Chondrocyte hypertrophy in skeletal development, growth, and disease

Sun, Margaret Man Ger; Beier, Frank

doi:10.1002/bdrc.21062

Cited by 114 publications

(124 citation statements)

References 77 publications

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“…Such responses include upregulation of inflammatory mediators that leads to cartilage extracellular matrix (ECM) degradation via increased expression of matrix metalloproteinases (MMPs) and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTSs) (23–27). Chondrocyte phenotype also changes during catabolism including cell clustering/proliferation (28), apoptosis, and/or hypertrophic differentiation with increased expression of markers such as Col10a1 , Runx2 , and Mmp13 (29,30). A number of gene polymorphisms have been reported in human OA (e.g., GDF5 , SMAD3 ) (31,32), and there are now several, robustly replicated, significant OA loci that have been identified by large-scale genome-wide association studies (GWASs) (33–35).…”

Section: Oa Pathologymentioning

confidence: 99%

Inflammation and epigenetic regulation in osteoarthritis

Shen

Abu‐Amer

O’Keefe

et al. 2016

Connective Tissue Research

185

140

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Osteoarthritis (OA) was once defined as a non-inflammatory arthropathy, but it is now well-recognized that there is a major inflammatory component to this disease. In addition to synovial cells, articular chondrocytes and other cells of diarthrodial joints are also known to express inflammatory mediators. It has been proposed that targeting inflammation pathways could be a promising strategy to treat OA. There have been many reports of cross-talk between inflammation and epigenetic factors in cartilage. Specifically, inflammatory mediators have been shown to regulate levels of enzymes that catalyze changes in DNA methylation and histone structure, as well as alter levels of non-coding RNAs. In addition, expression levels of a number of these epigenetic factors have been shown to be altered in OA, thereby suggesting potential interplay between inflammation and epigenetics in this disease. This review provides information on inflammatory pathways in arthritis and summarizes published research on how epigenetic regulators are affected by inflammation in chondrocytes. Furthermore, we discuss data showing how altered expression of some of these epigenetic factors can induce either catabolic or anti-catabolic effects in response to inflammatory signals. A better understanding of how inflammation affects epigenetic factors in OA may provide us with novel therapeutic strategies to treat this condition.

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Section: Oa Pathologymentioning

confidence: 99%

Inflammation and epigenetic regulation in osteoarthritis

Shen

Abu‐Amer

O’Keefe

et al. 2016

Connective Tissue Research

185

140

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“…Stratification of chondrocytes in various states of maturity causes formation of the growth plate, in which the most mature cells cease proliferating and undergo hypertrophy. This critical milestone in the process of endochondral ossification is typified by characteristic changes in chondrocyte morphology, including dramatic increases in cell volume, and a defined gene expression profile (Man-Ger Sun and Beier, 2014). Hypertrophic chondrocytes begin to produce a very specialized matrix consisting of collagen type X (Col10) and express alkaline phosphatase (Alk Phos), and matrix calcification is initiated (Adams et al, 2007;van der Eerden et al, 2003;Anderson et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Lizard tail regeneration: regulation of two distinct cartilage regions by Indian hedgehog

Lozito

Tuan

2015

Developmental Biology

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Lizards capable of caudal autotomy exhibit the remarkable ability to "drop" and then regenerate their tails. However, the regenerated lizard tail (RLT) is known as an "imperfect replicate" due to several key anatomical differences compared to the original tail. Most striking of these "imperfections" concerns the skeleton; instead of the vertebrae of the original tail, the skeleton of the RLT takes the form of an unsegmented cartilage tube (CT). Here we have performed the first detailed staging of skeletal development of the RLT CT, identifying two distinct mineralization events. CTs isolated from RLTs of various ages were analyzed by micro-computed tomography to characterize mineralization, and to correlate skeletal development with expression of endochondral ossification markers evaluated by histology and immunohistochemistry. During early tail regeneration, shortly after CT formation, the extreme proximal CT in direct contact with the most terminal vertebra of the original tail develops a growth plate-like region that undergoes endochondral ossification. Proximal CT chondrocytes enlarge, express hypertrophic markers, including Indian hedgehog (Ihh), apoptose, and are replaced by bone. During later stages of tail regeneration, the distal CT mineralizes without endochondral ossification. The sub-perichondrium of the distal CT expresses Ihh, and the perichondrium directly calcifies without cartilage growth plate formation. The calcified CT perichondrium also contains a population of stem/progenitor cells that forms new cartilage in response to TGF-β stimulation. Treatment with the Ihh inhibitor cyclopamine inhibited both proximal CT ossification and distal CT calcification. Thus, while the two mineralization events are spatially, temporally, and mechanistically very different, they both involve Ihh. Taken together, these results suggest that Ihh regulates CT mineralization during two distinct stages of lizard tail regeneration.

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“…Destruction of cartilage, loss of cartilage matrix, aberrant chondrocyte hypertrophy, 1,2 and disruption of the tidemark accompanied by angiogenesis at the osteochondral junction 3 are characteristics of OA. Unfortunately, no effective medical therapy for the condition is available for clinical use because of limited understanding of its pathogenesis.…”

Section: Introductionmentioning

confidence: 99%

Intra-articular Delivery of Antago-miR-483-5p Inhibits Osteoarthritis by Modulating Matrilin 3 and Tissue Inhibitor of Metalloproteinase 2

et al. 2017

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MicroRNAs (miRNAs) are emerging as important regulators in osteoarthritis (OA) pathogenesis. In our study, a real-time PCR assay revealed that miR-483-5p was upregulated in articular cartilage from OA patients and experimental OA mice induced by destabilization of the medial meniscus compared to their controls. Overexpression of miR-483-5p by intra-articular injection of lentivirus LV3-miR-483-5p significantly enhanced the severity of experimental OA. Consequently, we synthesized antago-miR-483-5p to silence the endogenous miR-483-5p and delivered it intra-articularly, which revealed that antagomiR-483-5p delayed the progression of experimental OA. To investigate the functional mechanism of miR-483-5p in OA development, we generated doxycycline-inducible miR-483 transgenic (TG483) mice. TG483 mice exhibited significant acceleration and increased severity of OA, and age-related OA occurred with higher incidence and greater severity in TG483 mice compared with their controls. Furthermore, our results revealed miR-483-5p directly targeted to the cartilage matrix protein matrilin 3 (Matn3) and tissue inhibitor of metalloproteinase 2 (Timp2) to stimulate chondrocyte hypertrophy, extracellular matrix degradation, and cartilage angiogenesis, and it consequently initiated and accelerated the development of OA. In conclusion, our findings reveal an miRNA functional pathway important for OA development. Targeting of miR-483-5p by intra-articular injection of antago-miR-483-5p represents an approach that could prevent the onset of OA and delay its progression.

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Chondrocyte hypertrophy in skeletal development, growth, and disease

Cited by 114 publications

References 77 publications

Inflammation and epigenetic regulation in osteoarthritis

Inflammation and epigenetic regulation in osteoarthritis

Lizard tail regeneration: regulation of two distinct cartilage regions by Indian hedgehog

Intra-articular Delivery of Antago-miR-483-5p Inhibits Osteoarthritis by Modulating Matrilin 3 and Tissue Inhibitor of Metalloproteinase 2

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