A combination of two previously studied osteoarthritis drugs works better than either drug alone.
People with osteoarthritis, or “wear and tear” arthritis, have limited treatment options: pain relievers or joint replacement surgery. Now, Salk researchers have discovered that a powerful combination of two experimental drugs reverses the cellular and molecular signs of osteoarthritis in rats as well as in isolated human cartilage cells. Their results were published in the journal Protein & Cell on January 16, 2020.
“What’s really exciting is that this is potentially a therapy that can be translated to the clinic quite easily,” says Juan Carlos Izpisua Belmonte, lead author and a professor in Salk’s Gene Expression Laboratory. “We are excited to continue refining this promising combination therapy for human use.”
“From the very first time we tested this drug combination on just a few animals, we saw a huge improvement.” — Isabel Guillen-Guillen
Affecting 30 million adults, osteoarthritis is the most common joint disorder in the United States and its prevalence is expected to rise in the coming years due to the aging population and increasing rate of obesity. The disease is caused by gradual changes to the cartilage that cushions bones and joints. During aging and repetitive stress, molecules, and genes in the cells of this articular cartilage change, eventually leading to the breakdown of the cartilage and the overgrowth of the underlying bone, causing chronic pain and stiffness.
Previous research had pinpointed two molecules, alpha-KLOTHO and TGF beta receptor 2 (TGFβR2), as potential drugs to treat osteoarthritis. αKLOTHO acts on the mesh of molecules surrounding articular cartilage cells, keeping this extra-cellular matrix from degrading. TGFβR2 acts more directly on cartilage cells, stimulating their proliferation and preventing their breakdown.
While each drug alone had only moderately curbed osteoarthritis in animal models of the disease, Izpisua Belmonte and his colleagues wondered if the two drugs would act more effectively in concert.
“We thought that by mixing these two molecules that work in different ways, maybe we could make something better,” says Paloma Martinez-Redondo, a Salk postdoctoral fellow and co-first author of the new study.
The researchers treated young, otherwise healthy rats with osteoarthritis with viral particles containing the DNA instructions for making αKLOTHO and TGFβR2.
Six weeks after the treatment, rats that had received control particles had more severe osteoarthritis in their knees, with the disease progressing from stage 2 to stage 4. However, rats that had received particles containing αKLOTHO and TGFβR2 DNA showed recovery of their cartilage: the cartilage was thicker, fewer cells were dying, and actively proliferating cells were present. These animals’ disease improved from stage 2 to stage 1, a mild form of osteoarthritis, and no negative side effects were observed.
“From the very first time we tested this drug combination on just a few animals, we saw a huge improvement,” says Isabel Guillen-Guillen, also a Salk postdoctoral fellow and the paper’s co-first author. “We kept checking more animals and seeing the same encouraging results.”
“We think that this could be a viable treatment for osteoarthritis in humans.” — Pedro Guillen
Further experiments revealed 136 genes that were more active and 18 genes that were less active in the cartilage cells of treated rats compared to control rats. Among those were genes involved in inflammation and immune responses, suggesting some pathways by which the combination treatment works.
To test the applicability of the drug combination to humans, the team treated isolated human articular cartilage cells with αKLOTHO and TGFβR2. Levels of molecules involved in cell proliferation, extra-cellular matrix formation, and cartilage cell identity all increased.
“That’s not the same as showing how these drugs affect the knee joint in humans, but we think it’s a good sign that this could potentially work for patients,” says Martinez-Redondo.
The research team plans to develop the treatment further, including investigating whether soluble molecules of the αKLOTHO and TGFβR2 proteins can be taken directly, rather than administered through viral particles. They also will study whether the combination of drugs can prevent the development of osteoarthritis before symptoms develop.
“We think that this could be a viable treatment for osteoarthritis in humans,” says Pedro Guillen, director of the Clinica CEMTRO and co-corresponding author.
Reference: “αKLOTHO and sTGFβR2 treatment counteract the osteoarthritic phenotype developed in a rat model” by Paloma Martinez-Redondo, Isabel Guillen-Guillen, Noah Davidsohn, Chao Wang, Javier Prieto, Masakazu Kurita, Fumiyuki Hatanaka, Cuiqing Zhong, Reyna Hernandez-Benitez, Tomoaki Hishida, Takashi Lezaki, Akihisa Sakamoto, Amy N. Nemeth, Yuriko Hishida, Concepcion Rodriguez Esteban, Kensaku Shojima, Ling Huang, Maxim Shokhirev, Estrella Nuñez-Delicado, Josep M. Campistol, Isabel Guillen-Vicente, Elena Rodriguez-Iñigo, Juan Manuel Lopez-Alcorocho, Marta Guillen-Vicente, George Church, Pradeep Reddy, Pedro Guillen-Garcia and Guang-Hui Liu, 16 January 2020, Protein & Cell.
Other authors were Chao Wang, Javier Prieto, Masakazu Kurita, Fumiyuki Hatanaka, Cuiqing Zhong, Reyna Hernandez-Benitez, Tomoaki Hishida, Takashi Lezaki, Akihisa Sakamoto, Amy Nemeth, Yuriko Hishida, Concepcion Rodriguez Esteban, Kensaku Shojima, Pradeep Reddy, Ling Huang and Maxim Shokhirev of Salk; Noah Davidson and George Church of Harvard University; Estrella Nuñez-Delicado of Universidad Católica San Antonio de Murcia; Josep Campistol of Hospital Clinic of Barcelona; Isabel Guillen-Vicente, Elena Rodriguez-Iñigo, Juan Manuel Lopez-Alcorocho, Marta Guillen-Vicente and Pedro Guillen-Garcia of Clinica CEMTRO; and Guang-Hui Liu of Chinese Academy of Sciences.
I just wanna say God bless the scientist who’s committed their life to such pursuits for the benefit of humanity. Seriously, thank you for living your life’s purpose.
It nice to think someday there may be a treatment or drug to reverse this disease. I’ve had both hips replaced and my shoulder , knees, and hands are very painful. My God bless these doctors in finding a cure.
Thanks for the info about your advances in research on osteoarthritis meds…I look forward to learning more.
Thank you so much for this latest developement in the treatment of OA. Looking forward to hear more news towards the betterment of this scientific discovery.
Best news I’ve heard so far! If this works I can’t wait to try it. Big thank you to all of you who are working to bring hope and relief to the millions of us suffering with osteoarthritis.
Thank-you and God bless you for all your on going research on osteoarthritis . Mine is mostly located in my hands and top of my feet. Walking is very difficult. Your research is very encouraging…..
I have this condition so severely, it is unbearable.
Please notify me when you have the product.
We all badly need this. It’s shocking that there’s not better care or cures for OA. I so far have OA in my hands, but my mother had it in almost every joint, so who knows? Please, please fast track this.
I have been living in hope most of my life I’ve completely refused a total knee replacement 10 years ago please bless these fantastic scientists for their dedication in committing their lives to this horrible disease I will never give up waiting .God bless you all .
I desperately need this. My hip has gotten so bad it wears me out yet if I sit around and do nothing for a week it improves enough that I can walk without a cane.