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

Date:
January 18, 2022
Source:
Keck School of Medicine of USC
Summary:
The IL-6 family of proteins are associated with inflammation,
arthritis, autoimmune disease and even cancer. However, a new
study reveals the importance of IL-6 and associated genes for
maintaining and regenerating cartilage in both the joints and in the
growth plates that enable skeletal growth in children. Scientists
took a close look at a key gene activated by IL-6: STAT3. In both
lab-grown human cells and in mice, the scientists demonstrated that
STAT3 is 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.



FULL STORY ==========================================================================
The IL-6family of proteins has a bad reputation: it can promote
inflammation, arthritis, autoimmune disease and even cancer. However,
a new USC-led study published in Communications Biology reveals the
importance of IL-6 and associated genes for maintaining and regenerating cartilage in both the joints and in the growth plates that enable skeletal growth in children.


==========================================================================
"We show, for the first time, that the IL-6 family, 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 by IL-6: STAT3. In both lab-grown human cells and in mice,
the scientists demonstrated that STAT3 is 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 activate
Stat3. Deactivating another gene Lifr, which encodes a protein that
works with gp130 to recognize one of the IL-6proteins called Lif,
produced similar but milder skeletal and cartilage changes.

In mice lacking gp130, the scientists could restore normal growth plates
by over-activating Stat3 -- although this also caused an overgrowth of cartilage that led to other skeletal abnormalities.

Interestingly, the researchers noted significant sex-related differences:
when Stat3 ceased 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 of Stat3, suggesting that females might rely more heavily on this gene.

The study has clinical implications for the use of existing drugs that
inhibit STAT3 to 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 of STAT3and 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 how IL-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).

========================================================================== Story Source: Materials provided by
Keck_School_of_Medicine_of_USC. Original written by Cristy Lytal. Note:
Content may be edited for style and length.


========================================================================== Journal Reference:
1. Nancy Q. Liu, Yucheng Lin, Liangliang Li, Jinxiu Lu, Dawei Geng,
Jiankang
Zhang, Tea Jashashvili, Zorica Buser, Jenny Magallanes, Jade
Tassey, Ruzanna Shkhyan, Arijita Sarkar, Noah Lopez, Siyoung Lee,
Youngjoo Lee, Liming Wang, Frank A. Petrigliano, Ben Van Handel,
Karen Lyons, Denis Evseenko. gp130/STAT3 signaling is required
for homeostatic proliferation and anabolism in postnatal growth
plate and articular chondrocytes.

Communications Biology, 2022; 5 (1) DOI: 10.1038/s42003-021-02944-y ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/01/220118145941.htm

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