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.

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.

Objective The objective of this study was to describe in life methods by which osteoarthritis can be staged in order to time therapeutic interventions that are relevant to osteoarthritis (OA) clinical trials Methods Twenty-two sheep underwent arthroscopic meniscal destabilization to induce OA. Serial computed tomography (CT) imaging and arthroscopy were used to monitor osteoarthritis progression at 3-month intervals over 9 months. Eleven sheep received 1 intra-articular injection of hyaluronate 3 months after OA induction and another group of 11 received saline. A linear mixed model was used to define the trajectory of shape change in the medial joint compartment. Ordinal logistic regression was used to investigate the association between morphological changes and sclerosis. Results Three months after meniscal destabilization there were early bipolar chondral lesions in the medial compartment of the knee, as well as osteophytes and bone remodeling. Superficial fissures and cartilage cracks progressed to discrete areas of cartilage thinning and fibrillation on the medial tibial plateau by 6 months that became cartilage erosions by nine months. A linear mixed effect model demonstrated significant change in medial compartment length and width with over time ( P < 0.05) for both groups. A significant association between severity of sclerosis and medial compartment morphology was also observed. Conclusions The induction of osteoarthritic lesions with meniscal release model can be followed using noninvasive and minimally invasive procedures allowing for real-time decisions about redosing therapies, or other changes such as extending trial timelines without sacrificing animals to conduct assessments.

This study addressed difficulties in evaluating osteoarthritis (OA) progression in species with thin cartilage. Feasibility of using short, nonequilibrium contrast-enhanced micro–computed tomography (CE-μCT) to evaluate the physical and biochemical properties of cartilage was investigated. A preliminary in vitro study using CE-μCT study was performed using bovine osteochondral blocks with intact, mildly damaged (fibrillated), or severely damaged (delaminated) cartilage. Delamination of the superficial zone resulted in elevated apparent density compared with intact cartilage after 10 minutes of anionic contrast exposure ( P < 0.01). OA was induced by unilateral meniscal destabilization in n = 20 sheep divided into: early phase OA ( n = 9) and late phase OA ( n = 11), while n = 4 remained as naive controls. In vivo anionic nonequilibrium contrast CT of the operated stifle was conducted in the early phase sheep 13 weeks postoperatively using clinical resolution CT. Cartilage visibility in the contrasted leg was significantly improved compared with the noncontrasted contralateral stifle ( P < 0.05). Animals were sacrificed at 3 months (early phase) or 12 months (late phase) for additional ex vivo CE-μCT, and correlative tests with biochemical and histological measures. Concentration of sulfated glycosaminoglycan (sGAG) significantly varied between control, early, and late phase OA ( P < 0.005) and showed a negative ( r = −0.56) relationship with apparent density in the medial tibial plateau ( R2 = 0.28, P < 0.001). Histologically, parameters in proteoglycan and cartilage surface structure correlated with increasing attenuation. While previous studies have shown that CE-CT increases the apparent density of proteoglycan-depleted cartilage, we concluded that superficial zone disruption also contributes to this phenomenon.

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