Translational Research Program in Pediatric Orthopaedics, Division of Orthopaedic Surgery, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Department of Orthopaedic Surgery, School of Medicine, University of Maryland, Baltimore, MD, USA.
J Bone Miner Res. 2021 Jul;36(7):1387-1402. doi: 10.1002/jbmr.4291. Epub 2021 Apr 20.
The growth plates are key engines of skeletal development and growth and contain a top reserve zone followed by maturation zones of proliferating, prehypertrophic, and hypertrophic/mineralizing chondrocytes. Trauma or drug treatment of certain disorders can derange the growth plates and cause accelerated maturation and premature closure, one example being anti-hedgehog drugs such as LDE225 (Sonidegib) used against pediatric brain malignancies. Here we tested whether such acceleration and closure in LDE225-treated mice could be prevented by co-administration of a selective retinoid antagonist, based on previous studies showing that retinoid antagonists can slow down chondrocyte maturation rates. Treatment of juvenile mice with an experimental dose of LDE225 for 2 days (100 mg/kg by gavage) initially caused a significant shortening of long bone growth plates, with concomitant decreases in chondrocyte proliferation; expression of Indian hedgehog, Sox9, and other key genes; and surprisingly, the number of reserve progenitors. Growth plate involution followed with time, leading to impaired long bone lengthening. Mechanistically, LDE225 treatment markedly decreased the expression of retinoid catabolic enzyme Cyp26b1 within growth plate, whereas it increased and broadened the expression of retinoid synthesizing enzyme Raldh3, thus subverting normal homeostatic retinoid circuitries and in turn accelerating maturation and closure. All such severe skeletal and molecular changes were prevented when LDE-treated mice were co-administered the selective retinoid antagonist CD2665 (1.5 mg/kg/d), a drug targeting retinoid acid receptor γ, which is most abundantly expressed in growth plate. When given alone, CD2665 elicited the expected maturation delay and growth plate expansion. In vitro data showed that LDE225 acted directly to dampen chondrogenic phenotypic expression, a response fully reversed by CD2665 co-treatment. In sum, our proof-of-principle data indicate that drug-induced premature growth plate closures can be prevented or delayed by targeting a separate phenotypic regulatory mechanism in chondrocytes. The translation applicability of the findings remains to be studied. © 2021 American Society for Bone and Mineral Research (ASBMR).
生长板是骨骼发育和生长的关键引擎，包含一个顶端储备区，然后是增殖、预肥大和肥大/矿化软骨细胞的成熟区。某些疾病的创伤或药物治疗会扰乱生长板，导致加速成熟和过早闭合，一个例子是抗 Hedgehog 药物，如用于治疗小儿脑癌的 LDE225（索奈得吉）。在这里，我们基于先前的研究表明，视黄酸拮抗剂可以减缓软骨细胞成熟率，测试了在 LDE225 处理的小鼠中，通过共同给予选择性视黄酸拮抗剂是否可以预防这种加速和闭合。用实验剂量的 LDE225（灌胃 100mg/kg）处理幼年小鼠 2 天，最初导致长骨生长板显著缩短，同时伴随着软骨细胞增殖减少；印度 Hedgehog、Sox9 和其他关键基因的表达；以及令人惊讶的是，储备祖细胞的数量。随着时间的推移，生长板逐渐退化，导致长骨生长不良。从机制上讲，LDE225 处理显著降低了生长板内视黄酸分解酶 Cyp26b1 的表达，而增加并扩大了视黄酸合成酶 Raldh3 的表达，从而破坏了正常的内稳态视黄酸循环，并反过来加速了成熟和闭合。当用 LDE 处理的小鼠同时给予选择性视黄酸拮抗剂 CD2665（1.5mg/kg/d）时，所有这些严重的骨骼和分子变化都得到了预防，CD2665 是一种针对视黄酸受体 γ 的药物，视黄酸受体 γ 在生长板中表达最丰富。当单独给予时，CD2665 会引起预期的成熟延迟和生长板扩张。体外数据表明，LDE225 直接作用于抑制软骨细胞的表型表达，这种反应完全被 CD2665 共同处理所逆转。总之，我们的原理验证数据表明，通过靶向软骨细胞中独立的表型调节机制，可以预防或延迟药物诱导的生长板过早闭合。这些发现的转化适用性仍有待研究。
