Osteocytes, mechanosensing and Wnt signaling

Abstract

The majority of bone cell biology focuses on activity on the surface of the bone with little attention paid to the activity that occurs below the surface. However, with recent new discoveries, osteocytes, cells embedded within the mineralized matrix of bone, are becoming the target of intensive investigation. In this article, the distinctions between osteoblasts and their descendants, osteocytes, are reviewed. Osteoblasts are defined as cells that make bone matrix and osteocytes are thought to translate mechanical loading into biochemical signals that affect bone (re)modeling. Osteoblasts and osteocytes should have similarities as would be expected of cells of the same lineage, yet these cells also have distinct differences, particularly in their responses to mechanical loading and utilization of the various biochemical pathways to accomplish their respective functions. For example, the Wnt/ β-catenin signaling pathway is now recognized as an important regulator of bone mass and bone cell functions. This pathway is important in osteoblasts for differentiation, proliferation and the synthesis bone matrix, whereas osteocytes appear to use the Wnt/β-catenin pathway to transmit signals of mechanical loading to cells on the bone surface. New emerging evidence suggests that the Wnt/β-catenin pathway in osteocytes may be triggered by crosstalk with the prostaglandin pathway in response to loading which then leads to a decrease in expression of negative regulators of the pathway such as Sost and Dkk1. The study of osteocyte biology is becoming an intense area of research interest and this review will examine some of the recent findings that are reshaping our understanding of bone/bone cell biology. KeywordsOsteocytes; bone; Wnt/β-catenin signaling; Mechanosensation; Mechanical loading Osteocytes compose over 90-95% of all bone cells in the adult skeleton and are thought to respond to mechanical strain to send signals of resorption or formation (70). Osteocytes are usually regularly dispersed throughout the mineralized matrix especially in cortical bone. These cells are connected to each other and cells on the bone surface through dendritic processes that occupy tiny canals called canaliculi (For review see (17)). Not only do these cells communicate with each other and with cells on the bone surface but their dendritic processes are in contact with the bone marrow (59) giving them the potential to recruit osteoclast precursors to stimulate bone resorption (133)(12) and to regulate mesenchymal stem cell differentiation (48).

CXXC5 is a negative-feedback regulator of the Wnt/β-catenin pathway involved in osteoblast differentiation

“…Furthermore, DMP-1 expression levels were higher in the osteocytes of CXXC5 − / − mice (Supplementary Figure S3A, and Figures 3c and d). The number and length of osteocyte dendrites, which are essential for osteocytes to function as regulators of bone turnover and mechanosensors, 12 were also higher in CXXC5 − / − mice than in wild-type mice (Figures 3d-f, and Supplementary Figure S3B). Calcein double-labeling analyses 13 showed that bone formation by osteoblasts was accelerated in the femur of CXXC5 − / − mice (Figures 3g and h, and Supplementary Figures S3A and B).…”

Functional heterogeneity of osteocytes in FGF23 production: the possible involvement of DMP1 as a direct negative regulator

“…[1][2][3] This network guarantees the supply of nutrition to distant osteocytes and allows the transit of small molecules and minerals that originate from the extracellular fluid. Furthermore, it enables direct intercellular communication among osteocytes, thus establishing an osteocyte network.…”

Multiple functions of Osterix are required for bone growth and homeostasis in postnatal mice

“…It has been suggested that osteocytes are mediators of mechanical and hormonal stimulations to control the activity of both osteoblasts and osteoclasts (1). Osteocytes are regulators of mineralization and mineral homeostasis (2,3), and by controlling Sost expression also act as modulators of Wnt signaling (4).…”