Unravelling the function of “mechanostat” genes in subchondral bone remodelling, bone innervation and osteoarthritis progression

Have you ever experienced pain in your back, knees, or hips? Now, imagine a similar pain but long-lasting that could get worse and worse to the point that it is impossible to walk. Unfortunately, this is a current reality and symptom that many of us have or will have at some moment in our lives. Osteoarthritis is an incurable disease found in as many as 70% of the ageing population worldwide.

Along with the pain symptoms, osteoarthritis is characterised by the breakdown of the cartilages covering the bones at the joints.

Curiously, sometimes the problem might not start at the cartilage itself but is triggered by defects in the bones underlying the cartilage. Alterations in the bone cause increase in bone innervation and pain.

Therefore, I aim to answer why the bone structure underneath the cartilage suffers changes and what mechanisms favour increased innervation. For this, I will focus on the most abundant cell type of our bones, osteocytes, and their molecular machinery. My research will take us forward towards ways to prevent and treat osteoarthritis.

Osteocytes are star-shaped cells, resembling neurons, immersed in the hard bone matrix and forming a neuron-like network within the bone.

They are also called “mechanostat” of the bone because they sense the mechanical load and respond accordingly, sending messages to other bone cells to make or resorb bone.

Surprisingly, some osteocyte genes function in neurons, controlling neuronal branching and guiding them to their final target tissues.

I argue that neuronal genes operating in osteocytes regulate osteocyte branching and/or serve as signals to attract or repel nerves to the bone, contributing to joint function and likely pain.

To test this, I will ablate selected genes in zebrafish and check their effect on bone, cartilage, osteocytes, and neurons.

Zebrafish are freshwater fish with bones and joints that have been used worldwide to study the role of genes in different biological processes and diseases, including osteoarthritis. Zebrafish are see-through during an extended period of their lives.

Combining their transparency with genetic engineering to label neurons, bones, and cartilages with glowing proteins, we can visualise these cells in live fish just under the scope. Moreover, it is straightforward to modify genes in zebrafish, and when we do so, we call them mutants.

I will generate zebrafish mutants for osteocyte genes and track neuronal cells labelled with glowing proteins to observe how they are attracted to the bones and joints in mutants.

Also, I will study osteocyte shape, branching, the bone underlying the cartilage and changes to the cartilage leading to osteoarthritis.

My research will help us identify genetic causes of OA, and disease progression, with spins off to understanding joint pain.

The results from my research will be highly translational, meaning that it will position us closer to identifying drugs to treat and prevent OA.