Stanford team regenerate cartilage in joints using chemical triggers.

Cartilage is the smooth white tissue that covers the ends of bones, supporting them and protecting them where they come together in joints. However, it degenerates with age causing pain and mobility loss.

Now a Stanford team has made a breakthrough that could mitigate this damage, prevent osteoarthritis, prolong healthspan, and keep weekend warriors on their game.

Longevity.Technology: Osteoarthritis is the most common cause of chronic disability in older adults [1]. The cartilage cushion that sits in our knees degrades with age, either from wear and tear, injury or degrading enzymes. Lost cartilage is not replaced by the body so the situation just deteriorates.

The Stanford research has not only found a way to prompt cartilage regeneration, but also to onboard preventative therapy that boosts cartilage before a problem develops. They are coming at the problem from a different direction from senolytic therapy developer UNITY Biotechnology

Disappointingly, UNITY announced the 12-week results from its Phase 2 study of UBX0101, a p53/MDM2 interaction inhibitor (in 183 patients with moderate-to-severe painful osteoarthritis of the knee) which found no statistically significant difference in pain reduction between the use of UBX0101 and a placebo.

“What we ended up with was cartilage that is made of the same sort of cells as natural cartilage with comparable mechanical properties …”

Stem cells are able to generate new bone cells in response to injury, and this response has been converted into a therapy technique called microfracture; minute holes are drilled in the surface of a joint, prompting the body to generate new tissue in response. However, the body doesn’t create cartilage, but fibrocartilage, an ‘interim’ version that covers the ends of the bone, but lacks the elastic cushioning effect of actual cartilage. Effectively scar tissue, fibrocartilage is also quick to wear away.

The Stanford team wanted to change the regeneration process to result in cartilage, rather than fibrocartilage, and they used proteins to do it. The researchers added two proteins to the bone ends in a murine model: BMP2 (bone morphogenetic protein 2), which encourages the stem cells to make new bone cells and VEGFR1 (vascular endothelial growth factor), which stops the bone formation process midway, at a point that leaves it as cartilage.
“What we ended up with was cartilage that is made of the same sort of cells as natural cartilage with comparable mechanical properties, unlike the fibrocartilage that we usually get,” assistant professor of surgery Charles Chan, PhD said. “It also restored mobility to osteoarthritic mice and significantly reduced their pain [2].”

“… you don’t wait for damage to accumulate – you go in periodically and use this technique to boost your articular cartilage before you have a problem.”

In order to see if the therapy might work in humans, the research team transferred human tissue into mice that had been bred not to reject the tissue; this experiment demonstrated that human skeletal stem cells could be nudged toward bone development but halted at the cartilage stage.

The team plan to test on larger animals and then move onto human clinical trials, with the team optimistic that working in comparatively larger joints (mouse vs human) would allow them to refine the technology for even more successful outcomes and the therapy has the built-in advantage that BMP2 is already FDA-approved. Nice.

Professor of surgery Michael Longaker, MD, explained: “BMP2 has already been approved for helping bone heal, and VEGF inhibitors are already used as anti-cancer therapies. This would help speed the approval of any therapy we develop [3].”

Longaker also discussed the preventative side of the treatment: “One idea is to follow a ‘Jiffy Lube’ model of cartilage replenishment; you don’t wait for damage to accumulate – you go in periodically and use this technique to boost your articular cartilage before you have a problem [4].”

[1] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2920876/
[2] https://stan.md/35ve523
[3] https://bit.ly/2RdsBTn
[4] https://bit.ly/2FerXma

Image credit: Stefan Holm / Shutterstock