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FOXO Proteins in Joint Health and Osteoarthritis

Linda Crampton is an experienced teacher with a first-class honors degree in biology. She writes about the scientific basis of disease.

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 obtained 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.

The synovial joint is the most common type of joint in our body.

The synovial joint is the most common type of joint in our body.

Osteoarthritis Facts

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 articular cartilage covering 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. In addition, younger people sometimes develop the disorder.

Other risk factors for osteoarthritis 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

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 act as transcription factors. In order to understand their action, a basic knowledge of transcription may be helpful.

The Transcription Process

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.

Transcription Factors

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 our metabolic ones. Problems with the proteins are linked to some diseases. One of these diseases is osteoarthritis. The effort to understand the activity of the proteins could be very worthwhile.

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. FoxO proteins are involved in the regulation of autophagy genes.

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.

Many Fox protein discoveries have been made in mice.

Many Fox protein discoveries have been made in mice.

Other 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. Since mice are mammals like us, the processes that occur in their body are often (but not always) the same as in ours.

  • 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.

In 2020, another group of researchers from The Scripps Research Institute reported the results of their examination of human and mouse menisci and found further evidence of the importance of FOXO1 and FOXO3, as shown in the quote below. Martin Lotz was once again part of the group.

Our results show that FoxOs are suppressed in degenerated meniscus and that FoxO1 regulates meniscus growth and maturation, while both FoxO1 and 3 have protective functions in meniscus during aging and OA.

— Kwang ll Lee eta al, The Scripps Institute 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 (a PDF document)
  • Dysregulated FOXO transcription factors in articular cartilage in aging and osteoarthritis from the Osteoarthritis and Cartilage journal
  • Scientists find key proteins control risk of osteoarthritis from The Scripps Research Institute
  • A report about FoxO transcription factors from Science Translational Medicine
  • FOXO1 and FOXO2 transcription factors have unique functions in meniscus development and homeostasis during aging and osteoarthritis from PNAS (Proceedings of the National Academy of Sciences of the United States of America)

Questions & Answers

Question: Are clinical trials for FOXO proteins open for volunteers?

Answer: You should consult your doctor with respect to clinical trials, for several reasons. First, they will know more about the existence of relevant clinical trials and their requirements than me. Secondly, they will be able to tell you about the nature of a particular trial and about its potential benefits and risks with respect to your health.

Question: Where can I buy FOXO proteins?

Answer: FOXO proteins aren't for sale for pharmaceutical or commercial use. They are still being studied by researchers. Perhaps one day they will be useful as medications and will be sold for this purpose, but we aren't at that stage yet.

© 2018 Linda Crampton


Linda Crampton (author) from British Columbia, Canada on March 07, 2018:

Hi, Lorelei. Thanks for the visit. I'm happy that knowledge of the human body body is increasing. Its operation is complex, but it's vital to gain a better understanding of its systems in order to treat some diseases.

Lorelei Cohen from Canada on March 07, 2018:

It constantly amazes me how complex our body and its functions are. I have a chronic illness and am greatly affected by proteins so find this fascinating. They truly are learning so much as we move further into investigating these illnesses.

Linda Crampton (author) from British Columbia, Canada on March 01, 2018:

Thank you, Nikki. Blessings to you, too.

Nikki Khan from London on March 01, 2018:

I hope so too Linda.

God bless you always.

Linda Crampton (author) from British Columbia, Canada on March 01, 2018:

I'm so sorry about your problem, Audrey. I hope the specialist can help you. Best wishes to you.

Audrey Hunt from Pahrump NV on March 01, 2018:

I have this in my right thumb and it's so painful! My thumb clicks in two joints. When I put my thumb back in place I let out a howl. I'm in a hand brace until I see a specialist next week. My biggest fear is not being able to play piano professionally anymore.

Linda Crampton (author) from British Columbia, Canada on February 24, 2018:

Thank you, Peggy. I will be following the research with interest.

Peggy Woods from Houston, Texas on February 24, 2018:

It would be wonderful if a treatment could be developed to prevent and/or help alleviate osteoarthritis. This was certainly an interesting article! Thanks!

Linda Crampton (author) from British Columbia, Canada on February 24, 2018:

Hi, Dianna. I hope the substance becomes a medication if it's found to be an effective treatment. It might be very helpful. Thank you for the comment.

Dianna Mendez on February 24, 2018:

FoxO shows wonderful potential for those suffering from join damage and osteoarthritis. If it increases the quality of life for many, I hope it becomes available. Great article, as usual!

Linda Crampton (author) from British Columbia, Canada on February 24, 2018:

Thank you very much for the comment, Nikki. I hope your family continues to stay free of osteoarthritis.

Nikki Khan from London on February 24, 2018:

Another informative and interesting article on osteoarthritis, have learnt a lot about it Linda.Thank God nobody suffered this in my family.

Very terrible experience for people who have it,May God give them strength and courage to recover from it.

keep it up dear Linda, great work.

Linda Crampton (author) from British Columbia, Canada on February 23, 2018:

Hi, Natalie. I'm sorry about your knee pain. I wish better ways to prevent or at least postpone osteoarthritis existed. Thanks for commenting.

Natalie Frank from Chicago, IL on February 23, 2018:

Thanks for another info filled article. I used to dance and as I've gotten older have noticed old injuries seemingly giving me a fit. My knees are definitely bothering me and the Dr. said it is at least in part osteoarthritis. So much fun getting older!

Linda Crampton (author) from British Columbia, Canada on February 22, 2018:

Hi again, Nell. I'm hoping that animal research doesn't continue for much longer. Scientists have managed to grow organoids in the lab. I hope these soon become sophisticated enough to at least greatly reduce animal research.

Nell Rose from England on February 22, 2018:

That's good to know, I know it was and is a necessity, but its still one of those subjects isn't it. But it does good so I am not against it in that way.

Linda Crampton (author) from British Columbia, Canada on February 22, 2018:

Hi, Nell. Yes, the use of animals for experiments is a worrying topic. The experiments can help us discover new treatments for human diseases, but like you I cringe when I think about what the animals sometimes have to endure. Some organizations are working to reduce or replace animal testing, such as by using cells and tissues grown in the lab or by using computer models. I hope these efforts are successful.

Nell Rose from England on February 22, 2018:

A friend of the family an elderly guy is suffering at the moment with something like this, not sure exactly if its the same. Interesting and informative. and those poor mice. I totally understand why they are used but I do tend to cringe a bit, lol!

Linda Crampton (author) from British Columbia, Canada on February 22, 2018:

Hi, Nithya. Thanks for the visit and comment. I hope researchers come up with better treatments, too.

Nithya Venkat from Dubai on February 22, 2018:

An interesting and informative article, learned a lot about FOXO proteins. Very nicely presented and explained, thank you for sharing. I hope the researchers come up with a solution to effectively treat this condition.

Linda Crampton (author) from British Columbia, Canada on February 22, 2018:

Hi, Flourish. Yes, biology discoveries can be very interesting, but the way that lab animals are treated is of great concern. Thank you for the visit.

FlourishAnyway from USA on February 21, 2018:

Both my mother and an aunt have osteoarthritis and both have had surgery for a torn meniscus. Bones rubbing on bones are very painful from what they tell me. Thank you for describing the science behind it. All I can see is those poor little rats on the treadmills with intentionally made bum knees. Sad.

Linda Crampton (author) from British Columbia, Canada on February 21, 2018:

Thanks for the visit and the comment, Devika. I'm sorry that your friend broke her wrist. That must have been painful. I'm wondering if her condition is osteopenia. That can increase the risk of a fracture.

Devika Primić from Dubrovnik, Croatia on February 21, 2018:

A friend of mine broke her wrist and her condition with osteopine is the reason for such an injury. An interesting hub on this topic.

Linda Crampton (author) from British Columbia, Canada on February 21, 2018:

Hi, Cynthia. Thanks for the visit. The osteoarthritis in my neck was diagnosed by a doctor while he was investigating another disorder. It hasn't made much difference to me so far. I hope it stays that way! I hope you don't have the condition.

Cynthia Zirkwitz from Vancouver Island, Canada on February 21, 2018:

Hi Linda, This is a fascinating article, and I plan to go through it again with my husband. We are, of course, older and both afflicted by joint pain from time to time. I was interested to read that my crackly neck bones, although painless, might also indicate osteoarthritis.

Linda Crampton (author) from British Columbia, Canada on February 21, 2018:

Thank you very much, Dora. Osteoarthritis can sometimes cause a lot of problems. It would be good to have more ways to treat it.

Dora Weithers from The Caribbean on February 21, 2018:

My mother suffered from osteoarthritis in her spine, or say they said. She seemed to be in pain more often than not. Thanks for explaining FOX, the letters and numbers. I always learn so much from your articles.