Retinoid-impregnated nanoparticles enable control of bone growth by site-specific modulation of endochondral ossification in mice

Abstract

Growth-plate (GP) injures in limbs and other sites can impair GP function and cause deceleration of bone growth, leading to progressive bone lengthening imbalance, deformities and/or physical discomfort, decreased motion and pain. At present, surgical interventions are the only means available to correct these conditions by suppressing the GP activity in the unaffected limb and/or other bones in the ipsilateral region. Here, we aimed to develop a pharmacologic treatment of GP growth imbalance that involves local application of nanoparticles-based controlled release of a selective retinoic acid nuclear receptor gamma (RAR{gamma}) agonist drug. When RAR{gamma} agonist-loaded nanoparticles were implanted near the medial and lateral sides of proximal tibial growth plate in juvenile C57BL/6j mice, the GP underwent involution and closure. Overall tibia length was shortened compared to the contralateral element implanted with drug-free control nanoparticles. Importantly, when the RAR{gamma} agonist nanoparticles were implanted on the lateral side only, the adjacent epiphysis tilted toward the lateral site, leading to apical angulation of the tibia. In contrast to the local selectivity of these responses, systemic administration of RAR{gamma} agonists led to GP closure at many sites, inhibiting skeletal growth over time. Agonists for RAR and RAR{beta} elicited no obvious responses over parallel regimens. Our findings provide novel evidence that RAR{gamma} agonist-loaded nanoparticles can control activity, function and directionality of a targeted GP, offering a potential and clinically-relevant alternative or supplementation to surgical correction of limb length discrepancy and angular deformities. Lay summaryGrowth-plates (physes), which are cartilage tissues near the ends of bones, support normal bone growth in children. Growth plate injures in limbs and other sites can impair growth plate function, leading to inhibited or imbalanced bone growth, skeletal deformities, decreased motion, discomfort or pain. At present, surgical interventions are the only means available to correct these conditions. Here, we aimed to develop a pharmacologic treatment for bone growth imbalance. Nanoparticles loaded with a selective agonist for the retinoic acid nuclear receptor gamma were prepared and implanted near the tibial growth plate in juvenile mice. The growth plate underwent involution and closure, and overall tibia length was shortened compared to the contralateral element implanted with drug-free control nanoparticles. Importantly, when the same drug nanoparticles were implanted in only one side of the tibia, the tibia was tilted toward the injection site. Our findings provide novel evidence that retinoic acid receptor gamma agonist-loaded nanoparticles can control activity, function and directionality of a targeted growth plate, offering a potential and clinically-relevant alternative or supplementation to surgical correction of limb length imbalances and deformities.