Are Your Cartilage Proteins Salamander Like?

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There has been a very active focus on cartilage repair for decades. We see studies published all the time about this or that new stem cell or protein-mediated cartilage repair. Throw in the hype added by university PR departments and you would think that we should be handing out 100 Nobel prizes each year instead of one. However, a study popped up a few weeks ago that’s worth discussing. Basically, it showed that the cartilage in your joints and a salamander’s ability to regenerate limbs may be linked. Let me explain.

Salamanders and Their Limbs

Salamanders have the ability to regenerate limbs just like Deadpool. If you don’t follow this foul-mouthed, but hilarious Marvel franchise, Deadpool can regenerate his tissues including limbs. This superpower also happens in lowly salamanders and has been studied for decades as a template for how natural regenerative medicine works. See below:

The Quandry of the Hip

The hip is a strange joint. Unlike other joints in the leg where arthritis can smolder for years before the joint gets bad, the hip goes fast. I’ve seen patients with mild arthritis progress to severe disease in months to just under a year. Compare that to the knee, where it can often take 5-10 years or more to progress from mild to severe osteoarthritis.

We’ve known for a few years that the cartilage in the hip is less able to repair itself (1). Our research group has also noted that the outcomes from the use of stem cells in the hip were much more impacted by age and degenerative arthritis than in the knee (2). Meaning older patients with more severe arthritis in the hip just don’t have the same positive results as older patients with more severe knee arthritis.

The New Research

The researchers at Duke University did some fairly complex testing, but in the end, concluded that the cartilage proteins in the ankle were younger than the knee which were younger than the hip (3). All of this was in the context of a better cartilage self-repair ability in the ankle than in the hip. Hence, the press picked up the piece as analogous to how Salamanders regenerate limbs. Meaning that human joints showed a similar, but weaker self-repair capacity. See image to the right created by Duke Health. The research team also found a unique micro RNA that produced collagen that they thought they could exploit to enhance cartilage repair (mRNA21).

What Does This All Mean?

We’ve known about the innate ability of human cartilage repair for decades (4), so some of the press this article received is pure university generated hype. We’ve also known about how unique growth factors and cytokines can be used to enhance cartilage repair (5,6). So the idea that there could be a mass-produced substance that you can inject or use to prompt cartilage repair is also not new. Finally, we’ve also known for years that there were differences in the age of hip proteins versus other joints. So what is new here? That the cartilage proteins get younger the farther you get away from the trunk, which looks like there could be some evolutionary similarities between us and the salamander.

The upshot? While I’m not sure this article is as earth-shattering as Duke portrayed it to be (I’m shocked), it is pretty cool to think that the proteins in our ankle cartilage are younger than in our hips. Now maybe in a decade or two we’ll have a drug that can be injected to repair cartilage that comes from this discovery? Or maybe we’ll just use stem cells?

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References:

(1) Catterall JB, Hsueh MF, Stabler TV, et al. Protein modification by deamidation indicates variations in joint extracellular matrix turnover. J Biol Chem. 2012;287(7):4640–4651. doi: 10.1074/jbc.M111.249649

(2) Centeno CJ, Pitts JA, Al-Sayegh H, Freeman MD (2014) Efficacy and Safety of Bone Marrow Concentrate for Osteoarthritisof the Hip;
Treatment Registry Results for 196 Patients. J Stem Cell Res Ther 4: 242. doi: 10.4172/2157-7633.1000242

(3) Hsueh MF, Önnerfjord P, Bolognesi MP, Easley MP, Kraus VB. Analysis of “old” proteins unmasks dynamic gradient of cartilage turnover in human limbs. Science Advances 09 Oct 2019: Vol. 5, no. 10, eaax3203. DOI: 10.1126/sciadv.aax3203

(4) Kristjánsson B, Honsawek S. Mesenchymal stem cells for cartilage regeneration in osteoarthritis. World J Orthop. 2017;8(9):674–680. Published 2017 Sep 18. doi: 10.5312/wjo.v8.i9.674

(5) Blaney Davidson EN, Vitters EL, van den Berg WB, van der Kraan PM. TGF beta-induced cartilage repair is maintained but fibrosis is blocked in the presence of Smad7. Arthritis Res Ther. 2006;8(3):R65. doi: 10.1186/ar1931

(6) Mimpen JY, Snelling SJB. Chondroprotective Factors in Osteoarthritis: a Joint Affair. Curr Rheumatol Rep. 2019;21(8):41. Published 2019 Jun 21. doi: 10.1007/s11926-019-0840-y

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