Elsevier

Bone

Volume 42, Issue 4, April 2008, Pages 606-615
Bone

Review
Osteocytes, mechanosensing and Wnt signaling

https://doi.org/10.1016/j.bone.2007.12.224Get rights and content

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.

Introduction

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].

Section snippets

Osteocytes as coordinators of skeletal responses to mechanical loading

In the absence of loading, bone is lost and in the presence of loading, bone is either maintained or increased. The skeleton is unique in its ability to adaptively remodel in response to its perception of mechanical loading or lack of loading or disuse (reviewed in [21], [31], [18]). Adaptive remodeling is defined as the constant remodeling of the bone in order to resist and withstand average daily loads. The cells of bone with the potential for sensing mechanical strain and translating these

Role of the Wnt pathway in bone cell function

The Wnt signaling pathway was known to be important in the development and patterning of the skeleton since the early-mid 1990s when studies demonstrated that Wnt-3a mutations resulted in altered mouse axial development [42]. A few years later it was shown that the low-density lipoprotein receptor-related protein 6 (Lrp6) knockout (Lrp6−/−) mouse had developmental abnormalities that phenocopied many of the defects observed in mice carrying mutations in Wnt-3a, Wnt-1 or Wnt-7a genes [97].

In vitro models of mechanical strain

The parameters of in vivo mechanical loading of bone that results in bone formation and/or bone resorption are fairly well established [106], [107]. However, how this external loading signal in bone is transmitted at the cellular level is not well established and can be controversial. Clearly, the bone matrix is undergoing tissue deformation, but to what extent and how is not clear. It is also not clear whether this tissue deformation is transmitted to the osteocyte cell membrane through

Osteocytes are not osteoblasts

The differences between markers, morphology, and function of the polygonal matrix producing osteoblast and the embedded, dendritic osteocyte are dramatic, yet the practice of using osteoblast cell lines to represent osteocytes continues. The osteoblast is unlikely to be subjected to fluid flow shear stress in vivo and if so, the form and magnitude would be distinctly different from what occurs in the osteocyte lacuno-canalicular system. The osteoblast may be more likely to be subjected to

The role of Wnt signaling in response to load

The original analysis from studies of the High Bone Mass kindred suggested that affected family members had an inappropriate bone formation response to normal physiologic loads [55] as if the bone “mechanostat” [36] had been set differently. The HBM transgenic mice that carry the LRPG171V cDNA driven by the 3.6 kb Col1A1 promoter have been shown to recapitulate the phenotype observed in the skeleton of the affected members of the kindred [8] and interestingly it was noted that these mice had

Concluding comments

The study of osteocyte biology is rapidly becoming an important area of research in the bone field as more and more investigators appreciate the importance of this often overlooked bone cell. There are still many challenges to be overcome. The need to develop more “osteocyte-like” cell lines is clearly one hurdle that confronts this research. There is still much to be learned regarding how the osteocyte senses and transmits signals in response to or absence of loading and orchestrates the

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