Inhibition of a signaling modality within the gp130 receptor enhances tissue regeneration and mitigates osteoarthritis

Abstract

Adult mammals are incapable of multitissue regeneration, and augmentation of this potential may shift current therapeutic paradigms. We found that a common co-receptor of interleukin 6 (IL-6) cytokines, glycoprotein 130 (gp130), serves as a major nexus integrating various context-specific signaling inputs to either promote regenerative outcomes or aggravate disease progression. Via genetic and pharmacological experiments in vitro and in vivo, we demonstrated that a signaling tyrosine 814 (Y814) within gp130 serves as a major cellular stress sensor. Mice with constitutively inactivated Y814 (F814) were resistant to surgically induced osteoarthritis as reflected by reduced loss of proteoglycans, reduced synovitis, and synovial fibrosis. The F814 mice also exhibited enhanced regenerative, not reparative, responses after wounding in the skin. In addition, pharmacological modulation of gp130 Y814 upstream of the SRC and MAPK circuit by a small molecule, R805, elicited a protective effect on tissues after injury. Topical administration of R805 on mouse skin wounds resulted in enhanced hair follicle neogenesis and dermal regeneration. Intra-articular administration of R805 to rats after medial meniscal tear and to canines after arthroscopic meniscal release markedly mitigated the appearance of osteoarthritis. Single-cell sequencing data demonstrated that genetic and pharmacological modulation of Y814 resulted in attenuation of inflammatory gene signature as visualized by the anti-inflammatory macrophage and nonpathological fibroblast subpopulations in the skin and joint tissue after injury. Together, our study characterized a molecular mechanism that, if manipulated, enhances the intrinsic regenerative capacity of tissues through suppression of a proinflammatory milieu and prevents pathological outcomes in injury and disease.

p53-induced GDF-15 expression promotes a pro-regenerative response in human chondrocytes upon cartilage injury

“…However, our findings demonstrated that addition of exogenous rhGDF-15 does not promote spreading of the senescent phenotype, but, on the contrary, induced proliferation, migration, and cell survival of hAC. Similar results were currently reported in case of IL-6, which is a common SASP factor and controversially discussed in cartilage degeneration and regeneration [34][35][36]. Overall, it is widely accepted that transient senescence contributes to tissue regeneration and that SASP factors initially accelerate related processes, such as immune and stem cell recruitment, fibroblast activation, and ECM remodeling [37].…”

Redox-active endosomes mediate α5β1 integrin signaling and promote chondrocyte matrix metalloproteinase production in osteoarthritis

“…The finding that signaling redoxosomes containing NOX2 and SRC were found in increased amounts in human osteoarthritic cartilage, especially at sites of damaged matrix, supports a role for redox regulation of SRC in OA. The importance of SRC in OA is supported by previous studies demonstrating that SRC inhibition reduces OA severity in preclinical animal models (44)(45)(46)48).…”

“…Stimulation of the chondrocyte α5β1 integrin by FN7-10 activates mitogen-activated protein kinase (MAPK) signaling, as well as signaling by the redox-regulated kinase SRC, resulting in the production of multiple matrix metalloproteinases (MMPs) and proinflammatory mediators involved in OA (39,40). Here, we focused on MMP-13 production as a general measure of catabolic integrin signaling given its prominent role in OA (19,41,42) and examined MAPK and SRC activation because they are required for FN7-10 stimulation of MMP-13 production (39,40,43) and can contribute to OA pathology (44)(45)(46)(47)(48).…”

Inactivation of a non-canonical gp130 signaling arm attenuates chronic systemic inflammation and multimorbidity induced by a high-fat diet

“…The majority of mutant mice on HFD had mild or minimal symptoms of OA, while WT counterparts developed mild to severe OA (Figure 2F). SFK activation is reported to be critical for cartilage degeneration in OA, and our group has demonstrated that F814 cartilage explants were resistant to OSM-induced degeneration (18,33). Mild synovitis, a characteristic of OA induced by low-grade chronic inflammation, was present in the majority of mice in both WT and F814 groups, although F814 mice exhibited a lower trend in synovitis score (Figure 2F).…”

“…Endogenous products arising from tissue senescence, which is associated with aging, may also cause maladaptive hyperactivation of this sensor, which is highly detrimental. CRISPR/Cas9 mice with a constitutively inactivated gp130 Y814 (mutation of tyrosine (Y) 814 to phenylalanine (F) – “F814” mice exhibit substantially accelerated regenerative responses (18). Both genetic and drug-mediated inactivation of SFK recruitment to gp130 receptor result in enhanced resolution of inflammation and accelerated regenerative outcomes in several injury models (18).…”