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

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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.