Signaling modality within gp130 receptor enhances tissue regeneration

Abstract

Adult mammals are incapable of multi-tissue regeneration and augmentation of this potential may drastically shift current therapeutic paradigms. Here, we found that a common co-receptor of 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) exhibit regenerative, not reparative, responses after wounding in skin and anti-degenerative responses in the synovial joint. In addition, pharmacological inhibition of gp130 Y814 results in regeneration of multiple tissues in several species as well as disease modification in animal models of osteoarthritis. Our study characterizes a novel molecular mechanism that, if selectively manipulated, enhances the intrinsic regenerative capacity while preventing pathological outcomes in injury and disease.

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

“…Treatments, including NSAIDs, opioids, corticosteroids, anxiolytics, muscle relaxants, antidepressants, and anticonvulsants (29) only mask the symptoms and do not treat the underlying cause. We have previously reported that a small molecule agent, R805, synthesized by our group can not only promote tissue regeneration, but also prevents articular cartilage degeneration in a rat model of PTOA (14). Strikingly, R805 inhibited inflammation in the joint, prevented articular cartilage degeneration, and mitigated pain and lameness in a posttraumatic joint injury dog model of OA (14).…”

“…Our group has extensive surgical experience in successfully inducing OA in small and large animal models of degenerative joint disease (14,23,24). We have previously shown that partial meniscectomy in rats can induce OA formation in the knee joint (23).…”

“…We have previously reported that a small molecule agent, R805, synthesized by our group can not only promote tissue regeneration, but also prevents articular cartilage degeneration in a rat model of PTOA (14). Strikingly, R805 inhibited inflammation in the joint, prevented articular cartilage degeneration, and mitigated pain and lameness in a posttraumatic joint injury dog model of OA (14). Improvement of the structural and functional outcomes confirmed that R805 can treat the symptoms of OA whilst concurrently preventing disease progression by alleviating the causal destructive processes.…”

“…In agreement with that, we have demonstrated that IL-6 cytokines drive both regenerative and destructive outcomes through selective and context specific-activation of signaling residues (modules) within the intracellular domain of gp130 receptor. Most recently, we have identified a signaling residue (Y814) within gp130 that represents an initiating factor responsible for the activation of a highly destructive c-SRC/MAPK circuit in response to IL-6 cytokines (14). To translate these findings into the clinically relevant technology, we have created a new class of chemicals capable of selective inactivation of the gp130 Y814 /c-SRC/MAPK module and showed their efficacy in small and large animal models of knee post-traumatic osteoarthritis (PTOA) PTOA (14).…”

“…Most recently, we have identified a signaling residue (Y814) within gp130 that represents an initiating factor responsible for the activation of a highly destructive c-SRC/MAPK circuit in response to IL-6 cytokines (14). To translate these findings into the clinically relevant technology, we have created a new class of chemicals capable of selective inactivation of the gp130 Y814 /c-SRC/MAPK module and showed their efficacy in small and large animal models of knee post-traumatic osteoarthritis (PTOA) PTOA (14). The current study was designed to explore the therapeutic potential of a novel gp130 modulator R805 in a porcine model of TMJ OA.…”