy that’s going to be available to all Americans, not just a privileged few,” Payne said, noting that researchers will include a demographically diverse group of study participants and minimize cost to make the treatments as affordable as possible.

Perhaps the most profound advance in primate evolution occurred about 6 million years ago when our ancestors started walking on two legs. The gradual shift to bipedal locomotion is thought to have made primates more adaptable to diverse environments and freed their hands to make use of tools, which in turn accelerated cognitive development. With those changes, the stage was set for modern humans.

The genetic changes that made possible the transition from knuckle-based scampering in great apes to upright walking in humans have now been uncovered in a new study by researchers at Columbia University and the University of Texas.

Using a combination of deep learning (a form of artificial intelligence) and genome-wide association studies, the researchers have created the first map of the genomic regions responsible for skeletal changes in primates that led to upright walking. The map reveals that genes that underlie the anatomical transitions observed in the fossil record were strongly acted on by natural selection and gave early humans an evolutionary advantage.

“On a more practical level, we’ve also identified genetic variants and skeletal features that are associated with hip, knee, and back arthritis, the leading causes of adult disability in the United States,” says Tarjinder Singh, PhD, assistant professor of computational and statistical genomics (in psychiatry) at the Columbia University Vagelos College of Physicians and Surgeons and a co-leader of the study. 

For example, slight deviations from the average hip width-to-height ratio were associated with an increased risk of hip osteoarthritis, while slight deviations in the tibia-femur angle were associated with an increased risk of knee osteoarthritis. These insights could help researchers devise new ways to prevent and treat these debilitating conditions.

The findings were published July 21 in Science. The study was co-led by Vagheesh M. Narasimhan, PhD, assistant professor of integrative biology and of statistics and data sciences at the University of Texas at Austin.

New techniques deployed

The researchers applied deep learning to analyze more than 30,000 full-body X-rays from the UK Biobank. Deep learning, a technology modeled after the brain’s neural networks, trains computers to do what comes naturally to humans, such as driving a car or translating languages. In this case, the technique was used to standardize the X-rays, remove any images with quality issues, and then precisely measure dozens of skeletal features, tasks that would have taken the researchers months, if not years, to complete. 

Next, the researchers scanned the human genome to identify chromosomal regions associated with variations in 23 key skeletal measures, such as shoulder width, torso length, and tibia-to-femur angle. (These scans, called genome-wide association studies, involve surveying the genomes of large groups of people, looking for genomic variants that occur more frequently in those with a specific disease or trait compared to those without the disease or trait.) This process revealed 145 regions associated with genes that regulate skeletal development. Only a handful of these loci were known from previous studies.

Many of the 145 regions overlapped with “accelerated” regions of the human genome, which have rapidly evolved over eons compared with the same regions in great apes. In contrast, few genes associated with the heart, immune system, metabolism, and other traits were found in accelerated regions. 

“What we’re seeing is the first genomic evidence that there was selective pressure on genetic variants that affect skeletal proportions, enabling a transition from knuckle-based walking to bipedalism,” says Narasimhan.  

The study also shows the power of combining large-scale biobank data, machine learning, and genomics to help us understand human health and disease. Singh, who joined Columbia in 2022, is now applying these techniques to understand the causes of mental illness.

Anxiety and depression are the mental health issues most commonly associated with inflammatory arthritis, and it is well-established that there is a link between mental health issues and poor health outcomes.² The EULAR recommendations emphasize the need to assess mental health regularly;¹ however, little is known about the association between self-management and mental health in people with inflammatory arthritis.

At the 2023 EULAR congress, Vestergaard and colleagues report on their cross-sectional study in Denmark. This included 42,407 adult patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), or spondylarthritis (axSpA). The aim was to find out more about the association between low self-management behavior and people’s mental health status.

A total of 12,713 people responded to the questionnaire. The results showed the prevalence of anxiety was highest for patients with axSpA and lowest for RA: 34.5% compared to 22.1%. When looking at depression, the prevalence was highest for patients with PsA and lowest for RA: 27.2% compared to 18.6%. For both anxiety and depression, the prevalence was higher in women, younger patients under the age of 55, those with more newly diagnosed diseases (less than 3 years), and patients with basic education.

Patients with clinical anxiety and depression were more likely to have low self-management behaviour for all included self-management measures, such as adherence to treatment, physical activity, and taking an active role in their healthcare.

These findings call for a systematic approach to identifying mental health issues in patients with inflammatory arthritis.