FOXO Proteins in Joint Health and Osteoarthritis
Joint Cartilage and FOXO Proteins
Osteoarthritis is a condition in which the cartilage lining in certain joints degenerates. The cartilage provides cushioning in the joint and prevents the surface of one bone from rubbing on another. Damage to the cartilage often causes pain and mobility problems. Osteoarthritis is unfortunately a common disorder, especially in older people.
Researchers have found that the amount of FOXO proteins is significantly reduced in the joints of humans and mice affected by osteoarthritis. They've also found that removing the proteins from healthy mice increases the risk of the disorder. Adding the proteins to cartilage cells from human osteoarthritis patients corrects some of the problems in the cells. If the proteins are found to help the disease inside the human body, it might be possible to use them medicinally.
Osteoarthritis Causes and Symptoms
Osteoarthritis is the most common form of arthritis. According to The Scripps Research Institute, the disease affects about thirty million people in the United States. It involves the breakdown of the cartilage enclosing the bone in a joint. As a result, the person may experience pain, swelling, and difficulty in moving the joint. As the cartilage degenerates, it may develop projecting growths called spurs, which can cause further pain. Bits of broken bone may enter the joint and cause even more irritation. Eventually, so much cartilage disappears that the surface of one bone rubs directly on the other one as the joint moves.
Osteoarthritis is sometimes referred to as wear and tear arthritis because it usually occurs in people who are middle aged or older. The cause is more complicated than simply aging, however, since not all older people develop the condition. It's not an inevitable consequence of aging. Other risk factors for the disorder besides age are gender (females are more likely to get the condition than males), genetics, an injury to the joint, repetitive stress applied to the joint, a pre-existing bone injury, and obesity.
Osteoarthritis Development in the Knee
Someone with osteoarthritis should be under a doctor's care. Physicians can suggest treatments for improving symptoms and ways of dealing with the problems that the disease causes. In addition, they will probably know about any new developments in treatment methods for the disease. Although osteoarthritis more often occurs in older people, younger ones need to remember that they may develop the disorder as well.
Structure of DNA or Deoxyribonucleic Acid
Activation of specific genes in DNA seems to be important in relation to preventing osteoarthritis. A DNA molecule is a double helix. Each strand in the helix contains a sequence of nitrogenous bases: thymine (T), adenine (A), cytosine (C), and guanine (G). The order of bases on one strand of the DNA forms a code. A sequence of bases that codes for a specific protein is called a gene. The DNA strand contains multiple genes and therefore codes for multiple proteins. Transcription factors activate or inhibit the genes, thereby determining whether a protein is actually made.
Transcription and Transcription Factors
FOXO is the general name for a class of proteins that are also transcription factors. In order to understand their action, a basic knowledge of transcription may be helpful.
DNA molecules and their code for making proteins are located in the nucleus of a cell. Proteins are made on the surface of ribosomes, which are located outside the nucleus. DNA is unable to leave the nucleus. In order for its instructions to reach the ribosomes, a molecule known as messenger RNA (or mRNA) copies the instructions and transports them to the ribosomes. The process of making mRNA is known as transcription.
A transcription factor is a special protein that binds to a specific gene in DNA and either stimulates or inhibits transcription. In this way it controls gene expression, which can be thought of as the turning on of a gene. The transcription factor makes sure that the correct gene is turned on or off at the right moment in the cell's life.
FOXO proteins are transcription factors that turn on genes involved in keeping the cartilage in joints healthy, which may explain why the level of the proteins is linked to osteoarthritis. While someone with the disease generally doesn’t experience a problem in all of their joints, it’s possible that injury to a specific joint or stress on the joint combined with a FOXO deficiency in that joint could trigger cartilage damage.
Some scientists think that transcription factors test one spot at a time on a DNA molecule until they find the right gene to join. Others think that the factors slide rapidly along the DNA while following a helical path until they reach the correct binding site. The two theories are shown in the video below.
Gene Regulation by Transcription Factors
Unfortunately, the rule for writing the name of Fox proteins is different in humans and mice. In humans, every letter in the name "FOX" is capitalized. In mice and other animals, only the first letter is capitalized. In the text below, I've chosen to capitalize only the first letter when I describe information that might apply to both humans and animals.
A Brief Overview of Fox Proteins
The word "Fox" in reference to proteins stands for Forkhead box. The first gene for a Fox protein was discovered in the fruit fly named Drosophila. A mutation in the gene caused the appearance of a structure resembling a fork on the fly's head, giving the gene and its protein their name.
The Fox class of proteins is very large. At first the names of the proteins in the class followed no rules and were confusing. In 2000, a logical system for naming the proteins was established and accepted by scientists.
Each individual protein is now identified by the word Fox followed by a letter and a number. Fox is the class, the letter represents the subclass, and the number represents the member. The FOXO class in humans includes four proteins: FOXO1, FOXO3, FOXO4, and FOXO6. The second member of the subclass was found to be the same as the third one and was dropped. The fifth member is found in fish and isn't used in humans.
The various FOX proteins are produced in many places in the human body and are involved in a wide variety of functions, including metabolism. Problems with the proteins are linked to some diseases. One of these diseases is osteoarthritis.
Forkhead box proteins are sometimes referred to as winged helix proteins because part of their structure resembles the appearance of butterfly wings, as in the image above. At least to my eyes, the structure above looks like a butterfly heading towards the upper righthand corner of the image.
Interesting Discoveries in Mice and Humans
In 2014, a group of researchers from multiple institutions made some interesting discoveries related to osteoarthritis. They examined normal and aging joints as well as joints with osteoarthritis and found similar results in both mice and humans.
The researchers discovered that human joints produced FOXO1 and FOXO3. In older people, the amounts of these proteins in the joints were "markedly" decreased in the part of the cartilage exposed to the greatest weight-bearing load. People with osteoarthritis had additional changes in relation to their FOXO proteins.
The team also discovered that people with osteoarthritis had a lower expression (activity) of the genes controlling autophagy. Autophagy is the process in which a cell destroys damaged or unnecessary structures that are present inside the cell.
The research didn't prove that a decrease or alteration in FoxO proteins causes osteoarthritis in mice or humans. A correlation between two factors doesn’t necessarily mean that one factor causes the other. More recent discoveries support the idea that a FoxO deficiency plays an important role in the disease, however.
New Discoveries About FoxO in Mice
One of the 2014 researchers was Martin Lotz from The Scripps Research Institute. In 2018, he and other researchers in the team published some new research related to osteoarthritis. Their research involved knockout mice. In knockout animals, a particular gene or gene is inactivated by being blocked or deleted.
- Mice that lacked active genes for FoxO production experienced joint damage at a much younger age than mice with the genes.
- When the meniscus in the knee was deliberately damaged, the knockout mice developed a more severe form of post-traumatic osteoarthritis than the healthy mice who received the same injury. (A meniscus is a fibrous cartilage in the knee.)
- The knockout mice were more likely to develop joint damage as a result of running on a treadmill.
- In addition, they were found to have problems with autophagy.
- The researchers also discovered that the knockout mice had a decreased ability to fight damaging molecules called oxidants.
- The knockout mice had a reduced level of lubricin in their joints. As might be suspected from its name, lubricin helps to lubricate joints and protect the cartilage from damage.
- The scientists found that the loss of lubricin was associated with the loss of healthy cells in a part of the knee cartilage known as the superficial zone.
The inability to make FoxO proteins seems to have stopped or reduced multiple processes involved in protecting mouse joints.
There are two menisci in each knee: a lateral one on the outer side of the knee and a medial one on the inner side. The menisci acts as shock absorbers during movement and also have other functions. A torn meniscus may increase the risk for osteoarthritis in the joint. In addition, pre-existing osteoarthritis in the joint may increase the risk of a meniscus tear.
Observations in Human Cells
The researchers also examined chondrocytes (cartilage cells) obtained from human joints affected by osteoarthritis. They found that the cells had a reduced activity of genes producing FOXO proteins and reduced activity of autophagy genes. Increasing the expression of the FOXO genes increased the activity of other protective genes, reduced inflammation, decreased the level of enzymes that destroy cartilage, and increased the level of lubricin.
Drugs that boost the expression and activity of FoxO could be a strategy for preventing and treating osteoarthritis.— Martin Lotz, MD, via The Scripps Research Institute
A Potential Treatment for Osteoarthritis
FOXO proteins appear to be necessary for the maintenance of joint health. Boosting their level might one day be helpful in treating or preventing osteoarthritis. The discoveries so far relate to mice and isolated human cells, however. Clinical trials are necessary in order to determine whether the proteins help humans with osteoarthritis and to discover whether some members of the FOXO subclass are more helpful than others.
I have osteoarthritis in my neck. At the moment, my bones often click as I move my neck, but the condition is painless. I'm hoping it stays that way as I grow older. From a personal point of view, it would be nice if researchers found that increasing the level of FOX proteins in joints is safe and helpful. I'm sure that many people with painful osteoarthritis feel the same way.
Facts about osteoarthritis from the NIH (National Institute of Health)
Unified nomenclature for forkhead transcription factors from Genes & Development
A guide to FOXO transcription factors from cell.com
Akasaki, Y., Hasegawa, A., Saito, M., Asahara, H., Iwamoto, Y., & Lotz, M. K. (2014). Dysregulated FOXO transcription factors in articular cartilage in aging and osteoarthritis. Osteoarthritis and Cartilage / OARS, Osteoarthritis Research Society, 22(1), 162–170. http://doi.org/10.1016/j.joca.2013.11.004
Scientists find key proteins control risk of osteoarthritis from The Scripps Research Institute
An abstract of the 2018 research report about Foxo transcription factors from Science Translational Medicine
© 2018 Linda Crampton