Impairment of Cyclo-oxygenase-2 Function Results in Abnormal Growth Plate Development and Bone Microarchitecture but Does Not Affect Longitudinal Growth of the Long Bones in Skeletally Immature Mice

Caron, M.M.; Castermans, Tessy M. R.; Rietbergen, Bert van; Haartmans, Mirella J. J.; Rhijn, Lodewijk W. van; Witlox, Adhiambo M.; Welting, Tim J. M.

doi:10.1177/1947603519833149

Cited by 5 publications

(10 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For analysis of the knee joint itself, the contour was shifted in the proximal direction and only the region that was nonoverlapping with the original contoured region or the femoral subchondral bone was then analysed. From the segmented images, the volumetric bone mineral density (vBMD) was determined [25,26].…”

Section: Quantification Of Cartilage and Bone Calcification By High-r...mentioning

confidence: 99%

Combining phosphate binder therapy with vitamin K2 inhibits vascular calcification in an experimental animal model of kidney failure

Neradová

Wasilewski

Prisco

et al. 2021

Nephrology Dialysis Transplantation

Self Cite

View full text Add to dashboard Cite

Background Hyperphosphatemia is strongly associated with cardiovascular disease and mortality. Recently, phosphate binders (PBs), which are used to bind intestinal phosphate have been shown also to bind vitamin K, thereby potentially aggravating vitamin K deficiency. This vitamin K-binding by PBs may offset beneficial effects of phosphate level reduction on reducing vascular calcification (VC). Here we assessed whether combining PBs with vitamin K2 supplementation inhibits VC. Methods We performed 3/4Nx in rats, after which warfarin was given for three weeks to induce vitamin K-deficiency. Next, animals were fed a high phosphate diet in the presence of low or high vitamin K2 and were randomized to either control or one of four different PBs for eight weeks. Primary outcome was the amount of thoracic and abdominal aorta VC measured by high-resolution micro-Computed Tomography (μ-CT). Vitamin K status was measured by plasma MK7 levels and immunohistochemically analyzed in vasculature using ucMGP specific antibodies. Results Combination of high vitamin K2 diet and PB treatment significantly reduced VC as measured by μ-CT, for both thoracic (p = 0.026) and abdominal aorta (p = 0.023), compared to MK7 or PB treatment alone. UcMGP stain was significantly more present in the low vitamin K2 treated groups in both thoracic (p<0.01) and abdominal aorta (p<0.01) as compared to high vitamin K2 treated groups. Moreover, high vitamin K diet and PBs led to reduced vascular oxidative stress. Conclusion In an animal model of kidney failure with vitamin K-deficiency, neither PB therapy nor vitamin K2 supplementation alone prevented VC. However, the combination of high vitamin K2 with PB treatment significantly attenuated VC.

show abstract

Section: Quantification Of Cartilage and Bone Calcification By High-r...mentioning

confidence: 99%

Combining phosphate binder therapy with vitamin K2 inhibits vascular calcification in an experimental animal model of kidney failure

Neradová

Wasilewski

Prisco

et al. 2021

Nephrology Dialysis Transplantation

Self Cite

View full text Add to dashboard Cite

show abstract

“…Our previous studies 11,14,24 determined that COX enzyme activity is involved in regulating the chondrogenic phase of endochondral ossification. Clinically, this is relevant as inhibition of COX enzymes by NSAIDs can result in hampered endochondral ossification.…”

Section: Discussionmentioning

confidence: 99%

“…Contours were drawn manually to identify a volume of interest (VOI) of subchondral bone just distal of the growth plate with a thickness of approximately 200 microns. From the segmented images, the following morphology indices were determined: bone density, bone volume fraction (BV/TV), trabecular number (Tb.N), trabecular thickness (Tb.Th), and trabecular separation (Tb.Sp) 14 …”

Section: Methodsmentioning

confidence: 99%

“…Enzymatic activity of alkaline phosphatase (ALP) and hydroxyproline levels were determined using a colorimetric assay as described before 14 . ALP activity was determined by measuring ALP‐depend enzymatic conversion of p ‐nitrophenyl phosphate to nitrophenyl phosphate.…”

Section: Methodsmentioning

confidence: 99%

“…Enzymatic activity of alkaline phosphatase (ALP) and hydroxyproline levels were determined using a colorimetric assay as described before. 14 white bars). 13 From day 14 in differentiation, these cells also express highly increased levels of chondrocyte hypertrophic marker collagen type X (Col10a1) and Runt-related transcription factor 2 (Runx2) 13 ( Figure 1C; white bars).…”

Section: Alkaline Phosphatase Activity and Hydroxyproline Assaymentioning

confidence: 99%

See 2 more Smart Citations

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

Self Cite

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

Cisplatin triggers oxidative stress, apoptosis and pro‐inflammatory responses by inhibiting the SIRT1‐mediated Nrf2 pathway in chondrocytes

Hsieh

Tsai

Chou

et al. 2023

Environmental Toxicology

View full text Add to dashboard Cite

Although the height of the proliferating layer that was suppressed in the growth plate has been recognized as an adverse effect of cisplatin in pediatric cancer survivors, the detailed pathological mechanism has not been elucidated. Sirtuin‐1 (SIRT1) has been reported as an essential modulator of cartilage homeostasis, but its role in cisplatin‐induced damage of chondrocytes remains unclear. In this study, we examined how cisplatin affected the expression of SIRT1 and cell viability. Next, we showed downregulation of SIRT1 after cisplatin treatment resulted in suppression of Peroxisome proliferator‐activated receptor‐gamma coactivator (PGC‐1α), leading to inhibition of Nrf2 nuclear translocation and subsequently decreased Heme oxygenase‐1(HO‐1) and NAD(P)H Quinone Dehydrogenase 1(NQO‐1) expression. Blockage of the SIRT1/ PGC‐1α axis not only increased oxidative stress with lower antioxidant SOD and GSH, but also contributed to mitochondrial dysfunction evidenced by the collapse of membrane potential and repression of mitochondrial DNA copy number and ATP. We also found that Cisplatin up‐regulated the p38 phosphorylation, pro‐inflammatory events and matrix metalloproteinases (MMPs) in chondrocytes through the SIRT1‐modulated antioxidant manner. Collectively, our findings suggest that preservation of SIRT1 in chondrocytes may be a potential target to ameliorate growth plate dysfunction for cisplatin‐receiving pediatric cancer survivors.

show abstract

Impairment of Cyclo-oxygenase-2 Function Results in Abnormal Growth Plate Development and Bone Microarchitecture but Does Not Affect Longitudinal Growth of the Long Bones in Skeletally Immature Mice

Abstract: *adhiambo M. a. Witlox and tim J. M. Welting contributed equally to the study.

Cited by 5 publications

References 49 publications

Combining phosphate binder therapy with vitamin K2 inhibits vascular calcification in an experimental animal model of kidney failure

Combining phosphate binder therapy with vitamin K2 inhibits vascular calcification in an experimental animal model of kidney failure

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

Cisplatin triggers oxidative stress, apoptosis and pro‐inflammatory responses by inhibiting the SIRT1‐mediated Nrf2 pathway in chondrocytes

Contact Info

Product

Resources

About