The Effects of Naproxen on Chondrogenesis of Human Mesenchymal Stem Cells

Antoniou, John; Wang, Hong; Hadjab, I.; Aldebeyan, Sultan; Alaqeel, Motaz; Meij, Björn P.; Tryfonidou, Marianna A.; Mwale, Fackson

doi:10.1089/ten.tea.2014.0668

Cited by 6 publications

(10 citation statements)

References 53 publications

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“…We showed that naproxen can regulate chondrogenic differentiation in normal human MSCs by suppressing the gene expression of Indian hedgehog and parathyroid hormone/parathyroid hormone-related protein (PTH/PTHrP) signaling pathways in a time-dependent manner, suggesting a complex interaction of different signaling pathways 78 , but NSAIDs had a concentrationdependent effect on the differentiation and growth of MSCs, accelerated differentiation and growth at low concentrations, and negatively affected differentiation at high concentrations 79 . NSAIDs may inhibit bone formation via blockage of MSC chondrogenic differentiation, an important intermediate phase in normal endochondral bone formation 80 .…”

Section: Effects On Osteoblastsmentioning

confidence: 99%

Disease-modifying effects of COX-2 selective inhibitors and non-selective NSAIDs in osteoarthritis: a systematic review

Nakata

Hanai

Take

et al. 2018

Osteoarthritis and Cartilage

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Osteoarthritis (OA) is a potentially disabling disease whose progression is dependent on several risk factors. OA management usually involves the use of non-steroidal anti-inflammatory drugs (NSAIDs) that are the primary pharmacological treatments of choice. However, NSAIDs have often been associated with unwanted side effects. Cyclooxygenase (COX)-2 specific inhibitors, such as celecoxib, have been successfully used as an alternative in the past for OA treatment and have demonstrated fewer side effects. While abundant data are available for the clinical efficacy of drugs used for OA treatment, little is known about the disease-modifying effects of these agents. A previous review published by Zweers et al. (2010) assessed the available literature between 1990 and 2010 on the disease-modifying effects of celecoxib. In the present review, we aimed to update the existing evidence and identify evolving concepts relating to the disease-modifying effects of not just celecoxib, but also other NSAIDs. We conducted a review of the literature published from 2010 to 2016 dealing with the effects, especially disease-modifying effects, of NSAIDs on cartilage, synovium, and bone in OA patients. Our results show that celecoxib was the most commonly used drug in papers that presented data on disease-modifying effects of NSAIDs. Further, these effects appeared to be mediated through the regulation of prostaglandins, cytokines, and direct changes to tissues. Additional studies should be carried out to assess the disease-modifying properties of NSAIDs in greater detail.

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Section: Effects On Osteoblastsmentioning

confidence: 99%

Disease-modifying effects of COX-2 selective inhibitors and non-selective NSAIDs in osteoarthritis: a systematic review

Nakata

Hanai

Take

et al. 2018

Osteoarthritis and Cartilage

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“…This gene increases bone resorption by stimulating osteoclastic formation, 28 meaning that a downregulated IL11 could promote osteogenesis. Specific genes for ossification, namely COL10A1 and TIMP3 , 29 were downregulated in Winter vs. Control. TIMP3 decreased in the category Winter vs. Summer.…”

Section: Discussionmentioning

confidence: 92%

Expression of Paracrine Effectors in Human Adipose‐Derived Mesenchymal Stem Cells Treated With Plasma From Brown Bears (Ursus arctos)

Linde

Johansson

Kruse

et al. 2020

Clinical Translational Sci

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Adipose-derived mesenchymal stem cells (ADSCs) are promising candidates for novel cell therapeutic applications. Hibernating brown bears sustain tissue integrity and function via unknown mechanisms, which might be plasma borne. We hypothesized that plasma from hibernating bears may increase the expression of favorable factors from human ADSCs. In an experimental study, ADSCs from patients with ischemic heart disease were treated with interventional media containing plasma from hibernating and active bears, respectively, and with control medium. Extracted RNA from the ADSCs was sequenced using next generation sequencing. Statistical analyses of differentially expressed genes were performed using fold change analysis, pathway analysis, and gene ontology. As a result, we found that genes associated with inflammation, such as IGF1, PGF, IL11, and TGFA, were downregulated by > 10-fold in ADSCs treated with winter plasma compared with control. Genes important for cardiovascular development, ADM, ANGPTL4, and APOL3, were upregulated in ADSCs when treated with winter plasma compared with summer plasma. ADSCs treated with bear plasma, regardless if it was from hibernating or active bears, showed downregulation of IGF1, PGF, IL11, INHBA, IER3, and HMOX1 compared with control, suggesting reduced cell growth and differentiation. This can be summarized in the conclusion that plasma from hibernating bears suppresses inflammatory genes and activates genes associated with cardiovascular development in human ADSCs. Identifying the involved regulator(s) holds therapeutic potential. Adipose-derived mesenchymal stem cells (ADSCs) are promising candidates for autologous and allogenous regenerative therapy for organ failure and tissue injury. ADSCs are capable of differentiating into several cell types 1 and also secrete paracrine effectors, which provide injured tissues with a regenerative microenvironment. 2 However, ADSCs decline in regenerative capacities while aging 3 and, therefore, improving the therapeutic potential of ADSCs is warranted. Previous cell culturing strategies with intention to augment the therapeutic capability of stem cells,

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“…The results are in line with our findings as presented in Figure 1. Overall, mixed results are found in the literature on the effect of naproxen on chondrogenic marker expression (COL2A1, SOX9, ACAN, and GAG content) and this might be influenced by the cell model, chondrogenic differentiation induction, time of exposure to naproxen and concentration used in these studies 25,26 . In this study, ATDC5 cells were used, which is a (murine) cell model described to resemble the chondrogenic phase of endochondral ossification 13 .…”

Section: Discussionmentioning

confidence: 99%

“…PTHrP shares the same receptor as PTH and is also described to influence the chondrogenic differentiation of MSCs 40 . Interestingly, for naproxen it was already described that its effects on hypertrophic differentiation during osteogenic and chondrogenic differentiation of MSCs could be explained via deregulation of the Ihh/PTHrP signaling 25,26 . Amano et al, 41 showed that Ihh regulates expression of Col10a1 directly via binding of the Gli1/2 transcription factors on the Col10a1 promoter, but also indirectly via induction of Runx2 and subsequent transcriptional complex formation of Gli1/2, Runx2, and Smads which are able to induce Col10a1 expression.…”

Section: Discussionmentioning

confidence: 99%

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Evaluation of impaired growth plate development of long bones in skeletally immature mice by antirheumatic agents

Caron

Rietbergen

Castermans

et al. 2020

Journal Orthopaedic Research

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Restriction of physical growth and development is a known problem in patients with juvenile idiopathic arthritis (JIA). However, the effect of medical treatment for JIA on skeletal growth in affected children has not been properly investigated. We, therefore, hypothesize that naproxen and methotrexate (MTX) affect endochondral ossification and will lead to reduced skeletal development. Treatment of ATDC5 cells, an in vitro model for endochondral ossification, with naproxen or MTX resulted in increased chondrogenic but decreased hypertrophic differentiation. In vivo, healthy growing C57BL/6 mice were treated with naproxen, MTX, or placebo for 10 weeks. At 15 weeks postnatal, both the length of the tibia and the length of the femur were significantly reduced in the naproxen‐ and MTX‐treated mice compared to their controls. Growth plate analysis revealed a significantly thicker proliferative zone, while the hypertrophic zone was significantly thinner in both experimental groups compared to their controls, comparable to the in vitro results. Micro‐computed tomography analysis of the subchondral bone region directly below the growth disc showed significantly altered bone microarchitecture in naproxen and MTX groups. In addition, the involvement of the PTHrP‐Ihh loop in naproxen‐ and MTX‐treated cells was shown. Overall, these results demonstrate that naproxen and MTX have a profound effect on endochondral ossification during growth plate development, abnormal subchondral bone morphology, and reduced bone length. A better understanding of how medication influences the development of the growth plate will improve understanding of endochondral ossification and reveal possibilities to improve the treatment of pediatric patients.

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The Effects of Naproxen on Chondrogenesis of Human Mesenchymal Stem Cells

Cited by 6 publications

References 53 publications

Disease-modifying effects of COX-2 selective inhibitors and non-selective NSAIDs in osteoarthritis: a systematic review

Disease-modifying effects of COX-2 selective inhibitors and non-selective NSAIDs in osteoarthritis: a systematic review

Expression of Paracrine Effectors in Human Adipose‐Derived Mesenchymal Stem Cells Treated With Plasma From Brown Bears (Ursus arctos)

Evaluation of impaired growth plate development of long bones in skeletally immature mice by antirheumatic agents

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