This down-regulation allows Lrp5 to be instead bound by Wnts, which may already be present or may have been up-regulated by the mechanical loading [107], and the result is activation of the Wnt/β-catenin signaling pathway. The reports at the beginning of the last decade demonstrating that mutations in LRP5 are causally associated with changes in human bone mass stimulated extensive research into understanding the underlying mechanisms. This work demonstrated that components of this pathway, including LRP5, are required for osteocytes to Fluorouracil ic50 respond to mechanical load. In addition, regulation of secretion of the Wnt inhibitor, SOST, from osteocytes

plays a key role in coordinating the response to these mechanical signals. However, there are several outstanding questions remaining to be addressed. For example, what is the mechanism by which LRP5 is activated via mechanical loading? Does this involve a Wnt ligand? If so, which one(s)?

Answers to these questions will further inform the development of therapies based on activating this pathway to treat osteoporosis and other bone diseases. buy JQ1 The authors thank David Nadziejka for technical editing of the manuscript and Michaela Kneissel for comments. Work in the Williams Laboratory is supported by National Institutes of Health grant AR053293 (BOW) and by Van Andel Research Institute. The authors declare that they have no conflicts of interest. “
“Osteocytes represent the terminally differentiated state of the osteoblast lineage and are embedded within the mineralized bone matrix. Because they are trapped within a mineralized “prison”, osteocytes are not easily accessible and therefore our understanding of their role in bone remodeling remains incomplete. Advanced imaging techniques (ex vivo and in vivo) and

the exploitation of in vivo models to extract Thiamet G quantitative biochemical information are tools which are beginning to provide more clues about both the anatomy and biology of osteocytes, respectively. Synthesis of these data will therefore greatly facilitate a more complete understanding of the osteocyte’s function. Ex vivo imaging of osteocytes has proved challenging due to the need to develop methodologies for imaging and sectioning of undecalcified specimens or to develop protocols for decalcifying specimens to enable conventional sectioning and imaging techniques to be used. Early imaging approaches relied mainly on staining of the lacuno-canalicular network (LCN) rather than the osteocyte itself using histological stains combined with conventional light microscopy. With the advent of confocal imaging approaches it has become relatively straightforward to image osteocytes and their lacuno-canalicular system three-dimensionally (3D) in situ within their bone environment.