Drug-induced modulation of gp130 signalling prevents articular cartilage degeneration and promotes repair

Shkhyan, Ruzanna; Handel, Ben Van; Bogdanov, Jacob; Lee, Siyoung; Yu, Yifan; Scheinberg, Mila; Banks, Nicholas W.; Limfat, Sean; Chernostrik, Arthur; Franciozi, Carlos Eduardo da Silveira; Alam, Mohammad Parvez; John, Varghese; Wu, Ling; Ferguson, Gabriel B.; Nsair, Ali; Petrigliano, Frank A.; Vangsness, C. Thomas; Vadivel, Kanagasabai; Bajaj, Paul; Wang, Liming; Liu, Nancy Q.; Evseenko, Denis

doi:10.1136/annrheumdis-2017-212037

Cited by 52 publications

(89 citation statements)

References 51 publications

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“…5f–i ). Our analysis demonstrated that BMPR1B + ITGA4 + chondrocytes are enriched for GLI1 40 , SOX9 2 , RUNX2 3 and pSTAT3 41 , suggesting that they may represent a more plastic sub-population of chondrocytes within articular cartilage. We next performed RNA-seq on each chondrocyte population; in parallel, we sequenced multipotent CD45 − CD31 − CD146 + synovial pericytes 42 .…”

Section: Resultsmentioning

confidence: 69%

Mapping molecular landmarks of human skeletal ontogeny and pluripotent stem cell-derived articular chondrocytes

et al. 2018

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Tissue-specific gene expression defines cellular identity and function, but knowledge of early human development is limited, hampering application of cell-based therapies. Here we profiled 5 distinct cell types at a single fetal stage, as well as chondrocytes at 4 stages in vivo and 2 stages during in vitro differentiation. Network analysis delineated five tissue-specific gene modules; these modules and chromatin state analysis defined broad similarities in gene expression during cartilage specification and maturation in vitro and in vivo, including early expression and progressive silencing of muscle- and bone-specific genes. Finally, ontogenetic analysis of freshly isolated and pluripotent stem cell-derived articular chondrocytes identified that integrin alpha 4 defines 2 subsets of functionally and molecularly distinct chondrocytes characterized by their gene expression, osteochondral potential in vitro and proliferative signature in vivo. These analyses provide new insight into human musculoskeletal development and provide an essential comparative resource for disease modeling and regenerative medicine.

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Section: Resultsmentioning

confidence: 69%

Mapping molecular landmarks of human skeletal ontogeny and pluripotent stem cell-derived articular chondrocytes

et al. 2018

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“…Importantly, IL-6 and other soluble factors that strongly promote cellular plasticity by activating cellular reprogramming in nearby non-senescent cells 105 , 107 , 109 , 111 probably halt redifferentiation by potentiating the chronic dedifferentiation of chondrocytes in OA. In fact, it has recently been reported that targeting of the gp130 receptor for the IL-6 family and activation of ERK and NF-κB improves cartilage healing in an animal model of OA 112 . Our discovery that Cx43 regulates dedifferentiation/redifferentiation, in addition to senescence, highlights an important intersection between chondrocyte reprogramming and wound healing relevant for understanding the molecular basis of cartilage degeneration in OA, which offers opportunities for new therapies.…”

Section: Discussionmentioning

confidence: 99%

Targeting of chondrocyte plasticity via connexin43 modulation attenuates cellular senescence and fosters a pro-regenerative environment in osteoarthritis

et al. 2018

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Osteoarthritis (OA), a chronic disease characterized by articular cartilage degeneration, is a leading cause of disability and pain worldwide. In OA, chondrocytes in cartilage undergo phenotypic changes and senescence, restricting cartilage regeneration and favouring disease progression. Similar to other wound-healing disorders, chondrocytes from OA patients show a chronic increase in the gap junction channel protein connexin43 (Cx43), which regulates signal transduction through the exchange of elements or recruitment/release of signalling factors. Although immature or stem-like cells are present in cartilage from OA patients, their origin and role in disease progression are unknown. In this study, we found that Cx43 acts as a positive regulator of chondrocyte-mesenchymal transition. Overactive Cx43 largely maintains the immature phenotype by increasing nuclear translocation of Twist-1 and tissue remodelling and proinflammatory agents, such as MMPs and IL-1β, which in turn cause cellular senescence through upregulation of p53, p16INK4a and NF-κB, contributing to the senescence-associated secretory phenotype (SASP). Downregulation of either Cx43 by CRISPR/Cas9 or Cx43-mediated gap junctional intercellular communication (GJIC) by carbenoxolone treatment triggered rediferentiation of osteoarthritic chondrocytes into a more differentiated state, associated with decreased synthesis of MMPs and proinflammatory factors, and reduced senescence. We have identified causal Cx43-sensitive circuit in chondrocytes that regulates dedifferentiation, redifferentiation and senescence. We propose that chondrocytes undergo chondrocyte-mesenchymal transition where increased Cx43-mediated GJIC during OA facilitates Twist-1 nuclear translocation as a novel mechanism involved in OA progression. These findings support the use of Cx43 as an appropriate therapeutic target to halt OA progression and to promote cartilage regeneration.

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“…OA therefore can be a serious disease with an unmet medical need for therapies that modify its underlying pathophysiology and translate to long-term, clinically relevant benefits 17 . Currently, there are several drugs in phases II OR III or in the preclinical stage, including fibroblast growth factor-18 (Sprifermin) targeting cartilage regeneration 18 , and Kartogenin that promotes the dissociation and nucleus internalization of core binding factor beta (CBF) and stimulates cascaded chondrogenesis 19 . All of these developing…”

Section: Application In Disease-modifying Oa Drugs (Dmoads)mentioning

confidence: 99%

Functionalized osteoarthritis targeting peptides for MRI, lubricant and regenerative medicine

Lin¹,

Wang²,

Chi³

et al. 2020

Preprint

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Despite the efforts made for osteoarthritis (OA) treatment, the results are limited and can be improved by enhancing the OA homing strategy. Here, we used a phage display system to identify OA-targeting peptides, and combined them with magnetic resonance imaging detection reagents to expand their application to early OA diagnosis in rat and swine models. OA-targeting peptides showed better static and kinetic friction characteristics than scrambled peptides, when conjugated with hyaluronic acid for rheological lubrication studies using human OA specimens. Furthermore, mesenchymal stem cells, through CD44 binding to hyaluronic acid conjugated with OA-targeting peptides, showed better capacity for OA homing and repair than those conjugated with scrambled peptides. Protein–peptide docking revealed WXPXW as the consensus binding motifs that bind to collagen XII, a protein exclusively expressed in human and animal OA models. These results suggest the potential of OA-targeting peptides to promote diagnosis, treatment, and regenerative medicine for OA.

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Drug-induced modulation of gp130 signalling prevents articular cartilage degeneration and promotes repair

Abstract: These results identify a novel strategy for AC remediation via small molecule-mediated modulation of gp130 signalling.

Cited by 52 publications

References 51 publications

Mapping molecular landmarks of human skeletal ontogeny and pluripotent stem cell-derived articular chondrocytes

Mapping molecular landmarks of human skeletal ontogeny and pluripotent stem cell-derived articular chondrocytes

Targeting of chondrocyte plasticity via connexin43 modulation attenuates cellular senescence and fosters a pro-regenerative environment in osteoarthritis

Functionalized osteoarthritis targeting peptides for MRI, lubricant and regenerative medicine

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