Evidence for Genetic Contribution to Variation in Posttraumatic Osteoarthritis in Mice

Chinzei, Nobuaki; Farooq, Muhammad; Hashimoto, Shingo; Schmidt, Edward M.; Takebe, K.; Cheverud, James M.; Sandell, Linda J.

doi:10.1002/art.40730

Cited by 25 publications

(35 citation statements)

References 57 publications

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“…Recent studies also reported that Postn levels in synovial fluid correlate with radiographic signs of knee OA [41], and that Postn is the only protein whose expression levels significantly correlate with OARSI score, synovitis, and microCT-based bone parameters (e.g., Structure Model Index and trabecular threshold). Postn influences ECM homeostasis, bone remodeling, and OA development [42]. Therefore, Postn offers a unique target for OA treatment since it can mediate pathogenic events in both cartilage and bone.…”

Section: Plos Onementioning

confidence: 99%

Periostin interaction with discoidin domain receptor-1 (DDR1) promotes cartilage degeneration

et al. 2020

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Osteoarthritis (OA) is characterized by progressive loss of articular cartilage accompanied by the new bone formation and, often, a synovial proliferation that culminates in pain, loss of joint function, and disability. However, the cellular and molecular mechanisms of OA progression and the relative contributions of cartilage, bone, and synovium remain unclear. We recently found that the extracellular matrix (ECM) protein periostin (Postn, or osteoblastspecific factor, OSF-2) is expressed at high levels in human OA cartilage. Multiple groups have also reported elevated expression of Postn in several rodent models of OA. We have previously reported that in vitro Postn promotes collagen and proteoglycan degradation in human chondrocytes through AKT/β-catenin signaling and downstream activation of MMP-13 and ADAMTS4 expression. Here we show that Postn induces collagen and proteoglycan degradation in cartilage by signaling through discoidin domain receptor-1 (DDR1), a receptor tyrosine kinase. The genetic deficiency or pharmacological inhibition of DDR1 in mouse chondrocytes blocks Postn-induced MMP-13 expression. These data show that Postn is signaling though DDR1 is mechanistically involved in OA pathophysiology. Specific inhibitors of DDR1 may provide therapeutic opportunities to treat OA.

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Section: Plos Onementioning

confidence: 99%

Periostin interaction with discoidin domain receptor-1 (DDR1) promotes cartilage degeneration

et al. 2020

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“…Interestingly, the "super-healer" MRL/MpJ mice are resistant to cartilage damage and show reduced severity of PTOA when compared to C57BL/6 mice, whether following surgical DMM [22] or non-surgical IAF [88]. Similar results are seen in the LG/J strain [34], whereas p21 −/− mice seem to be vulnerable to cartilage damage following DMM surgery [89], despite its superior regenerative potential after full-thickness cartilage injury [49].…”

Section: Models Of Oa and Cartilage Damagementioning

confidence: 70%

“…Various animal models have been employed in cartilage injury and OA-related studies, including mice, rats, guinea pigs, rabbits, dogs, and larger animals such as goats and horses [30][31][32][33][34][35][36]. Each animal model presents advantages and limitations in terms of their cost-benefit, suitability to mechanistic and molecular studies, and translational potential (i.e., relevance to human OA), all of which have been previously reviewed [35,37].…”

Section: Diversity Of Regenerative Potential Across Animal Modelsmentioning

confidence: 99%

“…While a comprehensive genome screening of the greater human population remains elusive, mouse studies can provide some insights into how genetic variations might be associated with OA resistance or vulnerability [34]. Murine models are powerful tools in the investigation of specific genes related to mammalian tissue regeneration, owing to the ease and sophistication of current genetic manipulations, abundant availability of recombinant inbred lines, and a broad-spectrum of cartilage regenerative potential among strains, from healers to non-healers [42], to those displaying spontaneous cartilage degeneration [43].…”

Section: Diversity Of Regenerative Potential Across Animal Modelsmentioning

confidence: 99%

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Understanding cartilage protection in OA and injury: a spectrum of possibilities

Masson

Krawetz

2020

BMC Musculoskelet Disord

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Background: Osteoarthritis (OA) is a prevalent musculoskeletal disease resulting in progressive degeneration of the hyaline articular cartilage within synovial joints. Current repair treatments for OA often result in poor quality tissue that is functionally ineffective compared to the hyaline cartilage and demonstrates increased failure rates posttreatment. Complicating efforts to improve clinical outcomes, animal models used in pre-clinical research show significant heterogeneity in their regenerative and degenerative responses associated with their species, age, genetic/epigenetic traits, and context of cartilage injury or disease. These can lead to variable outcomes when testing and validating novel therapeutic approaches for OA. Furthermore, it remains unclear whether protection against OA among different model systems is driven by inhibition of cartilage degeneration, enhancement of cartilage regeneration, or any combination thereof. Main text: Understanding the mechanistic basis underlying this context-dependent duality is essential for the rational design of targeted cartilage repair and OA therapies. Here, we discuss some of the critical variables related to the cross-species paradigm of degenerative and regenerative abilities found in pre-clinical animal models, to highlight that a gradient of regenerative competence within cartilage may exist across species and even in the greater human population, and likely influences clinical outcomes. Conclusions: A more complete understanding of the endogenous regenerative potential of cartilage in a species specific context may facilitate the development of effective therapeutic approaches for cartilage injury and/or OA.

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“…Firstly, DMM and age-induced OA models were established, which are extensively studied in OA, while limitations also exist in these two models. DMM model is defined as one of the most usual-used OA models, which have lesions primarily on the central weight-bearing region of the medial tibial plateau and medial femoral condyles, and have no destruction of the subchondral bone [72,73]. However, it can still not naturally reflect human osteoarthritis, which makes it hard to allow the whole disease process to be studied.…”

Section: Discussionmentioning

confidence: 99%

Cortistatin binds to TNF-α receptors and protects against osteoarthritis

Zhao

et al. 2019

EBioMedicine

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Background Osteoarthritis (OA) is a common degenerative disease, and tumor necrosis factor (TNF-α) is known to play a critical role in OA. Cortistatin (CST) is a neuropeptide discovered over 20  years ago, which plays a vital role in inflammatory reactions. However, it is unknown whether CST is involved in cartilage degeneration and OA development. Methods The interaction between CST and TNF-α receptors was investigated through Coimmunoprecipitation and Biotin-based solid-phase binding assay. Western blot, Real-time PCR, ELISA, immunofluorescence staining, nitrite production assay and DMMB assay of GAG were performed for the primary chondrocyte experiments. Surgically induced and spontaneous OA models were established and western blot, flow cytometry, Real-time PCR, ELISA, immunohistochemistry and fluorescence in vivo imaging were performed for in vivo experiments. Findings CST competitively bound to TNFR1 as well as TNFR2. CST suppressed proinflammatory function of TNF-α. Both spontaneous and surgically induced OA models indicated that deficiency of CST led to an accelerated OA-like phenotype, while exogenous CST attenuated OA development in vivo. Additionally, TNFR1- and TNFR2-knockout mice were used for analysis and indicated that TNFRs might be involved in the protective role of CST in OA. CST inhibited activation of the NF-κB signaling pathway in OA. Interpretation This study provides new insight into the pathogenesis and therapeutic strategy of cartilage degenerative diseases, including OA. Fund The , the , .

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Evidence for Genetic Contribution to Variation in Posttraumatic Osteoarthritis in Mice

Cited by 25 publications

References 57 publications

Periostin interaction with discoidin domain receptor-1 (DDR1) promotes cartilage degeneration

Periostin interaction with discoidin domain receptor-1 (DDR1) promotes cartilage degeneration

Understanding cartilage protection in OA and injury: a spectrum of possibilities

Cortistatin binds to TNF-α receptors and protects against osteoarthritis

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