Jepsen Karl J, Hu Bin, Tommasini Steven M, Courtland Hayden-William, Price Christopher, Cordova Matthew, Nadeau Joseph H
Leni and Peter W. May Department of Orthopaedics, Mount Sinai School of Medicine, New York, NY 10029, USA.
Mamm Genome. 2009 Jan;20(1):21-33. doi: 10.1007/s00335-008-9158-1. Epub 2008 Dec 5.
Compensatory interactions among adult skeletal traits are critical for establishing strength but complicate the search for fracture susceptibility genes by allowing many genetic variants to exist in a population without loss of function. A better understanding of how these interactions arise during growth will provide new insight into genotype-phenotype relationships and the biological controls that establish skeletal strength. We tested the hypothesis that genetic variants affecting growth in width relative to growth in length (slenderness) are coordinated with movement of the inner bone surface and matrix mineralization to match stiffness with weight-bearing loads during postnatal growth. Midshaft femoral morphology and tissue-mineral density were quantified at ages of 1 day and at 4, 8, and 16 weeks for a panel of 20 female AXB/BXA recombinant inbred mouse strains. Path Analyses revealed significant compensatory interactions among outer-surface expansion rate, inner-surface expansion rate, and tissue-mineral density during postnatal growth, indicating that genetic variants affecting bone slenderness were buffered mechanically by the precise regulation of bone surface movements and matrix mineralization. Importantly, the covariation between morphology and mineralization resulted from a heritable constraint limiting the amount of tissue that could be used to construct a functional femur. The functional interactions during growth explained 56-99% of the variability in adult traits and mechanical properties. These functional interactions provide quantitative expectations of how genetic or environmental variants affecting one trait should be compensated by changes in other traits. Variants that impair this process or that cannot be fully compensated are expected to alter skeletal growth leading to underdesigned (weak) or overdesigned (bulky) structures.
成年骨骼特征之间的代偿性相互作用对于建立骨骼强度至关重要，但由于许多基因变异在群体中存在却不丧失功能，这使得寻找骨折易感性基因变得复杂。更好地理解这些相互作用在生长过程中是如何产生的，将为基因型 - 表型关系以及建立骨骼强度的生物学控制提供新的见解。我们检验了这样一个假设：影响宽度相对于长度生长（细长比）的基因变异与骨内表面移动和基质矿化相协调，以在出生后生长过程中使骨骼硬度与负重负荷相匹配。对一组20只雌性AXB/BXA重组近交系小鼠，在出生1天以及4周、8周和16周龄时对股骨干中段形态和组织矿物质密度进行了量化。路径分析显示，出生后生长过程中外表面扩展率、内表面扩展率和组织矿物质密度之间存在显著的代偿性相互作用，这表明影响骨骼细长比的基因变异通过骨表面移动和基质矿化的精确调节在机械上得到缓冲。重要的是，形态与矿化之间的协变源于一种遗传限制，该限制限制了可用于构建功能性股骨的组织量。生长过程中的功能相互作用解释了成年性状和力学性能变异的56 - 99%。这些功能相互作用提供了关于影响一个性状的基因或环境变异应如何由其他性状的变化进行代偿的定量预期。预计损害这一过程或无法得到充分代偿的变异会改变骨骼生长，导致结构设计不足（脆弱）或设计过度（粗壮）。
