Osteoarthritis: Painful Cartilage Breakdown

Osteoarthritis is a disease in which the slippery white tissue between bones in a joint, called articular cartilage, breaks down and causes pain. Osteoarthritis can affect any joint in the body but is particularly common in the hip and knee joints [1]. Osteoarthritis can happen with age because of wear and tear, but it can also happen to young people who injure their joints, possibly by tearing their cartilage or dislocating their joint. Even small injuries to articular cartilage can lead to osteoarthritis because cartilage lacks the ability to heal itself.

To prevent osteoarthritis, a procedure called autologous chondrocyte implantation (ACI) can be performed following a minor joint injury. Autologous means the cells used in the treatment are from the same patient. Unfortunately, ACI does not always provide lifelong protection against osteoarthritis. Our lab is studying the cause of this limitation and researching ways to make ACI more successful and long lasting—to improve the lives of the people who receive this surgery.

What Is Articular Cartilage?

Articular cartilage is essential for painless movement. It acts as a shock absorber and allows bones to move smoothly over one another. The cells in articular cartilage are called chondrocytes, and they are responsible for maintaining healthy cartilage [2]. Chondrocytes keep cartilage healthy by secreting the molecules that form what is called the matrix—a kind of living scaffold that gives structural support to the cartilage tissue (Figure 1).

The matrix is what provides cushion to bones. It is made of three main components: collagen type II, aggrecan, and water [2]. Collagen type II provides the matrix with the ability to endure forces like stretching and compression, and aggrecan gives the matrix the ability to attract water. The aggrecan-water mixture provides the shock-absorbing capabilities of articular cartilage.

Interestingly, articular cartilage does not have any blood vessels, so it cannot obtain nutrients and other resources from the blood like most organs and tissues can. So, when articular cartilage is damaged, chondrocytes do not have the resources necessary to repair the damage. When you break a bone, it heals after a while—but articular cartilage does not heal, even after a long time. In fact, even minor cartilage damage can cause further breakdown to cartilage over time, which is why even a small injury to articular cartilage can eventually develop into osteoarthritis.

An Overview of ACI

ACI is a common method used to prevent small cartilage injuries from developing into osteoarthritis in the knee, hip, or shoulder joints. ACI is a two-surgery therapy (Figure 2). In the first surgery, a surgeon removes a tiny piece of healthy articular cartilage (approximately the size of a Tic-Tac) from a healthy area in the joint. This tissue is taken to a laboratory where the chondrocytes are separated from the cartilage matrix. The chondrocytes are placed onto plastic dishes filled with a mixture of nutrients that help them to grow. The chondrocytes are grown until there are enough cells to cover the damaged area of the joint. Finally, the surgeon re-implants the lab-grown chondrocytes into the damaged area of the patient’s joint.

ACI cannot be used to prevent osteoarthritis that happens due to old age, but it is an important tool to prevent osteoarthritis in young people who have enough healthy cartilage to remove and grow in the lab. After injury, ACI allows active people to return to a similar level of physical activity and to require fewer surgeries to repair their articular cartilage. Unfortunately, many patients who receive ACI still end up developing osteoarthritis eventually [3]. This happens because chondrocytes that are grown outside of the body undergo certain changes, so the matrix that they make when they are re-implanted into the joint is different from the normal matrix.

What Happens to Chondrocytes Grown in the LAB?

The environment in which chondrocytes live has a big impact on their structure and function. When chondrocytes are grown outside of the body, they begin changing their shape until they look different from the way they would look inside the body. The changes are due to differences between the two environments. Within the body, chondrocytes live in a three-dimensional matrix, which is a comfortable environment for them. However, when cells are grown in the lab, they grow on two-dimensional, plastic tissue culture dishes. Although these dishes are ideal for growing more cells, they are stiffer than the chondrocytes’ natural environment. This causes the chondrocytes to become wider and flatter, and to produce different molecules than they would make inside the body. This process is called chondrocyte dedifferentiation, and we call these cells dedifferentiated chondrocytes (Figure 3).

Normal chondrocytes produce type II collagen for their matrix, while dedifferentiated chondrocytes produce type I collagen, which is more densely packed leading to a less durable matrix [4]. Dedifferentiated chondrocytes also produce less aggrecan. This change in the molecules produced by dedifferentiated chondrocytes leads to the creation of a tissue called fibrocartilage. Compared to articular cartilage, fibrocartilage has a shorter lifespan plus it is not as strong and nor absorptive of forces. Therefore, current scientific research is trying to to reverse chondrocyte dedifferentiation, to improve the matrix produced by these cells.

How Can We Improve ACI?

Currently, there are no ways to heal cartilage permanently, to prevent osteoarthritis. Our research aims to improve ACI by increasing the number of healthy chondrocytes that can be re-implanted into a joint. We have found that when chondrocytes are grown on a softer dish that is more like their natural environment, they produce matrix that is more similar to that produced by chondrocytes in the body. We try to reverse the initial shape changes chondrocytes undergo in the lab, and turn them back into their round, healthy form. We are discovering the molecules that cause this shape change and, by studying those molecules, we are trying to reverse the dedifferentiation process.

If we can reverse chondrocyte dedifferentiation, we will be able to grow chondrocytes in the lab that are healthy and function similarly to those that grow in the body. If more healthy chondrocytes are available for implantation, ACI can increase the quality and lifespan of regenerated cartilage. We anticipate that our research will result in fewer surgeries for people who damage their articular cartilage—and more time running, jumping, and living the lives they love!

Glossary

Osteoarthritis: ↑ A disease where articular cartilage, the tissue that cushions bone, breaks down and leads to painful bone on bone rubbing. Osteoarthritis can develop from even small joint injuries.

Articular Cartilage: ↑ The tissue found in joints that prevents bones from rubbing together and acts as a cushion to absorb forces when the person moves. Cartilage lacks any method to repair itself.

Autologous Chondrocyte Implantation (ACI): ↑ A surgical procedure in which chondrocytes are removed from healthy articular cartilage, grown in a lab, and then put into the damaged area of the joint.

Chondrocytes: ↑ The cells in cartilage that are responsible for building cartilage by making matrix molecules such as collagen type II and aggrecan.

Matrix: ↑ The structure created by chondrocytes that gives articular cartilage its cushion function.

Collagen Type II: ↑ An important building block of the cartilage matrix that provides strong structure to withstand pulling and pushing forces.

Aggrecan: ↑ A molecule of the cartilage matrix that draws in water to provide strength for shock absorbance.

Chondrocyte Dedifferentiation: ↑ A series of significant changes to chondrocytes that happen when they are grown in the lab and affect their ability to produce healthy cartilage.

Fibrocartilage: ↑ A type of cartilage that is mechanically inferior to articular cartilage. It is produced by cells grown on stiff plastic dishes in the lab. Fibrocartilage limits the lifespan of ACI.

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Acknowledgments

We would like to thank Marissa Heino for her help with the early stages of our project and Hiba Oumial and Cameron Schweiger for help with the editing process. This work was supported by the Delaware Center for Musculoskeletal Research from the National Institutes of Health’s National Institute of General Medical Sciences under grant number P20GM139760.