Knee Osteoarthritis: It's Not All the Same, Says New Research

 

                                                                      Image credit: https://openai.com/index/dall-e/  

We all know someone, or maybe it's you, who suffers from the aches and pains of knee osteoarthritis (OA). It's a very common problem, especially as we get a bit older, and it’s mainly known for the wearing away of the cartilage in the knee joint. This can lead to that familiar stiffness and discomfort that makes everyday activities a bit of a struggle.

Now, for a long time, we've mostly focused on the cartilage damage as the main culprit in OA. However, recent research is showing that other parts of the knee joint, like the synovium (that's the lining of the joint), also play a crucial role in how the disease develops and the symptoms we experience. Scientists have been taking a closer look at the cells within this synovium to understand what's going on.

A new study published in JCI Insight has delved deep into this, examining the synovial tissue from people with knee OA who were having knee replacement surgery or arthroscopy. What they found is quite revealing: it seems that knee OA isn't just one thing. By analysing the genes being expressed in the synovial tissue, the researchers identified two distinct types of knee OA. They've called these the "inflammatory" type and the "fibrotic" type.

So, what's the difference?
Well, the inflammatory group showed signs of, you guessed it, more inflammation. Their synovial tissue had higher levels of inflammatory molecules, and when the researchers looked at it under a microscope, they saw more inflammatory cells had gathered there. Interestingly, the people in this inflammatory group reported worse knee pain compared to the other group.
On the other hand, the fibrotic group had synovial tissue that looked different. It showed more fibrosis, which is like a build-up of tough, fibrous tissue around the blood vessels. These tissues also had higher levels of substances called fibroblast growth factors (FGFs) and bone morphogenetic proteins (BMPs). Perhaps surprisingly, people in this group tended to report less severe pain. It's worth noting that all the synovial samples from patients who had arthroscopy after an ACL reconstruction fell into the fibrotic group.

To get an even closer look, the scientists used a technique called single-cell RNA sequencing (scRNA-Seq). This allows them to see what genes are being expressed in individual cells within the synovial tissue. They looked at four patients, representing both the inflammatory and fibrotic types.

This detailed analysis revealed different populations of cells within the synovium, particularly types of cells called fibroblasts and macrophages.

Fibroblasts are like the workhorses of connective tissue, and the researchers identified three main types in the OA synovium, labelling them based on the presence of certain markers (CD34 and THY1) on their surface: CD34loTHY1lo, CD34loTHY1hi, and CD34hi. It seems that these different types of fibroblasts have different jobs. For example, the CD34loTHY1lo type seems to be involved in producing enzymes that can break down tissue, while the CD34loTHY1hi type produces inflammatory substances.

Crucially, the CD34hi fibroblasts were more abundant in the fibrotic type of OA. These fibroblasts expressed genes linked to fibrosis and the formation of new blood vessels. They also seemed to be more influenced by cells lining blood vessels (mural and endothelial cells) rather than immune cells.

As for macrophages, which are immune cells, they found two main subtypes: MERTKhiCD206hi and MERTKloCD206lo. The MERTKloCD206lo macrophages, which are known to be more pro-inflammatory, were more common in the inflammatory type of OA. These inflammatory macrophages appeared to be actively communicating with the CD34loTHY1lo and CD34loTHY1hi fibroblasts.

One of the most interesting findings was about a specific subset of the CD34hi fibroblasts that also had a marker called CD70 (so they were CD34hiCD70hi). These cells were particularly prevalent in the Fibro_2 subgroup, a further subdivision within the fibrotic group. The researchers discovered that these CD34hiCD70hi fibroblasts might actually help to dampen down inflammation.

They found that when they mixed these fibroblasts with a type of immune cell called CD4+ T cells, the T cells started to multiply more. Further experiments suggested that these CD34hiCD70hi fibroblasts could promote the growth of regulatory T cells (Tregs), which are known to suppress inflammation in the body. When they blocked CD70 in lab experiments using knee joint tissue, they saw an increase in inflammatory molecules and a decrease in cartilage-protecting molecules. This hints that these CD34hiCD70hi fibroblasts might be trying to control the inflammation in the fibrotic type of OA.

What does all this mean?
Well, it suggests that knee osteoarthritis is a more complex condition than just wear and tear of cartilage. There seem to be different pathways involved, leading to different types of the disease with varying levels of pain and different characteristics in the joint lining.
Understanding these different "inflammatory" and "fibrotic" types of knee OA could be really important for developing new and more targeted treatments. For example, someone with the inflammatory type might benefit more from therapies that specifically target inflammation, while the fibrotic type might need a different approach. The discovery of the potential protective role of CD34hiCD70hi fibroblasts could even open up new avenues for treatment, perhaps by finding ways to encourage their activity.

This research highlights the incredible complexity of our joints and how much we still have to learn about conditions like osteoarthritis. By digging deeper into the different cell types and their interactions within the synovium, scientists are paving the way for a better understanding and, hopefully, more effective treatments for this common and often debilitating condition.
 
Additional information: CD34hi subset of synovial fibroblasts contributes to fibrotic phenotype of human knee osteoarthritis. JCI insights (2025). https://insight.jci.org/articles/view/183690

Journal information: https://insight.jci.org