Hidden in the twists and turns of your ankle is a remarkable secret: the same biological magic that lets a salamander grow back a lost limb might also help humans repair worn-out joints.
In a groundbreaking study published July 11 in Science Advances, researchers at Duke Health have revealed that human ankle cartilage harbors potent regenerative powers—and they might one day help heal damaged knees and hips, offering hope to millions suffering from osteoarthritis.
“It’s like discovering that your ankle carries the blueprints for repair that the rest of your joints have mostly forgotten,” said Virginia Byers Kraus, M.D., Ph.D., a professor in Medicine, Pathology and Orthopedic Surgery at Duke University School of Medicine and the study’s senior author.
A Global Burden With Few Solutions
Osteoarthritis—the relentless wear-and-tear disease that eats away at the cartilage cushioning our joints—affects roughly 7.6% of people worldwide. For many, it means stiffness, pain, and joints that grind instead of glide. Despite being one of the leading causes of disability, there’s still no cure, and treatment options remain limited, usually focusing on pain relief rather than true repair.
That’s why scientists have long been fascinated by creatures like zebrafish and salamanders, which can regenerate entire limbs or tails. If humans could tap into similar biological pathways, we might finally be able to restore joints ravaged by arthritis instead of simply replacing them with metal and plastic.
A New Window Into Regeneration
For decades, researchers suspected the ankle might hold special regenerative powers. Compared to the knee and hip, ankle cartilage seems more resilient—it wears out less often and heals better after injury. But no one fully understood why.
The Duke team set out to find answers using a clever bit of detective work involving mass spectrometry. This sophisticated technique allowed them to analyze proteins in cartilage and distinguish newly formed molecules from older ones. Essentially, they could see regeneration happening in real time.
“The novelty of our work lies in the innovative use of mass spectrometry to distinguish newly synthesized from older proteins, providing a way to measure the active versus inactive state of cartilage regeneration,” said Kraus.
Their analysis led them to a fascinating discovery: tiny molecules called small RNAs (smRNAs), which act like conductors of a biological orchestra. In healthy joints, these smRNAs are disorganized, playing notes at random like musicians tuning up before a concert. But in the throes of osteoarthritis—or when cartilage repair is triggered—these molecules suddenly work together in a precise, coordinated “symphony.”
Some smRNAs switch on genes that promote cartilage growth. Others quiet down genes that normally inhibit regeneration. And many of these same smRNAs are found in species famous for regrowing limbs, like zebrafish and salamanders.
Why Ankles Heal—and Knees Don’t
The ankle’s regenerative talents might be an evolutionary leftover. As humans evolved upright walking, our lower legs and feet bore the brunt of our weight. The ankle may have retained extra healing capabilities to cope with life’s daily pounding.
But the Duke researchers discovered a crucial wrinkle: while smRNAs are abundant in human ankle cartilage, they’re far scarcer in the knee—and even rarer in the hip. That could help explain why ankles resist arthritis better, while knees and hips often crumble under the disease.
“Ankle cartilage represents a regenerative environment and could serve as a template for enhancing cartilage repair in less regenerative joints such as the knee and hip,” Kraus said.
Toward Healing Arthritic Joints
These insights could revolutionize how we approach osteoarthritis. Instead of simply managing pain, doctors might someday “reprogram” knees and hips to behave more like ankles, triggering natural cartilage repair.
The Duke team is now diving deeper, studying animals like zebrafish to figure out precisely how smRNAs coordinate regeneration—and how to mimic those pathways in humans.
“Our hope,” said Kraus, “is that by understanding and harnessing these regenerative mechanisms, we can one day help millions of people suffering from osteoarthritis avoid joint replacements and enjoy pain-free movement.”
A Future Written in Molecules
This research is still in its early stages. Kraus and her colleague Ming-Feng Hsueh have filed a provisional patent related to their findings, hinting at future therapies that might emerge. But for now, the simple act of walking, running, or dancing might carry a hidden message: deep in our ankles lies a spark of nature’s oldest healing magic.
And if scientists can learn how to unleash it, the future of joint health could be far brighter—and far less painful—than we ever imagined.
Reference: Ming-Feng Hsueh et al, Anabolic indices of matrix proteins identify regenerative small RNA intrinsic to human cartilage, Science Advances (2025). DOI: 10.1126/sciadv.adu8440