April 28, 2020

Blocking enzyme inhibits arthritis progression in mice

At a Glance

  • Loss of an enzyme called TET1 protected mice against the development of osteoarthritis.
  • Blocking TET1 in cells taken from people with osteoarthritis also prevented gene changes that help drive the disease.
  • The findings suggest a potential strategy for arthritis drug development.
3D reconstructions of mouse knees from phase-contrast micro-CT imaging Bone spurs and other arthritic damage appeared in normal mice after knee surgery (left); in contrast, mice lacking the enzyme TET1 were protected from arthritis progression (right).

Osteoarthritis occurs when cartilage, the tissue that cushions the ends of bones within joints, breaks down and wears away. It most often affects the fingers, knees, and hips. It typically develops after injury or surgery to a joint, or as part of the aging process. The resulting pain can prevent some people from working or doing daily living tasks.

Many people with osteoarthritis will eventually need surgery to repair or replace damaged joints. Currently, no drugs exist to prevent the progression of osteoarthritis. This is partially due to its complexity. Osteoarthritis is thought to be driven by changes in many different cellular pathways that the body uses to maintain cartilage health.

Researchers led by Dr. Nidhi Bhutani from Stanford University previously showed that a type of epigenetic change called cytosine hydroxymethylation (5hmC) builds up in the cartilage of people with osteoarthritis. Epigenetic changes are chemical changes that don’t alter the DNA sequence but modify the way genes are expressed—switched on or off. The changes found by the researchers affected the expression of many genes, including ones that have been linked with osteoarthritis development.

In a new study, they more closely examined 5hmC in a mouse model of osteoarthritis. The research was funded in part by NIH’s National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS). Results were published on April 15, 2020, in Science Translational Medicine.

The researchers first performed knee surgery on male mice and tracked them for the development of post-traumatic osteoarthritis. Mice that developed the condition showed substantial increases in 5hmC. This corresponded to changes in expression for many genes associated with osteoarthritis.

To test whether TET1, an enzyme known to help drive 5hmC, was required for these changes, the researchers used mice that had been engineered to lack the enzyme. Unlike normal mice, mice lacking TET1 did not show deterioration of their knee cartilage after surgery, either immediately after surgery or in later stages of healing.

Mice lacking TET1 also showed few of the epigenetic changes driven by the enzyme—or corresponding changes in gene expression that can lead to damaged cartilage. While mice lacking TET1 seemed to have normal inflammation responses overall, their cartilage appeared protected from the effects of chronic inflammation that accompany osteoarthritis.

The researchers next blocked TET1 in cells taken from people with osteoarthritis. Whether done genetically or with a drug, inhibiting TET1 decreased 5hmC and corresponding harmful changes in gene expression.

Normal mice that received injections of the same drug into their knees after surgery had a reduction in 5hmC. They also had less degradation of their cartilage, similar to that seen in mice engineered to lack TET1.

“These results show that inhibiting multiple cellular pathways associated with osteoarthritis through a single target may be a feasible strategy for drug development,” Bhutani says. “Further studies should test whether blocking TET1 can prevent the progression of osteoarthritis in larger animals that have joints more representative of human joints and the loads they bear.”

—by Sharon Reynolds

Related Links

References: Inhibition of TET1 prevents the development of osteoarthritis and reveals the 5hmC landscape that orchestrates pathogenesis. Smeriglio P, Grandi FC, Davala S, Masarapu V, Indelli PF, Goodman SB, Bhutani N. Sci Transl Med. 2020 Apr 15;12(539). pii: eaax2332. doi: 10.1126/scitranslmed.aax2332. PMID: 32295898.

Funding: NIH’s National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS); National Science Foundation.