Naproxen affects osteogenesis of human mesenchymal stem cells via regulation of Indian hedgehog signaling molecules

Salem, Omar; Wang, Hong; Alaseem, Abdulrahman; Ciobanu, Ovidiu; Hadjab, I.; Gawri, Rahul; Antoniou, John; Mwale, Fackson

doi:10.1186/ar4614

Cited by 22 publications

(25 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…(11,12) In addition, these results indicated that Npx can affect gene expression during osteogenic differentiation of MSCs through IHH signaling. (7) Elevated basal COL10A1 expression in OA MSCs also involved the activation of MAPK pathway and stimulation of the 5-lipoxygenase signaling pathway by Npx. (13) The present study is the first to demonstrate that Npx can regulate chondrogenic differentiation by affecting repair.…”

Section: After the Cells Were Cultured For 3 Days In Chondrogenic Difmentioning

confidence: 99%

“…(7) The effect of Npx on the expression of PTC1, IHH, GLI1, GLI2 and GLI3 when MSCs were cultured in chondrogenic differentiation medium was therefore assessed ( Figure 5). When the cells were cultured in this medium with Npx, the expression of PTC1 significantly decreased on day 6, compared with that in control cells ( Figure 5A).…”

Section: After the Cells Were Cultured For 3 Days In Chondrogenic Difmentioning

confidence: 99%

“…The expression of GLI2 significantly increased on day 12 (p = 0.031), while no significant difference was observed on days 3 and 6 ( Figure 5D Previous work has demonstrated a potential of Npx to interfere with MSC differentiation. (7,11,12) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.…”

Section: After the Cells Were Cultured For 3 Days In Chondrogenic Difmentioning

confidence: 99%

“…(6) We recently showed that Npx can affect gene expression during osteogenic differentiation of mesenchymal stem cells (MSCs), which are also called mesenchymal stromal cells, and downregulate mineral deposition in the extracellular matrix through Indian hedgehog (IHH) signaling, (7) suggesting that Npx could affect MSC-mediated repair of subchondral bone in OA patients. However, little is known about the effects of Npx on articular cartilage repair in OA patients.…”

Section: Introductionmentioning

confidence: 99%

“…However, regardless of the source, MSCs have a propensity to express markers of hypertrophic chondrocytes, (9) an undesired characteristic in cartilage repair. (10,11) Previous studies have shown that collagen type X, a marker of late stage chondrocyte hypertrophy (associated with endochondral ossification), is constitutively expressed by MSCs isolated from OA patients, (9) and NSAIDs can affect the expression of both hypertrophic and osteogenic marker genes in MSCs, (7,12,13) with Npx showing stronger effects than other drugs. The effect of these drugs on the transcriptome of (15) Parathyroid hormone (PTH) and parathyroid hormone-related protein (PTHrP), which share the same receptor, can affect the chondrogenesis of MSCs.…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

The Effects of Naproxen on Chondrogenesis of Human Mesenchymal Stem Cells

Antoniou

Wang

Hadjab

et al. 2015

Tissue Engineering Part A

Self Cite

View full text Add to dashboard Cite

Currently, there are no established treatments to prevent, stop, or even retard the degeneration of articular cartilage in osteoarthritis (OA). Biological repair of the degenerating articular cartilage would be preferable to surgery. There is no benign site where autologous chondrocytes can be harvested and used as a cell source for cartilage repair, leaving mesenchymal stem cells (MSCs) as an attractive option. However, MSCs from OA patients have been shown to constitutively express collagen type X (COL-X), a marker of late-stage chondrocyte hypertrophy. We recently found that naproxen (Npx), but not other nonsteroidal anti-inflammatory drugs, can induce collagen type X alpha 1 (COL10A1) gene expression in bone marrow-derived MSCs from healthy and OA donors. In this study, we determined the effect of Npx on COL10A1 expression and investigated the intracellular signaling pathways that mediate such effect in normal human MSCs during chondrogenesis. MSCs were cultured in standard chondrogenic differentiation media supplemented with or without Npx. Our results show that Npx can regulate chondrogenic differentiation by affecting the gene expression of both Indian hedgehog and parathyroid hormone/parathyroid hormone-related protein signaling pathways in a time-dependent manner, suggesting a complex interaction of different signaling pathways during the process.

show abstract

Section: After the Cells Were Cultured For 3 Days In Chondrogenic Difmentioning

confidence: 99%

Section: After the Cells Were Cultured For 3 Days In Chondrogenic Difmentioning

confidence: 99%

Section: After the Cells Were Cultured For 3 Days In Chondrogenic Difmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

The Effects of Naproxen on Chondrogenesis of Human Mesenchymal Stem Cells

Antoniou

Wang

Hadjab

et al. 2015

Tissue Engineering Part A

Self Cite

View full text Add to dashboard Cite

show abstract

Pirfenidone reduces subchondral bone loss and fibrosis after murine knee cartilage injury

Chan

Luo

et al. 2017

Journal Orthopaedic Research

View full text Add to dashboard Cite

Pirfenidone is an anti-inflammatory and anti-fibrotic drug that has shown efficacy in lung and kidney fibrosis. Because inflammation and fibrosis have been linked to the progression of osteoarthritis, we investigated the effects of oral Pirfenidone in a mouse model of cartilage injury, which results in chronic inflammation and joint-wide fibrosis in mice that lack hyaluronan synthase 1 (Has1 ) in comparison to wild-type. Femoral cartilage was surgically injured in wild-type and Has1 mice, and Pirfenidone was administered in food starting after 3 days. At 4 weeks, Pirfenidone reduced the appearance, on micro-computed tomography, of pitting in subchondral bone at, and cortical bone surrounding, the site of cartilage injury. This corresponded with a reduction in fibrotic tissue deposits as observed with gross joint surface photography. Pirfenidone resulted in significant recovery of trabecular bone parameters affected by joint injury in Has1 mice, although the effect in wild-type was less pronounced. Pirfenidone also increased Safranin-O staining of growth plate cartilage after cartilage injury and sham operation in both genotypes. Taken together with the expression of selected extracellular matrix, inflammation, and fibrosis genes, these results indicate that Pirfenidone may confer chondrogenic and bone-protective effects, although the well-known anti-fibrotic effects of Pirfenidone may occur earlier in the wound-healing response than the time point examined in this study. Further investigations to identify the specific cell populations in the joint and signaling pathways that are responsive to Pirfenidone are warranted, as Pirfenidone and other anti-fibrotic drugs may encourage tissue repair and prevent progression of post-traumatic osteoarthritis. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:365-376, 2018.

show abstract

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

View full text Add to dashboard Cite

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.

show abstract

Naproxen affects osteogenesis of human mesenchymal stem cells via regulation of Indian hedgehog signaling molecules

Cited by 22 publications

References 35 publications

The Effects of Naproxen on Chondrogenesis of Human Mesenchymal Stem Cells

The Effects of Naproxen on Chondrogenesis of Human Mesenchymal Stem Cells

Pirfenidone reduces subchondral bone loss and fibrosis after murine knee cartilage injury

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

Contact Info

Product

Resources

About