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"We show for the first time that the IL-6 family is required for the healthy growth and function of skeletal stem and progenitor cells, as well as joints and spine, and has previously been linked almost exclusively in the musculoskeletal domain with arthritis, bone and muscle loss, and Other chronic inflammatory diseases
.

" The study's corresponding author, Denis Evseenko, is the J.

In this study, first author Nancy Q.

Liu from the University of Southern California and her colleagues took a closer look at a key gene activated by IL-6: STAT3

Mice experienced the same problem when they lacked a protein called glycoprotein 130 (gp130), all IL-6 proteins that activate STAT3
.

Inactivating another gene, Lifr, which encodes a protein that works with gp130 to recognize an IL-6 protein called Lif, produced similar but milder changes in bone and cartilage

In mice lacking gp130, the scientists were able to restore normal growth plates by overactivating STAT3—though this also led to overgrowth of cartilage, which can lead to other skeletal abnormalities
.

Interestingly, the researchers noticed significant sex differences: When STAT3 stopped functioning, females experienced more severe cartilage and bone changes than males
.

To understand why, the researchers altered estrogen levels in mouse and laboratory-grown pig chondrocytes

The study has clinical implications for using existing STAT3-inhibiting drugs to suppress inflammation in autoimmune diseases: these drugs may also interfere with growth and regeneration
.

Instead, the Evseenko lab used their understanding of the nuances of STAT3 and its associated genes and proteins to develop a highly targeted drug with the potential to regenerate articular cartilage without triggering inflammation
.

The drug will soon be tested in human clinical trials

"Our findings are truly paradigm-shifting, challenging existing dogma in the field about how IL-6, STAT3, and related genes and proteins affect inflammation and regeneration," Evseenko said
.

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)