SAT-201 Effects Of Early Postnatal Undernutrition On Growth Plate Chondrocyte Gene Expression

Abstract Disclosure: K. Hansdah: None. A. Rama-Krishnan: None. K. Tailor: None. J. Lui: None. J. Baron: None. Introduction: During malnutrition, growth plate chondrogenesis is impaired, which results in a decreased bone length and therefore a decrease in overall body size. Objective: To explore the molecular mechanisms by which caloric restriction regulates growth plate chondrogenesis. Methods: The study investigated the effect of maternal food restriction during lactation on offspring in C57BL/6 mice. Beginning at 3 days after parturition, lactating dams were fed either ad-libitum (AL) or calorie-restricted (CR) with 60% of the food consumed by the AL group. After 9 days of caloric restriction, offspring were euthanized for measurements of body and tibial length, and histological analysis of the growth plate. We performed Visium HD spatial gene expression analysis to compare gene expressions in specific regions of growth plate. Results: CR mice exhibited lower body weight, body length, and tibial length compared to the AL group (all p less than 0.01). Histological analysis showed a significant decrease in heights of the growth plate, proliferative and hypertrophic zone in CR mice compared to AL mice (all p less than 0.01). Cell proliferation (by EdU incorporation) in the proliferative zone of growth plate was significantly (p=0.03) decreased in CR group compared to AL group. We also detected significantly (p less than 0.0001) lower levels of serum IGF-1 protein in CR group compared to AL (by ELISA). Spatial transcriptomic profiling revealed markedly upregulated expression of anti-apoptotic gene Bcl2 in the resting zone chondrocytes, which could enhance the survival of chondroprogenitor cells. Conversely, Gnai1 and Gna11, both of which are implicated in PTHrP and G-protein coupled receptor signaling that are important in the resting zone, were downregulated due to caloric restriction. In the proliferative zone we found that ITGA11, a gene associated with cell proliferation, was significantly downregulated in caloric restricted mice. Similarly, we found decreased expression of ADAMST4, which is involved in the degradation of aggrecan and matrix turnover, suggesting a slower rate of cartilage remodeling in proliferative zone under caloric restriction. In the hypertrophic zone, expression of Gdf10 and Prelp, which are markers typically associated with the proliferative zone, were upregulated suggesting delayed hypertrophy in caloric restricted mice. In contrast, we found downregulation of IGF1R, suggesting decreased IGF-1 signaling in the hypertrophic zone during caloric restriction. Conclusions: Our findings provide molecular insights into dysregulated growth plate chondrogenesis and cell survival that may help explain the etiology of short stature due to malnutrition. Presentation: Saturday, July 12, 2025