Review article
Cell-specific paracrine actions of IL-6 family cytokines from bone, marrow and muscle that control bone formation and resorption

https://doi.org/10.1016/j.biocel.2016.08.003Get rights and content

Abstract

Bone renews itself and changes shape throughout life to account for the changing needs of the body; this requires co-ordinated activities of bone resorbing cells (osteoclasts), bone forming cells (osteoblasts) and bone’s internal cellular network (osteocytes). This review focuses on paracrine signaling by the IL-6 family of cytokines between bone cells, bone marrow, and skeletal muscle in normal physiology and in pathological states where their levels may be locally or systemically elevated. These functions include the support of osteoclast formation by osteoblast lineage cells in response to interleukin 6 (IL-6), interleukin 11 (IL-11), oncostatin M (OSM) and cardiotrophin 1 (CT-1). In addition it will discuss how bone-resorbing osteoclasts promote osteoblast activity by secreting CT-1, which acts as a “coupling factor” on osteocytes, osteoblasts, and their precursors to promote bone formation. OSM, produced by osteoblast lineage cells and macrophages, stimulates bone formation via osteocytes. IL-6 family cytokines also mediate actions of other bone formation stimuli like parathyroid hormone (PTH) and mechanical loading. CT-1, OSM and LIF suppress marrow adipogenesis by shifting commitment of pluripotent precursors towards osteoblast differentiation. Ciliary neurotrophic factor (CNTF) is released as a myokine from skeletal muscle and suppresses osteoblast differentiation and bone formation on the periosteum (outer bone surface in apposition to muscle). Finally, IL-6 acts directly on marrow-derived osteoclasts to stimulate release of “osteotransmitters” that act through the cortical osteocyte network to stimulate bone formation on the periosteum. Each will be discussed as illustrations of how the extended family of IL-6 cytokines acts within the skeleton in physiology and may be altered in pathological conditions or by targeted therapies.

Introduction

Bone structure is determined and maintained by co-ordinated activities of two key cell types: osteoblasts (bone forming cells), and osteoblasts (bone resorbing cells). In the adult, once the size and shape of the skeleton is established, bone tissue is continually renewed and adapted to physiological stresses by a process termed remodelling. In this process, the amount of bone removed by the osteoclast must be matched to that formed by the osteoblast for bone structure and strength to be maintained. In osteoporosis, including secondary osteoporosis associated with inflammatory conditions where cytokine levels are elevated, the activity of osteoclasts outstrips that of osteoblasts, leading to bone loss; similar mechanisms exist at sites of local inflammation and local bone destruction, for example in rheumatoid arthritis.

It was through the study of bone-resorbing osteoclasts that a role of Interleukin 6 (IL-6) family cytokines in the skeleton was first discovered (Tamura et al., 1993). Indeed IL-6 was one of the first factors identified that stimulates osteoclast formation not by directly stimulating haematopoietic osteoclast precursors, but by promoting the ability of mesenchymal osteoblast lineage cells to support osteoclastogenesis in a contact-dependent manner. This RANKL-dependent communication pathway that intimately links osteoblasts to osteoclasts is now central to our understanding of the way that skeletal structure is controlled and an established mechanism by which osteoporosis is treated (Ominsky et al., 2011).

In recent years it has become clear that IL-6 and its related family of cytokines have multiple roles that regulate not only bone resorption, but also bone formation in health and disease, by virtue of their expression in normal physiology, and their elevated levels in pathologies. This review will describe a number of key intercellular pathways through which cell-specific production of IL-6 family cytokines regulate skeletal structure with a focus on the roles identified in studies of genetically altered mice.

Section snippets

The IL-6 family

The IL-6 family of cytokines is defined by their common use of the glycoprotein 130 (gp130) co-receptor, a ubiquitously expressed transmembrane receptor subunit capable of intracellular signalling. The most widely studied members of the family are IL-6, interleukin 11 (IL-11), leukemia inhibitory factor (LIF), cardiotrophin-1 (CT-1), oncostatin M (OSM) and ciliary neurotrophic factor (CNTF). Each cytokine that binds to gp130 generates specific intracellular JAK/STAT or Erk signalling cascades

Intercellular communication in bone growth and remodelling

During bone growth, shape change results from bone being deposited on surfaces where it is needed and removed from areas where it is no longer needed; in this process, termed “bone modelling”, osteoblasts and osteoclasts act on different bone surfaces (Fig. 2). Even though they are separated by both time and place, there appears to be some co-ordination between these processes, possibly by factors recently termed “osteotransmitters” (Johnson et al., 2015) or by changing mechanical needs sensed

The roles of IL-6 family members in promoting bone resorption

All IL-6 family cytokines, apart from the CNTFR-binding subfamily, stimulate osteoclast formation in cell culture, through an action that requires the presence of osteoblasts (McGregor et al., 2010, Richards et al., 2000, Tamura et al., 1993, Udagawa et al., 1995). It is for this reason that the IL-6 family, particularly IL-6 itself, has been proposed to contribute to both localised and systemic osteoclast-mediated bone destruction associated with Paget’s disease (Roodman et al., 1992),

The roles of IL-6 family members in promoting bone formation

Although IL-6 family cytokines are best known for stimulating osteoclastogenesis, there is a parallel body of literature that has shown that IL-6 family cytokines also stimulate bone formation. In the late 1980s, overexpression of LIF in vivo was shown to increase trabecular bone mass (Metcalf and Gearing, 1989), and local injection of LIF stimulated bone formation in vivo (Cornish et al., 1993). Later studies in vitro showed that LIF, IL-6, OSM and IL-11 could act directly on osteoblasts,

IL-6 family cytokines maintain bone material strength

In contrast to their to low trabecular bone mass, Osx1Cre.gp130f/f and Dmp1Cre.gp130f/f mice exhibited a greater cortical bone diameter than their respective controls (Johnson et al., 2014a). This increase in periosteal circumference was in direct opposition to the slimmer cortices observed in global knockouts for IL-6, IL-11R, CT-1 and OSMR (Sims et al., 2005, Walker et al., 2008, Walker et al., 2010). Although cortical expansion has not been a focus of skeletal research in genetically altered

CNTF: an IL-6 family myokine that suppresses bone formation?

Skeletal muscle secretes several members of the IL-6 cytokine family including leukemia inhibitory factor (LIF) (Hunt et al., 2010, Hunt et al., 2013), IL-6 (Hiscock et al., 2004), and OSM (Hojman et al., 2011). These factors are now recognised as myokines (muscle-derived cytokines) that influence local muscle cell homeostasis (Hunt and White, 2016) and enter the circulation as endocrine factors with effects on liver, adipose tissue, the immune system, cancer growth and pancreas function (

What is the direct influence of the IL-6 family on osteoclasts?

While OSMR and LIFR have not been detected in osteoclasts (Allan et al., 1990, Walker et al., 2010) precluding any direct action of OSM, CT-1, LIF or the CNTFR-associated subfamily, mature osteoclasts have the capacity to respond to IL-6 and IL-11, since IL-6R, IL-11R and gp130 itself have been identified in mature osteoclasts (Gao et al., 1998, Romas et al., 1996). IL-11 appeared to have no direct effect on osteoclast activity or survival (McCoy et al., 2013) in vitro and there was no

Conclusions

In summary, IL-6/gp130 family cytokines have a wide range of influences in the skeleton that are cell-specific, site-specific and in some instances, sex-specific. These have provided new insights into the paracrine mechanisms used by the cells of bone (osteoblasts, osteoclasts and osteocytes) as well as cells in the bone microenvironment (macrophages, bone marrow and muscle). There is much about these actions that remains to be defined, and their existence indicates that systemic therapies,

Acknowledgements

N.A.S. is supported by an NHMRC (Australia) Senior Research Fellowship. Work is also supported in part by the Victorian State Government Operational Infrastructure Support Program.

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