Progression of Gene Expression Changes following a Mechanical Injury to Articular Cartilage as a Model of Early Stage Osteoarthritis

McCulloch, Ryan; Ashwell, M.S.; Maltecca, Christian; O’Nan, A. T.; Mente, Peter L.

doi:10.1155/2014/371426

Cited by 16 publications

(14 citation statements)

References 49 publications

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“…(C)]. MMP13 (also called collagenase 3) is highly overexpressed in OA, and is implicated in the degradation of the main constituents of cartilage matrix, that is, COL2 and aggrecan . For this reason, MMP13 has been studied as a potential therapeutic target in OA .…”

Section: Resultsmentioning

confidence: 99%

“…MMP13 (also called collagenase 3) is highly overexpressed in OA, 33 and is implicated in the degradation of the main constituents of cartilage matrix, that is, COL2 and aggrecan. 34 For this reason, MMP13 has been studied as a potential therapeutic target in OA. 35 Because ANGPTL4 induces the release of MMPs from chondrocytes and is more highly expressed in OA cartilage than in normal cartilage, 23 exogenous ANGPTL4 silencing, as shown by the present study, might be useful for reducing MMP13 synthesis in OA.…”

Section: In Vivo Effect Of Ia Injections Of Transfected Adscsmentioning

confidence: 99%

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Dual functional nanoparticles containing SOX duo and ANGPT4 shRNA for osteoarthritis treatment

et al. 2019

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In our previous studies, we found that adult stem cells transfected with sex‐determining region Y‐box (SOX)‐9, ‐6 and ‐5 genes (SOX trio) enhanced chondrogenesis and suppressed the progression of osteoarthritis (OA). The inhibition of angiopoietin‐like 4 (ANGPT4) is known to reduce levels of cartilage damaging enzymes, such as, matrix metalloproteinases (MMPs). In this study, we designed nanoparticles comprising dexamethasone‐conjugated polyethylenimine (DEXPEI) complexed with minicircle plasmid (MC) harboring SOX duo (SOX‐9, ‐6) and ANGPTL4 small hairpin RNA (shANG) [MCSOX9/6/shANG] in the expectation that transfection of these nanoparticles would enhance chondrogenesis of stem cells and suppress inflammation in OA. Adipose‐derived stem cells (ADSCs) transfected with MCSOX9/6/shANG (MCSOX9/6/shANG‐tADSCs) showed significantly higher expressions of COL2 gene and protein than MCSOX9/6‐transfected ADSCs (MCSOX9/6‐tADSCs) during in vitro chondrogenesis while both enhanced chondrogenesis in the absence of growth factor addition as compared with negative controls. Furthermore, the expressions of MMP13 and MMP3 genes were significantly more diminished in MCSOX9/6/shANG‐tADSCs than in MCSOX9/6‐tADSCs. In vivo experiments using surgically‐induced OA rats showed MCSOX9/6/shANG‐tADSC‐treated rats had significantly lower levels of cyclooxygenase (COX‐2) and MMP13 in synovial fluids than MCSOX9/6‐tADSC‐treated rats, but no significant difference was observed between them in histological appearances. Both groups showed significantly less joint destruction than control groups did. These results demonstrate that dual functional nanoparticles containing SOX duo and ANGPT4 shRNA enhance chondrogenesis of ADSCs and suppress inflammation in OA. © 2019 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 108B:234–242, 2020.

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Section: Resultsmentioning

confidence: 99%

Section: In Vivo Effect Of Ia Injections Of Transfected Adscsmentioning

confidence: 99%

Dual functional nanoparticles containing SOX duo and ANGPT4 shRNA for osteoarthritis treatment

et al. 2019

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“…Studies on cartilage (Fehrenbacher et al, 2003; Li et al, 2013; McCulloch et al, 2014) motivated the hypothesis that cells in regions of damaged tendon ECM will form an enhanced PCM to maintain mechanical stimulation, thereby reducing cell stress and protecting against apoptosis. Interestingly, the results of this study show an increase in collagen VI that was not associated with any increase in procollagen I or any other change that could be indicative of a remodeling attempt.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of apoptosis exacerbates fatigue-damage tendon injuries in an in vivo rat model

Bell¹,

Robles-Harris²,

Anderson³

et al. 2018

eCM

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Tendinopathy is a common and progressive musculoskeletal disease. Increased apoptosis is an end-stage tendinopathy manifestation, but its contribution to the pathology of the disease is unknown. A previously established in vivo model of fatigue damage accumulation shows that increased apoptosis is correlated with the severity of induced tendon damage, even in early onset of the disease, supporting its implication in the pathogenesis of the disease. Consequently, this study aimed to determine: (1) whether apoptosis could be inhibited after fatigue damage and (2) whether its inhibition could lead to remodeling of the extracellular matrix (ECM) and pericellular matrix (PCM), to ultimately improve the mechanical properties of fatigue-damaged tendons. The working hypothesis was that, despite the low vascular nature of the tendon, apoptosis would be inhibited, prompting increased production of matrix proteins and restoring tendon mechanical properties. Rats received 2 or 5 d of systemic pan-caspase inhibitor (Q-VD-OPh) or dimethyl sulfoxide (DMSO) carrier control injections starting immediately prior to fatigue loading and were sacrificed at days 7 and 14 post-fatigue-loading. Systemic pan-caspase inhibition for 2 d led to a surprising increase in apoptosis, but inhibition for 5 d increased the population of live cells that could repair the fatigue damage. Further analysis of the 5 d group showed that effective inhibition led to an increased population of cells producing ECM and PCM proteins, although typically in conjunction with oxidative stress markers. Ultimately, inhibition of apoptosis led to further deterioration in mechanical properties of fatigue-damaged tendons.

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“…Seven genes related to cartilage damage were measured in the extracted RNA using quantitative real‐time PCR (qPCR): COL1, COL2, ACAN (cartilage matrix); MMP3, MMP13, ADAMTS5 (matrix proteases); and TIMP1 (protease inhibitor) (Table ). Primer pairs for qPCR were adopted from McCulloch et al and Nygard et al qPCR was performed in a 10 µl reaction, consisting of 3 µl of 50 times diluted cDNA, 1 µM of forward and reverse primers, and 5 µl of SYBR Green (Bio‐Rad, Veenendaal, The Netherlands). Gene expression was normalized to PPIA, identified as being most stable in porcine under mechanical loading .…”

Section: Methodsmentioning

confidence: 99%

The initial repair response of articular cartilage after mechanically induced damage

2016

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The regenerative potential of articular cartilage (AC) defects is limited and depends on defect size, biomechanical conditions, and age. Early events after overloading might be predictive for cartilage degeneration in the long term. Therefore, the present aim is to investigate the temporal response of cartilage to overloading at cell, matrix, and tissue level during the first period after mechanical overloading. In the present study, the effect of high loading (∼8 MPa) at a high rate (∼14 MPa/s) at day 0 during a 9 day period on collagen damage, gene expression, cell death, and biochemical composition in AC was investigated. A model system was developed which enabled culturing osteochondral explants after loading. Proteoglycan content was repeatedly monitored over time using μCT, whereas other evaluations required destructive measurements. Changes in matrix related gene expressions indicated a degenerative response during the first 6 h after loading. After 24 h, this was restored and data suggested an initial repair response. Cell death and microscopic damage increased after 24 h following loading. These degradative changes were not restored within the 9 day culture period, and were accompanied by a slight loss of proteoglycans at the articular surface that extended into the middle zones. The combined findings indicate that high magnitude loading of articular cartilage at a high rate induces an initial damage that later initiates a healing response that can probably not be retained due to loss of cell viability. Consequently, the matrix cannot be restored in the short term. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1265-1273, 2017.

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Progression of Gene Expression Changes following a Mechanical Injury to Articular Cartilage as a Model of Early Stage Osteoarthritis

Cited by 16 publications

References 49 publications

Dual functional nanoparticles containing SOX duo and ANGPT4 shRNA for osteoarthritis treatment

Dual functional nanoparticles containing SOX duo and ANGPT4 shRNA for osteoarthritis treatment

Inhibition of apoptosis exacerbates fatigue-damage tendon injuries in an in vivo rat model

The initial repair response of articular cartilage after mechanically induced damage

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