Ciliary IFT88 Protects Coordinated Adolescent Growth Plate Ossification From Disruptive Physiological Mechanical Forces.
Ciliary IFT88 Protects Coordinated Adolescent Growth Plate Ossification From Disruptive Physiological Mechanical Forces.
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DOI：
10.1002/jbmr.4502
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发表时间：
2022-06
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与我们对软骨内成骨的理解相比，我们对软骨生长板狭窄和融合所定义的生长的协调性停止知之甚少。在整个肌肉骨骼系统中，适当的细胞和组织对机械力的反应描绘了形态发生并确保了终身健康。目前还不清楚机械信号是如何整合到许多生物程序中，包括那些在生长停止时协调青春期生长板骨化的生物程序。初级纤毛是基于微管的细胞器，调节一系列细胞活动，包括由细胞外生物物理信号激活或调节的信号级联。纤毛被认为可以直接促进细胞的机械转导。为了探索初级纤毛对小鼠青春期肢体的影响，我们使用软骨特异性、可诱导的Cre （agrecancreert2 Ift88 fl/fl）有条件地靶向青少年和青少年骨骼中的纤毛基因腱束内运输蛋白88 （Ift88 fl/fl）。软骨中IFT88的缺失，减少了生长板的调节，破坏了软骨细胞分化、软骨吸收和矿化。这些影响主要局限于膝关节承重隔室下方的胫骨外周区域。这些区域的典型特征是肥大软骨细胞数量增加。虽然维持了正常的hedgehog信号传导模式，但靶向IFT88抑制了增生性软骨细胞VEGF表达、下游血管募集、破骨活性和软骨置换。在对照小鼠中，生理负荷的增加也会损害外周生长板的骨化，类似于IFT88缺失的影响。在Ift88cKO小鼠中，肢体固定抑制VEGF表达和骨骺形态的变化，表明在青春期生长板中IFT88的消耗是机械依赖的。我们认为，在青少年骨骼成熟的关键阶段，纤毛IFT88保护生长板均匀、协调的骨化，免受生理机械力的破坏性异质性的影响。©2022作者。由Wiley期刊有限责任公司代表美国骨与矿物研究协会（ASBMR）出版的骨与矿物研究杂志。
Compared with our understanding of endochondral ossification, much less is known about the coordinated arrest of growth defined by the narrowing and fusion of the cartilaginous growth plate. Throughout the musculoskeletal system, appropriate cell and tissue responses to mechanical force delineate morphogenesis and ensure lifelong health. It remains unclear how mechanical cues are integrated into many biological programs, including those coordinating the ossification of the adolescent growth plate at the cessation of growth. Primary cilia are microtubule‐based organelles tuning a range of cell activities, including signaling cascades activated or modulated by extracellular biophysical cues. Cilia have been proposed to directly facilitate cell mechanotransduction. To explore the influence of primary cilia in the mouse adolescent limb, we conditionally targeted the ciliary gene Intraflagellar transport protein 88 (Ift88 fl/fl ) in the juvenile and adolescent skeleton using a cartilage‐specific, inducible Cre (AggrecanCreERT2 Ift88 fl/fl ). Deletion of IFT88 in cartilage, which reduced ciliation in the growth plate, disrupted chondrocyte differentiation, cartilage resorption, and mineralization. These effects were largely restricted to peripheral tibial regions beneath the load‐bearing compartments of the knee. These regions were typified by an enlarged population of hypertrophic chondrocytes. Although normal patterns of hedgehog signaling were maintained, targeting IFT88 inhibited hypertrophic chondrocyte VEGF expression and downstream vascular recruitment, osteoclastic activity, and the replacement of cartilage with bone. In control mice, increases to physiological loading also impair ossification in the peripheral growth plate, mimicking the effects of IFT88 deletion. Limb immobilization inhibited changes to VEGF expression and epiphyseal morphology in Ift88cKO mice, indicating the effects of depletion of IFT88 in the adolescent growth plate are mechano‐dependent. We propose that during this pivotal phase in adolescent skeletal maturation, ciliary IFT88 protects uniform, coordinated ossification of the growth plate from an otherwise disruptive heterogeneity of physiological mechanical forces. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
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