Review
Regulation of cortical and trabecular bone mass by communication between osteoblasts, osteocytes and osteoclasts

https://doi.org/10.1016/j.abb.2014.05.015Get rights and content

Highlights

  • Bone remodelling involves communication between multiple cell types.

  • Osteoclasts stimulate adjacent osteoblasts in trabecular bone by a range of coupling factors.

  • Coupling factors from osteoclasts also stimulate osteoblast activity on periosteal surfaces.

  • RANKL provided by both early osteoblast lineage cells and osteocytes stimulate osteoclast formation.

  • IL-6 family cytokines regulate osteoblast activity differently on trabecular and periosteal bone.

Abstract

The size and strength of bone is determined by two fundamental processes. One process, bone remodelling, renews the skeleton throughout life. In this process existing bone is resorbed by osteoclasts and replaced, in the same location, by osteoblasts. The other process is bone modelling, where bone formation and resorption occur at different sites so that the shape of bone is changed. Recent data suggests that both remodelling and modelling are controlled by signals between the cells that carry out these two processes. Osteoclasts both resorb bone, and provide inhibitory and stimulatory signals, including cardiotrophin-1 and sphingosine-1-kinase, to the osteoblast lineage thereby regulating their differentiation and activity on both trabecular and cortical surfaces. In addition, the osteoblast lineage, including osteoblast progenitors, matrix-producing osteoblasts, bone lining cells, and matrix-embedded osteocytes, produce both inhibitory and stimulatory factors that stimulate osteoclast differentiation. We will discuss the roles of osteoblast- and osteocyte-derived RANKL, and paracrine, autocrine and endocrine factors, such as ephrinB2, the IL-6/gp130 family of cytokines, parathyroid hormone, and its related peptide, PTHrP. These factors not only stimulate RANKL production, but also stimulate osteoblast differentiation and activity. This review will focus on recent data, generated from pharmacological and genetic studies of mouse models and what these data reveal about these pathways at different stages of osteoblast differentiation and their impact on both bone remodelling and modelling in trabecular and cortical bone.

Introduction

The skeleton is constantly remodelled by repeated cycles of cellular activity occurring asynchronously throughout the skeleton in which tiny packets of bone are resorbed and then replaced. This process always occurs in the same sequence: bone resorption by osteoclasts followed by bone matrix production by osteoblasts. This is the fundamental process by which the skeleton changes in response to hormonal and mechanically-induced stresses.

In addition to this process, bone also adapts by the process of modelling; here bone formation and resorption do not occur in sequence at the same site. Modelling occurs during growth, and in response to mechanical loading; it can also be induced by pharmacological agents that promote bone formation without a requirement for prior resorption [1]. Modelling is also responsible for cortical expansion, where osteoblasts on the periosteal surface continue to form bone at the diaphysis of the long bones (Fig. 1). The mechanisms that determine why some bone surfaces remodel while others model are not known, but understanding the relationships between the cells involved in modelling and remodelling holds great potential for developing therapeutics that can restore bone strength in osteoporosis.

Originally, the basic multicellular unit (BMU)1 responsible for remodelling was thought to consist of two classes of specialized cells on the bone surface, osteoclasts and osteoblasts, which contribute to remodelling by bone resorption and formation, respectively. Although osteoclasts are derived from the hemopoietic lineage, and osteoblasts from the mesenchymal lineage, these cell types act in close apposition and regulate the function of the other lineage by appropriate production of both inhibitory and stimulatory factors [2], [3]. Over the past 50 years, this concept has been refined, and a number of regulatory factors have been identified, some of which we discuss below [4], [5], [6], [7]. The best understood example of this intercellular regulation is the production of both the osteoclast stimulus Receptor Activator of NFκB Ligand (RANKL) and its decoy receptor inhibitor osteoprotegerin (OPG) by cells of the osteoblast lineage [8]. It is therefore, the same cell lineage that both forms bone matrix and regulates osteoclast differentiation in response to paracrine and endocrine stimuli, including parathyroid hormone (PTH), 1,25-dihydroxyvitamin-D3 and cytokines [9], [10], [11]. The osteoblast lineage includes committed osteoblast precursors, matrix-producing osteoblasts, lining cells and matrix-embedded osteocytes; the major contributing cells to these two activities are unlikely to be at the same stage of differentiation within the lineage, and this concept is discussed below. Similarly, osteoclasts produce a range of “coupling factors”. This is achieved both by releasing factors from the bone matrix itself during the process of resorption, and by production of soluble, and possibly membrane bound, regulators of bone formation (for recent reviews see [4], [7], [12]).

Although the initial concept of remodelling focussed on the cells on the bone surface, we now understand that there are many other cellular contributors that regulate bone formation and resorption within the BMU. These include osteocytes, terminally differentiated osteoblast lineage cells that reside in an interconnected network that extends throughout the bone matrix, and multiple cell types in the marrow space (e.g., haemopoietic precursors, macrophages, T-cells, natural killer cells and adipocytes) [13]. Furthermore, different stages of osteoblast differentiation are now understood to play distinct roles in regulating the activities of osteoclasts [13], and each other [14]. This is particularly relevant for the initiation of the bone remodelling cycle, where osteocytes and osteoprogenitors produce the RANKL required for osteoclastogenesis [7].

The identification of a bone remodelling canopy that lifts from the bone surface when osteoclastic resorption initiates the remodelling cycle to enclose the BMU in an isolated environment is a concept that has been explored at length in human specimens by the Delaissé laboratory [15], [16]. This would provide a controlled locale in which osteoblast lineage cells, osteoclasts, and potentially other contributing marrow cells, may exchange factors and influence precursors provided by the associated vasculature. However, experimental interrogation of its contribution to the actions of specific coupling factors using genetically altered mouse models is limited because this anatomical structure has not been observed in the mouse, the model that has been used most extensively for defining the intercellular signalling pathways that modify bone remodelling.

Much work using genetically altered mice has focussed on the overall influence of these pathways on the internal trabecular network (Fig. 1), including the quantity of trabecular bone and the level of trabecular remodelling. However, major questions remain about the effects of the intercellular signalling pathways that regulate the cortical bone (Fig. 1), and cortical bone matrix quality and strength. Since it is now understood that intra-cortical remodelling and cortical bone loss are contributors to skeletal fragility [1], more attention is beginning to be paid to differences in effect of signalling pathways in cortical vs. trabecular bone. This review will focus on some notable intercellular pathways that control bone mass and bone strength in cortical and trabecular bone, as examples of a wider range of factors at play: osteoclast-derived coupling factors (cardiotrophin-1 and sphingosine-1-phosphate), osteoblast lineage-derived RANKL, IL-6 family cytokines, and ephrinB2.

Section snippets

Interpreting data on bone mass and remodelling in mouse models

Studies of bone strength, mass and remodelling in humans rely mainly on surrogate markers such as bone mineral density (BMD) and serum biochemical markers since biopsies are rarely obtained. The use of mouse models, particularly genetically altered mice, allows direct measurement of changes in bone mass, remodelling and strength when specific factors are removed from the body. Now that cell-specific deletion is possible, the contributions of individual cell types to bone mass can also be

Osteoclast-derived coupling factors in bone: roles in modelling and remodelling

The osteoclast lineage, including mature, resorbing osteoclasts and their precursors, provide coupling factors that match bone formation to the level of bone resorption [4], [7]. These include some released from the bone matrix during bone resorption, such as IGF-1 and TGFβ [29], [30], and an increasing number of factors secreted by both inactive and active osteoclasts, including cardiotrophin-1 [31], sphingosine-1-phosphate [32], BMP6 and Wnt10b [32], collagen triple helix repeat containing 1

EphrinB2:EphB4: osteoblast: osteoclast communication or an inter-osteoblast-lineage signal?

EphrinB2 is a membrane-bound receptor tyrosine kinase that, in bone, is expressed at all stages of osteoblast differentiation and in osteoclasts [64], [65]. To induce signalling above baseline levels of phosphorylation, EphrinB2 must interact with a membrane bound receptor, such as EphB4, which is expressed by the osteoblast lineage, but not by osteoclasts [64], [65]. Two distinct features of membrane-bound Ephs and ephrins are: (1) their requirement for direct cell-to-cell interaction, and (2)

What are the respective roles of preosteoblast- and osteocyte-derived RANKL?

Inhibition of the ephrinB2:EphB4 interaction in vivo and in vitro also promoted RANKL mRNA levels in cultured osteoblast lineage cells, and enhanced their support of osteoclast formation [65], [71], [72]. Consistent with this finding, in the context of fracture healing, EphB4 overexpression in the osteoblast lineage was associated with a lower number of osteoclasts at the fracture site [73]. The greater number of early-stage osteoblasts and increased support of osteoclast differentiation in

Are signals to osteoclasts maintained when osteoblasts or osteocytes are reduced?

If signals from the osteoblast are key to maintaining osteoclast numbers, what happens when osteoblasts are depleted? A number of genetic and pharmacological models provide clues. While some osteoblast-lineage specific deletions that lead to low osteoblast numbers, such as PTHrP [85], also cause low levels of osteoclasts, there are others, such as deletion of β-catenin, where osteoblast numbers are reduced and osteoclast formation is increased [86]. There are still other instances where

Role of osteocytic IL-6 family cytokines in trabecular and cortical bone

Another example of low bone formation in the presence of normal osteoclastogenesis is mice in which gp130, the IL-6 cytokine family transducing receptor subunit, was specifically deleted in the osteoblast lineage [82]. The IL-6 family is a large family of cytokines, including IL-6, interleukin 11 (IL-11), leukemia inhibitory factor (LIF), cardiotrophin-1 (CT-1) and oncostatin M (OSM). Each of these cytokines acts by forming a complex that includes a common transmembrane receptor subunit,

Concluding comments

In conclusion, the field has advanced to the point that we are now beginning to have a better appreciation of the key intercellular signals that control bone formation and resorption both in the context of bone remodelling and modelling. Since the 1950s, our view of the BMU has extended beyond the immediate interactions of cells on the surface of bone. Osteoclasts are still understood to produce coupling factors that stimulate remodelling on trabecular surfaces; it now seems that they can also

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