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

这种材料骨是一种常见的普遍存在的组织，构成了大多数脊椎动物的骨骼。这种复杂且层次分明的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)和骨骼的自我修复和更新能力(重塑)。骨细胞是骨中最丰富的细胞，存在于骨基质中，在骨生物学中发挥着关键作用，既是机械应变传感器，又是建模和重塑的调节器。因此，令人惊讶的是，在所有脊椎动物中占很大比例的进化最高级的鱼类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，可以合理地假设，高级硬骨鱼骨骼中骨细胞的丧失是由于某些功能优势所致。与所有其他脊椎动物的骨骼相似，鱼骨提供保护和承重，并充当肌肉锚和杠杆。因此，它们在长时间内反复加载，因此肯定也会积累损害，需要建模和重新建模。尽管缺乏骨细胞，但这是如何实现的还不清楚。显然，揭开高级硬骨鱼骨细胞丧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骨骼结构-功能关系的更广泛背景。我们假设高级硬骨鱼(青鱼)中的无骨细胞骨和基底硬骨鱼(斑马鱼)中的骨细胞骨具有不同的细胞和分子机制，它们对负荷做出反应。一个显著的区别可能是在无骨细胞骨骼中没有硬化素，或者它来自不同的细胞类型。我们还认为，骨细胞性和无骨细胞性骨在结构上是不同的，因此它们的机械性能也不同。我们预计，了解这些差异将有助于揭开骨生物学的基本问题和尚未解决的问题。我们认为，当前提案中概述的研究对于理解骨调节和适应的基本机制是必不可少的。

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.