TY - JOUR
T1 - Evaluation of impaired growth plate development of long bones in skeletally immature mice by antirheumatic agents
AU - Caron, Marjolein M. J.
AU - van Rietbergen, Bert
AU - Castermans, Tessy M. R.
AU - Haartmans, Mirella J. J.
AU - van Rhijn, Lodewijk W.
AU - Welting, Tim J. M.
AU - Witlox, Adhiambo M. A.
N1 - Funding Information:
The authors would like to thank the Dutch Arthritis Association (Grant No. LLP14), the Dutch Stichting Annafonds | NOREF (Grant No. O2012/66), and the profile rings fonds from the MUMC+ for their financial support. The study sponsors had no involvement in study design, collection, analysis, and interpretation of data; the writing of the manuscript or in the decision to submit the manuscript for publication. The authors would also like to thank the employees of the animal facility of the Maastricht University for their assistance during this study.
Publisher Copyright:
© 2020 The Authors. Journal of Orthopaedic Research ® published by Wiley Periodicals LLC on behalf of Orthopaedic Research Society
PY - 2021/3
Y1 - 2021/3
N2 - 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.
AB - 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.
KW - endochondral ossification
KW - growth plate
KW - JIA
KW - MTX
KW - naproxen
KW - MESENCHYMAL STEM-CELLS
KW - JUVENILE IDIOPATHIC ARTHRITIS
KW - HIGH-DOSE METHOTREXATE
KW - ENDOCHONDRAL BONE
KW - FINAL HEIGHT
KW - FOLINIC ACID
KW - SHORT-TERM
KW - COLLAGEN
KW - NAPROXEN
KW - DIFFERENTIATION
U2 - 10.1002/jor.24819
DO - 10.1002/jor.24819
M3 - Article
C2 - 32740982
SN - 0736-0266
VL - 39
SP - 553
EP - 564
JO - Journal of Orthopaedic Research
JF - Journal of Orthopaedic Research
IS - 3
ER -