Matsuoka Masatake, Uchibe Kenta, Tang Ningfeng, Tian Hongying, Suzuki Akiko, Oichi Takeshi, Usami Yu, Alferiev Ivan, Otsuru Satoru, Abzug Joshua M, Herzenberg John E, Pacifici Maurizio, Enomoto-Iwamoto Motomi, Chorny Michael, Iwamoto Masahiro
Department of Orthopaedics, University of Maryland School of Medicine, Baltimore, MD, United States.
Department of Orthopaedic Surgery, Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
J Bone Miner Res. 2025 Apr 21;40(4):535-547. doi: 10.1093/jbmr/zjaf018.
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 (NP)-based controlled release of a selective retinoic acid nuclear receptor gamma (RARγ) agonist drug. When RARγ agonist-loaded NP 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 NP. Importantly, when the RARγ agonist NP were implanted on the lateral side only, the adjacent epiphysis tilted toward the lateral side, leading to apical angulation of the tibia. In contrast to the local selectivity of these responses, systemic administration of RARγ agonists led to GP closure at many sites, inhibiting skeletal growth over time. Agonists for RARα and RARβ elicited no obvious responses over parallel regimens. Our findings provide novel evidence that RARγ agonist-loaded NP 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.
四肢及其他部位的生长板（GP）损伤会损害生长板功能，导致骨骼生长减速，进而引起骨骼生长逐渐失衡、畸形和/或身体不适、活动减少及疼痛。目前，手术干预是纠正这些情况的唯一可用方法，即通过抑制未受影响肢体和/或同侧区域其他骨骼中的生长板活性来实现。在此，我们旨在开发一种针对生长板生长失衡的药物治疗方法，该方法涉及局部应用基于纳米颗粒（NP）的选择性视黄酸核受体γ（RARγ）激动剂药物的控释制剂。当将负载RARγ激动剂的纳米颗粒植入幼年C57BL/6J小鼠胫骨近端生长板的内侧和外侧附近时，生长板发生退化和闭合。与植入无药物对照纳米颗粒的对侧相比，胫骨整体长度缩短。重要的是，当仅在外侧植入RARγ激动剂纳米颗粒时，相邻的骨骺向外侧倾斜，导致胫骨顶端成角。与这些反应的局部选择性相反，全身给予RARγ激动剂会导致多个部位的生长板闭合，随着时间的推移抑制骨骼生长。RARα和RARβ激动剂在平行方案中未引起明显反应。我们的研究结果提供了新的证据，表明负载RARγ激动剂的纳米颗粒可以控制靶向生长板的活性、功能和方向性，为手术矫正肢体长度差异和角畸形提供了一种潜在的、与临床相关的替代方法或补充方法。
