Arthritis-related gene also regenerates cartilage in joints and growth plates

"We show, for the first time, that theIL-6family, previously almost exclusively associated in the musculoskeletal field with arthritis, bone and muscle loss, and other chronic inflammatory diseases, is required for the maintenance of skeletal stem and progenitor cells, and for the healthy growth and function of the joints and spine," said the study's corresponding author Denis Evseenko, who is the J. Harold and Edna LaBriola Chair in Genetic Orthopedic Research, and an associate professor of orthopaedic surgery, and stem cell biology and regenerative medicine at the Keck School of Medicine of USC. "Our study establishes a link between inflammation and regeneration, and may explain why stem and progenitors are exhausted in chronic inflammation."

In the study, first author Nancy Q. Liu from USC and her colleagues took a close look at a key gene activated byIL-6:STAT3. In both lab-grown human cells and in mice, the scientists demonstrated thatSTAT3is critical for the proliferation, survival, maturation and regeneration of cartilage-forming cells in the joints and growth plates. When the gene ceased to function, cartilage-forming cells became increasingly dysfunctional over time, resulting in smaller body size, prematurely fused growth plates, underdeveloped skeletons and mildly degenerated joint cartilage.

Mice experienced the same issues when they lacked a protein called glycoprotein 130 (gp130), which allIL-6proteinsuse to activateStat3. Deactivating another geneLifr, which encodes a protein that works with gp130 to recognize one of theIL-6proteins calledLif, produced similar but milder skeletal and cartilage changes.

In mice lacking gp130, the scientists could restore normal growth plates by over-activatingStat3-- although this also caused an overgrowth of cartilage that led to other skeletal abnormalities.

Interestingly, the researchers noted significant sex-related differences: whenStat3ceased to function, females experienced more severe cartilage and skeletal changes than males. To understand why, the researchers altered estrogen levels in mice, as well as in lab-grown pig cartilage cells. In both cases, estrogen increased the amount and activity ofStat3, suggesting that females might rely more heavily on this gene.

The study has clinical implications for the use of existing drugs that inhibitSTAT3to curb inflammation in autoimmune diseases: these drugs may also interfere with growth and regeneration.

Conversely, the Evseenko Lab has leveraged their understanding of the nuances ofSTAT3and associated genes and proteins to develop a highly targeted drug with the potential to regenerate joint cartilage without triggering inflammation. This drug will soon be tested in human clinical trials.

"Our findings really shift the paradigm and challenge the existing dogmas in the field about howIL-6,STAT3, and associated genes and proteins influence not only inflammation, but also regeneration," said Evseenko.

About the study

Additional co-authors of the study include: Yucheng Lin from USC, Nanjing Medical University, and Southeast University in Nanjing; Liangliang Li and Dawei Geng from USC and Nanjing Medical University; Jinxiu Lu, Zorica Buser, Jenny Magallanes, Jade Tassey, Ruzanna Shkhyan, Arijita Sarkar, Siyoung Lee, Youngjoo Lee, Frank A. Petrigliano, Ben Van Handel, and Tea Jashashvili from USC; Jiankang Zhang from USC and Sichuan University; Noah Lopez and Karen Lyons from UCLA; and Liming Wang from Nanjing Medical University and Sichuan University.

The work was supported by federal funding from the National Institutes of Health (grants R01AR071734 and R01AG058624) and the Department of Defense (grant W81XWH-13-1-0465), and the California Institute for Regenerative Medicine (grant TRAN1-09288).