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TNF overexpression and dexamethasone treatment impair chondrogenesis and bone growth in an additive manner
Yunhan Zhao1, Bettina Celvin2, Maria C Denis3
1Department of Women's and Children´s Health, Karolinska Institutet and Pediatric Endocrinology Unit, Karolinska University Hospital, J9:30, Visionsgatan 4, 171 64, Solna, Sweden. yunhan.zhao.1@ki.se.
Abstract:
Children with chronic inflammation are often treated with glucocorticoids (GCs) and many of them experience growth retardation. It is poorly understood how GCs interact with inflammatory cytokines causing growth failure as earlier experimental studies have been performed in healthy animals. To address this gap of knowledge, we used a transgenic mouse model where human TNF is overexpressed (huTNFTg) leading to chronic polyarthritis starting from the first week of age. Our results showed that femur bone length and growth plate height were significantly decreased in huTNFTg mice compared to wild type animals. In the growth plates of huTNFTg mice, increased apoptosis, suppressed Indian hedgehog, decreased hypertrophy, and disorganized chondrocyte columns were observed. Interestingly, the GC dexamethasone further impaired bone growth, accelerated chondrocyte apoptosis and reduced the number of chondrocyte columns in huTNFTg mice. We conclude that TNF and dexamethasone separately suppress chondrogenesis and bone growth when studied in an animal model of chronic inflammation. Our data give a possible mechanistic explanation to the commonly observed growth retardation in children with chronic inflammatory diseases treated with GCs.
Insights
Tumor necrosis factor (TNF) and glucocorticoids (GCs) independently impair bone growth in a mouse model of chronic inflammation. This study explains why children with inflammatory diseases treated with GCs often experience growth retardation.
Area of Science:
- Biomedical Sciences
- Molecular Biology
- Pediatric Endocrinology
Background:
- Chronic inflammation is linked to growth retardation in children, particularly those treated with glucocorticoids (GCs).
- The mechanisms by which GCs and inflammatory cytokines like TNF interact to cause growth failure are not fully understood, especially in the context of inflammation.
- Previous studies on GCs and growth have primarily used healthy animal models, not accounting for inflammatory conditions.
Purpose of the Study:
- To investigate the combined effects of chronic inflammation and glucocorticoid treatment on bone growth.
- To elucidate the molecular mechanisms underlying growth plate dysfunction in an inflammatory setting.
- To provide a mechanistic explanation for GC-induced growth retardation in pediatric inflammatory diseases.
Main Methods:
- Utilized a transgenic mouse model (huTNFTg) overexpressing human TNF to induce chronic polyarthritis from an early age.
- Compared femur bone length and growth plate characteristics between huTNFTg mice and wild-type littermates.
- Administered the GC dexamethasone to huTNFTg mice to assess its impact on bone growth and growth plate histology.
Main Results:
- huTNFTg mice exhibited significantly reduced femur bone length and growth plate height compared to wild-type controls.
- Growth plates in huTNFTg mice showed increased chondrocyte apoptosis, suppressed Indian hedgehog signaling, reduced hypertrophy, and disorganized chondrocyte columns.
- Dexamethasone treatment exacerbated bone growth impairment, increased chondrocyte apoptosis, and further disorganized chondrocyte columns in huTNFTg mice.
Conclusions:
- Both TNF and dexamethasone independently suppress chondrogenesis and inhibit bone growth in the context of chronic inflammation.
- The findings offer a potential mechanistic basis for the growth retardation observed in children with chronic inflammatory conditions undergoing GC therapy.
- This study highlights the detrimental effects of combined inflammatory stimuli and GC treatment on skeletal development.
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