New Treatment for Osteoarthritis on the Horizon: Recent Research

Osteoarthritis is a leading cause of disability amongst older adults, causing severe pain and debilitation to over 30 million Americans. This decline in the ability to move leads to osteoarthritis patients often having comorbidities, including cardiovascular disease, obesity, or diabetes.  

In this article, learn more about how osteoarthritis develops and the details of a recent study that may have uncovered a potential new treatment for osteoarthritis.

The Basics of Osteoarthritis

Osteoarthritis (OA), the most common form of arthritis, is often referred to as “wear and tear” arthritis, as it tends to occur after injury or with increasing age. OA develops when the protective cartilage between bones breaks down, causing the otherwise-cushioned joints to grind together. This leads to painful and swollen joints, most commonly occurring in the hands, knees, neck, hips, and lower back. 

Specifically, the degeneration of articular cartilage is involved in OA. Articular cartilage is a type of hyaline cartilage, which is made up of an extracellular matrix (ECM). The ECM consists of collagen, various proteins, water, proteoglycans, and chondrocytes, which are the specialized and metabolically active cells of cartilaginous tissue. 

With age, injury, or obesity, the ECM structure, the metabolic activity of chondrocytes, and the composition of cartilage all start to degrade.

Most criteria of OA classify four stages of disease progression, with grade 0 indicating normal cartilage and grade 4 being the most severe, demonstrated by complete erosion down to the bone. 

Current treatments for osteoarthritis involve managing pain and inflammation symptoms, as OA is thought by most researchers to be incurable. This is because the body cannot easily repair damaged cartilage; it doesn’t contain blood vessels, nerves, or the necessary lymphatic system to regenerate its tissue. 

However, a recent study may have found a potential treatment for osteoarthritis, involving two molecules that play a role in cartilage homeostasis. 

New Research on Treatments for Osteoarthritis

The study, published in Protein & Cell in March 2020, looked at the impact of the therapeutic administration of the molecules α-Klotho and soluble transforming growth factor-beta receptor 2 (sTGFβR2) in rats with OA. 

What Are α-Klotho and sTGFβR2?

α-Klotho is a protein studied for its role in anti-aging and the modulation of oxidative stress. Animals without this protein commonly experience premature aging, organ failure, cardiovascular disease, and cognitive decline. 

The second compound, sTGFβR2, is a receptor that binds to a cytokine called TGFβ1. Although TGFβ1 has been found to upregulate chondrocyte growth, it may also contribute to OA development when in excess; thus, a moderate amount of TGFβ1 is desired. 

sTGFβR2 binds strongly to TGFβ1, which does the job of modulating TGFβ1 levels — inhibiting TGFβ1is linked to a reduction in osteophyte (bone spur) formation, which is a symptom of OA. 

Adequate amounts of α-Klotho are linked to improvements in OA, as the protein inhibits degradation of the ECM. In this study, α-Klotho was lower in the cartilage of rats with OA.

Based on these two compounds’ functions, the researchers hypothesized that combining them in a rat model could improve OA symptoms. 

What Did the Study Look At?

Four weeks after attempting to induce OA in rats using the enzyme papain, significant signs of grade 2 OA were found, including reduced cartilage thickness, loss of joint function, and the ECM’s calcification. In addition, rats with OA had reductions in chondrocyte cell markers, including type II collagen and SOX9, both necessary for bone development. 

Next, the researchers attempted to see if a combined therapy of α-Klotho and sTGFβR2 improved these symptoms. They delivered the molecules into the knee joint via adeno-associated virus (AAV) serotype DJ particles, which is a non-enveloped virus commonly used in gene therapy to deliver DNA into target cells.

The researchers verified that the injection worked, as the synovial fluid in their joint cavities had high expression of both α-Klotho and sTGFβR2. This group, made up of the rats with OA who received the injection, was referred to as the ‘KT’ group and was one of four that were studied. 

The other groups included two that acted as controls and did not receive an injection of any kind — one group was composed of healthy rats and the other had rats with OA. Lastly, the fourth group was the sham group, which received the AAV injection without the α-Klotho and sTGFβR2. 

What Were the Results of the Study? 

First, the researchers looked at a cellular model of the compounds. They found that in test tubes with cells modeling OA, the combination of α-Klotho and sTGFβR2 inhibited ECM breakdown and chondrocyte hypertrophy better than treatment with each compound separately. 

Next, they applied the same concept to the rats with grade 2 OA. Only two of the groups received an injection — the KT group and the sham group. After a 6-week recovery period, the sham group rats experienced a significantly greater deterioration of their cartilage and ECM, with a progression to grade 4 OA.

Not only did the KT group not experience this decline, they saw improvements. This group, who received the injection of α-Klotho and sTGFβR2, had recovered cartilage thickness and structure and repair of the ECM. 

Within these six weeks, the rats in the KT group went from grade 2 to grade 1 OA, indicating a partial reversal of the disease. The KT group rats also had restored type II collagen and SOX9 cells, signifying a recovery of chondrocyte function. 

Lastly, the researchers analyzed RNA sequencing from all the groups and found that the KT group had reduced expression of genes related to inflammation and excessive immune responses. Patients with OA experience high levels of both inflammatory and immune responses.

In summary, a combination of α-Klotho and sTGFβR2 injected into the knee joints of rats with OA reduced symptoms and severity of the disease by inhibiting cartilage and ECM degradation and reducing inflammation. The researchers hypothesize that this treatment could potentially benefit humans with OA, although more research is needed on this therapy before that point. 

Key Takeaway

• Administering a combination therapy of the two compounds α-Klotho and sTGFβR2 into rats with osteoarthritis led to a partial reversal of the disease and reduced inflammatory responses. 
• The α-Klotho and sTGFβR2 therapy inhibited the degradation of the extracellular matrix that is commonly seen in osteoarthritis and increased cartilage thickness and collagen levels. 
• This treatment for osteoarthritis has not yet been tested in humans, but may have promising results for treating osteoarthritic patients. 

References

Kohn MD, Sassoon AA, Fernando ND. Classifications in Brief: Kellgren-Lawrence Classification of Osteoarthritis. Clin Orthop Relat Res. 2016;474(8):1886-1893. doi:10.1007/s11999-016-4732-4

Naso MF, Tomkowicz B, Perry WL 3rd, Strohl WR. Adeno-Associated Virus (AAV) as a Vector for Gene Therapy. BioDrugs. 2017;31(4):317-334. doi:10.1007/s40259-017-0234-5

Martinez-Redondo P, Guillen-Guillen I, Davidsohn N, et al. αKLOTHO and sTGFβR2 treatment counteract the osteoarthritic phenotype developed in a rat model. Protein Cell. 2020;11(3):219-226. doi:10.1007/s13238-019-00685-7

Sophia Fox AJ, Bedi A, Rodeo SA. The basic science of articular cartilage: structure, composition, and function. Sports Health. 2009;1(6):461-468. doi:10.1177/1941738109350438