gp130/STAT3 signaling is required for homeostatic proliferation and anabolism in postnatal growth plate and articular chondrocytes

Abstract

Growth of long bones and vertebrae is maintained postnatally by a long-lasting pool of progenitor cells. Little is known about the molecular mechanisms that regulate the output and maintenance of the cells that give rise to mature cartilage. Here we demonstrate that postnatal chondrocyte-specific deletion of a transcription factor Stat3 results in severely reduced proliferation coupled with increased hypertrophy, growth plate fusion, stunting and signs of progressive dysfunction of the articular cartilage. This effect is dimorphic, with females more strongly affected than males. Chondrocyte-specific deletion of the IL-6 family cytokine receptor gp130, which activates Stat3, phenocopied Stat3-deletion; deletion of Lifr, one of many co-receptors that signals through gp130, resulted in a milder phenotype. These data define a new molecular circuit that regulates chondrogenic cell maintenance and output and reveals a novel, hitherto unrecognized function of IL-6 cytokines in the skeletal system with direct implications for skeletal development and regeneration.

STAT3 promotes a youthful epigenetic state in articular chondrocytes

“…Interestingly, DNMT3B was found to be among a few putative STAT3 binding targets overlapping between development and disease (Figure 4c,d). Upon analyzing the bulk RNA‐sequencing data obtained from STAT3 knocked down fetal chondrocytes (Liu, Lin, Li, Lu, Geng, Zhang, et al, 2022), we observed an increase in expression of DNMT3B (fold change = 2.386, p = 0.01), indicating that STAT3 binding represses transcription of DNMT3B, which is reversed upon STAT3 knock down (Figure 5a). Also, pharmacological activation of STAT3 signaling in adult chondrocytes (Shkhyan et al, 2018) results in significant downregulation of DNMT3B (fold change = −2.43, p = 0.05) (Figure 5b) accompanied with a significant decrease in DNA methylation.…”

“…Next, we found that differentially methylated CpGs gained methylation (hypermethylated) in STAT3 knocked down fetal chondrocytes (Figure 3b). Furthermore, we explored the concordance between genes associated with differentially methylated CpGs that gain methylation and genes downregulated (i.e., genes with inaccessible chromatin) in STAT3 knocked down fetal chondrocytes (Liu, Lin, Li, Lu, Geng, Zhang, & Evseenko, 2022) (Figure 3c). The 211 genes obtained from this overlap revealed an association with connective tissue development, extracellular matrix organization, response to oxygen levels, response to ATP, and glycolytic processes (Figure 3d).…”

“…We have previously reported that STAT3 is highly expressed in anabolic proliferative fetal chondrocytes (Shkhyan et al, 2018) and is involved in chondrocyte development. Recently, we have also shown that early postnatal STAT3 deletion in chondrocytes in mice leads to suppression of chondrocyte proliferation and eventually, degradation of the growth plate evident by 3 months of age (Liu, Lin, Li, Lu, Geng, Zhang, & Evseenko, 2022). On the other hand, overexpression of STAT3 in postnatal chondrocytes in mice resulted in their hyperproliferation (Liu, Lin, Li, Lu, Geng, Zhang, & Evseenko, 2022).…”

Local Drug-Induced Modulation of gp130 Receptor Signaling Delays Disease Progression in a Pig Model of Temporo-Mandibular Joint Osteoarthritis

“…Our previous data suggested that IL-6 cytokines drive both regenerative and destructive outcomes in synovial joints through selective and context specific activation of signaling residues within the intracellular domain of gp130 receptor (14,23), and are also required for homeostatic maintenance of skeletal progenitors (34)(35)(36)(37)(38). Complete inhibition of gp130 signaling has been attempted previously for several therapeutic indications.…”