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/beta-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/beta-catenin pathway to transmit signals of mechanical loading to cells on the bone surface. New emerging evidence suggests that the Wnt/beta-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.

Figure 1

A simplified diagram of the potential effects of tissue deformation on osteocytes. With the application of mechanical loading to the bone, bone matrix is deformed. Deformation of the bone matrix surrounding osteocytes could lead to the perturbation of bone fluid leading to shear stress. Alternatively or in combination with, tissue deformation could lead to perturbation of the cell membrane (whether the cell body or the dendritic processes) through tethering elements thought to be present in the glycocalyx. It is most likely that both contribute to mechanosensation and mechanotransduction.

Figure 2

Triggering and amplification of the Wnt/β-catenin pathway in osteocytes in response to load. Mechanical load applied to bone (ε) is perceived by the osteocyte through an unknown mechanism, although fluid flow induced through the lacunarcanalicular system may be a critical component of this perception, ‘step 1’. Perception of load (strain) triggers a number of intracellular responses including the release of PGE₂, ‘2’ through a poorly understood mechanism into the lacunar-canalicular fluid where it can act in an autocrine and/or paracrine fashion. Connexin-43 hemichannels (CX43 HC) in this PGE₂ and integrin proteins appear to be involved. Binding of PGE₂ to its EP2 and/or EP4 receptor, ‘3’, leads to a downstream inhibition of GSK-3β, ‘5’ (likely mediated by Akt, ‘4’) and the intracellular accumulation of free β-catenin, ‘6’. (Integrin activation can also lead to Akt activation and GSK-3β inhibition.) New evidence suggests that ER may participate in the nuclear translocation of β-catenin, ‘7’ which leads to changes in the expression of a number of key target genes ‘8’. One of the apparent consequences is the reduction in sclerostin and Dkk1,’9’ with increased expression of Wnt, ‘10’ (which one or ones is unknown). The net result of these changes is to create a permissive environment for the binding of Wnt to Lrp5-Fz and an amplification of the load signal, ‘11’. (See text for more details and references)