Kindlin-2 loss in condylar chondrocytes causes spontaneous osteoarthritic lesions in the temporomandibular joint in mice

Lai, Yisheng; Zheng, Wei; Qu, Minghao; Xiao, Christopher C.; Chen, Sheng; Yao, Qing; Gong, Weiyuan; Tao, Chu; Yan, Qinnan; Zhang, Peijun; Wu, Xiaohao; Xiao, Guozhi

doi:10.1038/s41368-022-00185-1

Cited by 18 publications

(14 citation statements)

References 52 publications

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“…Our previous studies have shown that both Kindlin-2 and Pinch proteins are required for chondrogenesis and skeletal development in mice ( Wu et al, 2015 ; Lei et al, 2020 ). Most recently, we have demonstrated that the expression of Kindlin-2 is also critical for the maintenance of cartilage homeostasis during adulthood ( Wu et al, 2022a ; Lai et al, 2022 ). It is interesting to compare the phenotypes of mice lacking Kindlin-2 in adult cartilage (Aggrecan CreERT2 ; Kindlin-2 flox/flox ) in our previous study with mice lacking Pinch1/2 in adult cartilage (Aggrecan CreERT2 ; Pinch1 flox/flox ; Pinch2 −/− ) in this study.…”

Section: Discussionmentioning

confidence: 99%

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Brief research report: Effects of Pinch deficiency on cartilage homeostasis in adult mice

Lin

Liao

et al. 2023

Front. Cell Dev. Biol.

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Pinch1 and Pinch2 are LIM domain-containing proteins with crucial functions in mediating focal adhesion formation. Our previous studies have demonstrated that Pinch1/2 expression is essential for cartilage and bone formation during skeletal development in mice. Loss of Pinch expression (Prx1Cre; Pinch1flox/flox; Pinch2−/−) inhibits chondrocyte proliferation and promotes chondrocyte apoptosis, resulting in severe chondrodysplasia and limb shortening. Based on these observations, we wonder if Pinch proteins have a role in adult cartilage and whether Pinch deficiency will compromise cartilage homeostasis and promote osteoarthritis (OA)-related defects in adult mice. To this end, we generated the AggrecanCreERT2; Pinch1flox/flox; Pinch2−/− mice, in which the Pinch1 gene can be inducibly deleted in aggrecan-expressing chondrocytes by tamoxifen and the Pinch2 gene is globally inactivated. Immunofluorescent staining confirmed that the expression of Pinch proteins was significantly decreased in articular cartilage in tamoxifen-treated adult AggrecanCreERT2; Pinch1flox/flox; Pinch2−/− mice. Unexpectedly, our results showed that Pinch loss did not induce marked abnormalities in articular cartilage and other joint tissues in the knee joints of either adult (10-month-old) mice or aged (17-month-old) mice. In a destabilization of the medial meniscus (DMM)-induced OA model, the surgically-induced OA lesions were comparable between Pinch-deficient mice and control mice. Given the fact that Pinch proteins are essential for chondrogenesis and cartilage formation during skeletal development, these findings suggest that Pinch expression is seemingly not indispensable for adult cartilage homeostasis in mice.

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Section: Discussionmentioning

confidence: 99%

“…The histological analyses of mouse knee joints were performed according to our previously established protocols ( Liu et al, 2021 ; Wu et al, 2022a ; Wu et al, 2022b ; Lai et al, 2022 ). The 5-μm thick knee joint sections were stained with safranin O and fast green using a commercial kit (Solarbio, Cat#G1371).…”

Section: Methodsmentioning

confidence: 99%

Brief research report: Effects of Pinch deficiency on cartilage homeostasis in adult mice

Lin

Liao

et al. 2023

Front. Cell Dev. Biol.

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“… 192 NF-κB promotes the activation of other transcription factors, such as hypoxia-inducible factor 2α (HIF-2α), E74-like factor 3 (ELF3), and RUNX2. 195 – 198 These transcription factors trigger the expression of ADAMTS5 and MMP13 proteases, which promotes the differentiation of pre-hypertrophic articular chondrocytes to terminal differentiated chondrocytes. 199 In addition, Deng and coworkers found that inflammatory cytokines regulated TAK1-mediate-phosphorylation to promote proteasomal degradation of YAP (Yes-associated protein), which is a downstream regulating factor of the Hippo pathway.…”

Section: Pathogenic Pathways and Moleculesmentioning

confidence: 99%

Osteoarthritis: pathogenic signaling pathways and therapeutic targets

Yao

Tao

et al. 2023

Sig Transduct Target Ther

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Osteoarthritis (OA) is a chronic degenerative joint disorder that leads to disability and affects more than 500 million population worldwide. OA was believed to be caused by the wearing and tearing of articular cartilage, but it is now more commonly referred to as a chronic whole-joint disorder that is initiated with biochemical and cellular alterations in the synovial joint tissues, which leads to the histological and structural changes of the joint and ends up with the whole tissue dysfunction. Currently, there is no cure for OA, partly due to a lack of comprehensive understanding of the pathological mechanism of the initiation and progression of the disease. Therefore, a better understanding of pathological signaling pathways and key molecules involved in OA pathogenesis is crucial for therapeutic target design and drug development. In this review, we first summarize the epidemiology of OA, including its prevalence, incidence and burdens, and OA risk factors. We then focus on the roles and regulation of the pathological signaling pathways, such as Wnt/β-catenin, NF-κB, focal adhesion, HIFs, TGFβ/ΒΜP and FGF signaling pathways, and key regulators AMPK, mTOR, and RUNX2 in the onset and development of OA. In addition, the roles of factors associated with OA, including MMPs, ADAMTS/ADAMs, and PRG4, are discussed in detail. Finally, we provide updates on the current clinical therapies and clinical trials of biological treatments and drugs for OA. Research advances in basic knowledge of articular cartilage biology and OA pathogenesis will have a significant impact and translational value in developing OA therapeutic strategies.

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“…More recent studies reveal that FA proteins are critical for control of formation and organs and tissues, including skeleton (Cao et al, 2020; S. Chen et al, 2022; Fu et al, 2020; Lai et al, 2022; Lei et al, 2020; Qin, Fu, et al, 2021; Theodosiou et al, 2016; Y. Wang et al, 2019; C.…”

Section: Introductionmentioning

confidence: 99%

Focal adhesion protein vinculin inhibits Mef2c-driven sclerostin expression in osteocytes to promote bone formation in mice

Wang

Huang

Lin

et al. 2022

Preprint

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The focal adhesion (FA) is the structural basis of the cell-extracellular matrix crosstalk and plays important roles in control of organ formation and function. Here we show that expression of FA protein vinculin is dramatically reduced in osteocytes in patients with aging-related osteoporosis. Deleting vinculin using the mouse 10-kb Dmp1-Cre transgenic mice causes a severe osteopenia in both young and aged mice by impairing osteoblast function without affecting bone resorption. Vinculin loss impairs the anabolic response of skeleton to mechanical loading in mice. At the molecular level, vinculin knockdown increases, while vinculin overexpression decreases, sclerostin expression in osteocytes without impacting expression of Mef2c, a major transcriptional regulator of the Sost gene, which encodes sclerostin. Vinculin interacts with Mef2c and vinculin loss enhances Mef2c nuclear translocation and binding to the Sost enhancer ECR5 to promote sclerostin production in osteocytes. Deleting Sost expression reverses the osteopenic phenotypes caused by vinculin loss in mice. We demonstrate that estrogen is a major regulator of vinculin expression in osteocytes and that more importantly vinculin loss mediates estrogen deficiency induction of bone loss in mice. Thus, we demonstrate a novel mechanism through which vinculin inhibits the Mef2c-driven sclerostin expression in osteocytes to promote bone formation.

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Kindlin-2 loss in condylar chondrocytes causes spontaneous osteoarthritic lesions in the temporomandibular joint in mice

Cited by 18 publications

References 52 publications

Brief research report: Effects of Pinch deficiency on cartilage homeostasis in adult mice

Brief research report: Effects of Pinch deficiency on cartilage homeostasis in adult mice

Osteoarthritis: pathogenic signaling pathways and therapeutic targets

Focal adhesion protein vinculin inhibits Mef2c-driven sclerostin expression in osteocytes to promote bone formation in mice

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