Individuals 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.
Dr Juan Carlos Izpisua Belmonte,
lead author and a Professor in Salk’s Gene Expression Laboratory told Thailand Medical
News, “What’s really exciting is that this is potentially a therapy that can be translated to the clinic quite easily. We are excited to continue refining this promising combination therapy for human use.”
With more than 95 million adults globally affected, , 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 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 underlying bone, causing chronic pain and stiffness.
Past 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.
As each drug alone had only moderately curbed osteoarthritis
in animal models of the disease,Dr Izpisua Belmonte and his colleagues wondered if the two drugs would act more effectively in concert.
Dr Paloma Martinez-Redondo, a Salk postdoctoral fellow and co-first author of the new study added, “We thought that by mixing these two molecules that work in different ways, maybe we could make something better.”
The medical researchers treated young, otherwise healthy rats with osteoarthritis
with viral particles containing the DNA instructions for making αKLOTHO and TGFβR2.
One and a half months 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.
Dr Isabel Guillen-Guillen, also a Salk postdoctoral fellow and the paper’s co-first author added, “From the very first time we tested this drug combination
on just a few animals, we saw a huge improvement. We kept checking more animals and seeing the same encouraging results.”
Additional 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 drug combination
To assess 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.
Dr Martinez-Redondo further added, “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.”
The medical researchers plan 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.
Dr Pedro Guillen, director of the Clinica CEMTRO and co-corresponding author commented, “We think that this could be a viable treatment for osteoarthritis
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.