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Published on: December 3, 2016
Aggrecan deficiency does not increase susceptibility to estrogen-induced growth plate senescence
Ameya Bendre1,2, Henrique Hadad1,2, Lars Ottosson1,2
1Division of Pediatric Endocrinology and Center for Molecular Medicine, Department of Women's and Children's Health, Karolinska Institutet, Stockholm SE-171 76, Sweden.
Insights
Aggrecan deficiency in children causes growth failure and advanced bone age. This study found that aggrecan deficiency does not increase sensitivity to estrogen, challenging previous hypotheses about growth cessation.
Area of Science:
- Endocrinology
- Genetics
- Skeletal Biology
Background:
- Estrogen accelerates skeletal maturation in children, leading to advanced bone age and growth cessation.
- Heterozygous pathogenic variants in the aggrecan gene (ACAN) cause growth failure, advanced bone age, and premature growth cessation in children.
- The mechanism underlying accelerated skeletal maturation in ACAN deficiency is not fully understood, with a hypothesis suggesting increased sensitivity to estrogen.
Purpose of the Study:
- To investigate whether aggrecan deficiency increases susceptibility to estrogen-induced growth plate senescence.
- To determine if accelerated skeletal maturation in aggrecan deficiency is driven by heightened estrogen sensitivity.
Main Methods:
- Utilized a mouse model with a heterozygous truncating variant in the Acan gene (Acan+/-).
- Ovariectomized wild-type and Acan+/- mice received estradiol or vehicle treatment for 4 weeks.
- Assessed tibial growth and structural markers of growth plate function.
Main Results:
- Estradiol treatment reduced tibial growth and growth plate function markers in wild-type mice.
- Fewer parameters were significantly affected by estradiol treatment in Acan+/- mice compared to wild-type.
- No evidence was found that aggrecan deficiency increases susceptibility to estrogen-induced growth plate senescence.
Conclusions:
- Accelerated skeletal maturation in ACAN deficiency does not appear to be caused by increased sensitivity to estrogen.
- Intrinsic abnormalities of growth plate cartilage, rather than heightened estrogen sensitivity, likely drive premature growth cessation in aggrecan deficiency.
Abstract:
In growing children, estrogen accelerates skeletal maturation, leading to advanced bone age, earlier growth cessation, and epiphyseal fusion. Children with heterozygous pathogenic variants in the aggrecan gene (ACAN) typically exhibit postnatal growth failure, advanced bone age, and premature growth cessation. To investigate whether accelerated skeletal maturation in aggrecan deficiency reflects increased sensitivity to estrogen-induced growth plate senescence, we used a mouse model carrying a heterozygous truncating variant in Acan (Acan +/-). Consistent with the human phenotype, these mice display postnatal growth failure and early growth cessation. Seven-week-old ovariectomized (OVX) wild-type and Acan +/- mice received weekly estradiol cypionate (0.15 µg/g) or vehicle treatment for 4 weeks. As expected, OVX reduced and estradiol increased uterine weights in both genotypes. In wild-type mice, estradiol treatment significantly reduced tibial growth and several structural markers of growth plate function. In Acan +/- mice, fewer parameters were significantly affected by estradiol treatment. Importantly, we found no evidence that aggrecan deficiency increases susceptibility to estrogen-induced growth plate senescence. These findings challenge the hypothesis that accelerated skeletal maturation in ACAN deficiency reflects heightened estrogen sensitivity and instead point to intrinsic abnormalities of growth plate cartilage as a driver of premature growth cessation.
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