The effects of mechanical loading on the material properties, structure and SOST expression/sclerostin levels in cellular and acellular bone

材料骨是一种常见的普遍存在的组织，形成大多数脊椎动物的骨骼。这种复杂和分层材料的两个特点是其适应不断变化的机械载荷的能力（所谓的建模）和骨骼自我修复和更新（重塑）的能力。骨细胞是骨组织中最丰富的细胞，存在于骨基质中，在骨生物学中起着重要作用，是骨组织的力学应变传感器，也是骨组织建模和重建的调节者。因此，令人惊讶的是，大多数进化先进的鱼类（占所有脊椎动物的很大一部分）的骨骼完全缺乏这些细胞。值得注意的是，进化上原始的“基底鱼”确实有骨细胞，这意味着骨细胞在进化过程中丢失了。因此，我们有理由认为，晚期硬骨鱼骨骼中骨细胞的丧失是由于某些功能优势造成的。鱼骨，类似于所有其他脊椎动物的骨头，提供保护和承重，并作为肌肉锚和杠杆。因此，它们在很长一段时间内反复加载，因此肯定也会积累损坏，需要建模和改造。尽管缺乏骨细胞，但这是如何实现的尚不清楚。显然，解开高级硬骨鱼骨细胞丢失背后的原因是一个重大挑战，超出了本提案的范围。尽管如此，探索从这个谜团中产生的重要问题将有助于我们理解更广泛的骨结构-功能关系。我们假设，在先进的硬骨鱼（青）和骨细胞骨在基础硬骨鱼（斑马鱼）有不同的细胞和分子机制，它们响应负载。一个突出的区别可能是在anosteocytic骨中没有sclerostin，或者它来自不同的细胞类型。我们还认为骨细胞和无骨细胞骨在结构上是不同的，因为它们的机械性能不同。我们希望了解这些差异将有助于解开基本的和尚未解决的骨生物学问题。我们认为，目前的建议中概述的研究是必不可少的了解骨调节和适应的基本机制。

The material bone is a common and ubiquitous tissue that forms the skeletons of most vertebrates. Two hallmarks of this complex and hierarchical material are its ability to adapt to changing mechanical loads (so-called modeling) and the capacity of bone for self-repair and renewal (remodeling). Osteocytes, the most abundant cells of bone, which reside within the bone matrix, are thought to play a key role in bone biology, acting as mechanical strain sensors as well as the regulators of modeling and remodeling. It is therefore surprising that the bones of most evolutionarily-advanced fish, which comprise a large portion of all vertebrates, entirely lack these cells. Remarkably, evolutionarily primitive 'basal fish' do have osteocytes, implying therefore that osteocytes were lost during evolution. It is therefore reasonable to assume that the loss of osteocytes in the bones of advanced teleosts resulted from some functional advantage. Fish bones, similar to the bones of all other vertebrates, provide protection and load-bearing and serve as muscle anchors and levers. They are therefore repeatedly loaded over long periods, and thus certainly also accumulate damage and need to model and remodel. How this is achieved, despite the lack of osteocytes, is not known.Clearly, unraveling the reasons behind the loss of osteocytes in advanced teleost fish is a major challenge, beyond the scope of this proposal. Nonetheless, exploring important questions that arise from this enigma will contribute to our understanding of the broader context of bone structure-function relationships. We hypothesize that anosteocytic bones in advanced teleosts (medaka) and osteocytic bones in basal teleosts (zebrafish) have different cellular and molecular mechanisms by which they respond to load. A prominent difference could be the absence of sclerostin in anosteocytic bones, or its origin from a different cell type. We also believe the osteocytic and anosteocytic bones are structurally different, as are their resulting mechanical properties. We expect that understanding these differences will help unravel fundamental and as yet unresolved questions of bone biology. We believe that the studies outlined in the current proposal are essential to understand fundamental mechanisms of bone regulation and adaptation.