Dec. 21, 2024
Jennifer J. Westendorf, Ph.D., chair of Biochemistry and Molecular Biology at Mayo Clinic in Minnesota, is striving to reverse the course of osteoarthritis (OA) progression. Her goals include halting degeneration and, ultimately, regeneration.
"If a person has a degenerative disease like osteoarthritis, it can be hard to turn the ship around," she says.
Dr. Westendorf's laboratory studies the cellular, molecular and epigenetic basis for skeletal formation, the regeneration of bone and cartilage, and the growth of primary and metastatic bone tumors.
A key focus of her research uses the model of posttraumatic OA, which encompasses 12% of all OA, according to Dr. Westendorf.
She says, "We are trying to generate knowledge by studying molecules that could be therapeutic targets. If we understand how the skeleton forms, we can understand how to regenerate."
Dr. Westendorf says regeneration is a particular challenge for patients whose stem cells are no longer present at the site of a previous traumatic injury.
Dr. Westendorf's research evolves to include Phlpp 1 and Phlpp 2
As Dr. Westendorf and her laboratory staff attempt to, as she likes to say, "flip" the script on OA, the protein phosphatases Phlpp1 and 2 have become research areas of focus. She has studied Phhlpp1 and 2 for over a decade, first publishing about them in 2013.
This 2013 publication launched Dr. Westendorf's continued study of these protein phosphatases. Dr. Westendorf and colleagues published findings in a 2015 issue of the Journal of Biological Chemistry demonstrating that Phlpp1's multiple-mechanism control of chondrogenesis and its inhibition could improve cartilage structure.
In 2016, she and her colleagues published a key study on Phlpp1's role in posttraumatic OA in the journal Osteoarthritis Cartilage.
"Phlpp1 regulates cartilage health, and if Phlpp1 is not present or is knocked down, it seems to prevent injury-induced osteoarthritis," says Dr. Westendorf.
Highlights of the last decade of Phlpp findings by Dr. Westendorf and colleagues
In the previously mentioned 2016 Osteoarthritis Cartilage publication, Dr. Westendorf and colleagues found that in wild-type mice, injury accelerates cartilage degradation typical of aging, prompting the start of degradation at 12 weeks postinjury. Publishing in the same journal in 2024, the investigators detected the beginnings of this degradation with atomic force microscopy at six weeks postinjury and histologically detected this degradation at 12 weeks. However, they found that the Phlpp1 knockout mice were protected from a similar degradation effect, with only slight degradation evident at 12 weeks.
"Essentially, having no Phlpp1 present protects the cartilage from damage caused by injury," says Dr. Westendorf.
She and fellow investigators also observed that damage from an injury sets off a cascade:
- Injury causes significant inflammation and pain.
- Signals from inflammation affect chondrocytes, cells in the cartilage and neurons.
- Chondrocytes are injured, become aged or die.
- If chondrocytes are not present, tissue repair does not occur.
However, Phlpp inhibitors have the potential to turn around this downward spiral or stop it, indicates Dr. Westendorf.
"Phlpp inhibitors can reboot chondrocytes that have been exposed to a negative, inflammatory environment," she says. "As Phlpp1 controls many pathways that affect cell proliferation, a mouse model — and ultimately, a human patient — may not need multiple injections of the Phlpp inhibitor for the cartilage to be OK."
Phlpp inhibitors also reduce pain from an injury and help increase a patient's function, allowing the patient to move more due to less pain.
"Phlpp1 regulates cartilage health, and if Phlpp1 is not present or is knocked down, it seems to prevent injury-induced osteoarthritis."
According to 2024 publications by Dr. Westendorf and colleagues in Osteoarthritis and Cartilage and in Bone, a Phlpp inhibitor injected into the joints postinjury promotes cartilage preservation. Phlpp, as a phosphatase, removes phosphates, and the phosphorylation status of proteins changes with Phlpp knockout inhibition.
Potential future clinical uses for Phlpp inhibitors with posttraumatic OA
Dr. Westendorf hopes that in the future, the joint itself and the cells in the joint of an injured patient exposed to a toxic environment will be able to be repaired and rebooted.
"This would involve removing cytokines that cause cells to degrade, giving cells the equivalent of fresh air or nutrition," she says.
Dr. Westendorf and her laboratory are investigating a pharmacological approach using Phlpp1 and 2 to slow OA degradation.
The use of Phlpp inhibitors is not intended to replace orthopedic surgeons, she notes, but rather they would be used in addition to surgery, promoting intrinsic cell repair.
"This is not preventing OA, but rather slowing the cellular processes leading to OA," she says. "While surgeons fix instability, we want to work with them and reboot joint cells pharmacologically."
According to Dr. Westendorf, the long-term objective with surgery plus cell reparation is to avoid or delay the need for joint replacement.
"We could potentially prevent joint replacement, especially for the younger population at risk of posttraumatic osteoarthritis at ages where it is not ideal to replace a joint," she says. "This type of posttraumatic osteoarthritis is especially common in those who have participated in athletics or the military."
A related future research objective for Dr. Westendorf is to study Phlpp's relationship to another major cause of OA: age. In healthy mice, cartilage degradation begins between 14 and 16 months, equivalent to humans 50 to 60 years old. Her lab is aging Phlpp1 knockout mice to 14 to 16 months to observe possible chondroprotective effects.
For more information
Bradley EW, et al. Deletion of the PH-domain and leucine-rich repeat protein phosphatase 1 (Phlpp1) increases fibroblast growth factor (Fgf) 18 expression and promotes chondrocyte proliferation. Journal of Biological Chemistry. 2015;290:16272.
Bradley EW, et al. Phlpp1 facilitates post-traumatic osteoarthritis and is induced by inflammation and promoter demethylation in human osteoarthritis. Osteoarthritis Cartilage. 2016;24:1021.
Arnold KM, et al. Inhibition of Phlpp1 preserves the mechanical integrity of articular cartilage in a murine model of post-traumatic osteoarthritis. Osteoarthritis Cartilage. 2024;32:680.
Weaver SR, et al. Phlpp1 alters the murine chondrocyte phospho-proteome during endochondral bone formation. Bone. 2024;189:117265.
Refer a patient to Mayo Clinic.