Review
Molecular mechanisms of inflammatory bone damage: emerging targets for therapy

https://doi.org/10.1016/j.molmed.2008.04.001Get rights and content

Chronic inflammatory bone diseases, such as rheumatoid arthritis (RA), ankylosing spondylitis and periodontal disease, demonstrate the major impact of chronic inflammation on both bone metabolism and bone architecture. During the past decade, scientists have gained increasing insight into the link between inflammation and bone. As a result of new discoveries about the molecular mechanisms of inflammatory bone loss, several molecules have been identified that are attractive and novel targets for the treatment of inflammatory bone loss. These novel therapeutic approaches include anti-tumor necrosis factor (TNF)-α blocking agents, neutralizing antibodies against certain pro-inflammatory cytokines, such as interleukin (IL)-6 and IL-17, and a set of other promising targets that still require extensive research, such as the Wnt signaling network.

Introduction

Rheumatoid arthritis (RA) belongs to the group of chronic inflammatory diseases that are characterized by profound bone loss. A hallmark of this disease is the destruction of periarticular bone, which leads to bone erosion and functional disability [1]. Osteoclast formation is an essential step in inflammatory bone erosion, and it appears that the tight balance between bone resorption and bone formation is disturbed in RA and other systemic chronic inflammatory diseases 2, 3, 4. Osteoclast formation is enhanced in RA and not balanced by increased activity of bone-forming osteoblasts. This unfavorable balance of bone resorption and bone formation is the basis for rapid bone loss in the joints of arthritic patients, which breaks down the physiological joint architecture and adds to the characteristic clinical picture of RA.

Moreover, patients suffering from RA and other chronic inflammatory diseases, such as inflammatory bowel disease, develop progressive systemic bone loss. The consequences of this imbalance between bone resorption and bone formation include both joint destruction on the one hand and an increased fracture risk on the other hand, both of which are major causes of functional disability in RA patients 1, 5. Inflammatory diseases demonstrate the dramatic impact of inflammation on bone metabolism and bone architecture, resulting in local and systemic changes of bone density and architecture. Accordingly, this link between inflammation and bone has achieved increasing attention over the past decade. Growing research on the molecular mechanisms involved in inflammation-induced changes in bone metabolism has revealed a set of molecular targets with the potential to stop inflammatory bone destruction.

A promising approach toward diminishing enhanced bone resorption during inflammation is the inhibition of osteoclast formation. Normal physiological circumstances ensure a balance between bone formation and bone resorption to maintain skeletal homeostasis. This process, called bone remodeling is mediated through the tightly coordinated interaction of osteoclasts and osteoblasts. Osteoclasts are multinucleated cells that are unique in their ability to resorb bone. They originate from hematopoietic mononuclear precursor cells, which, upon the influence of specific signals, undergo a series of differentiation steps to become mature osteoclasts. Essential signals for osteoclast differentiation are macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor-κB ligand (RANKL). During this differentiation and maturation process, osteoclasts acquire specific markers such as tartrate-resistant acid phosphatase (TRAP), fuse to multinucleated giant cells and polarize upon contact with bone [6]. Osteoclastogenesis is dependent on an adequate microenvironment, which provides essential signals such as M-CSF and RANKL and also certain cytokines, which further enhance osteoclast differentiation. Mesenchymal cells, such as pre-osteoblasts, express M-CSF and RANKL and can induce osteoclast formation, indicating the close interaction between bone formation and bone resorption [7]. Osteoblasts are cells of mesenchymal origin that are responsible for bone formation, which they achieve by secreting bone matrix proteins and promoting mineralization. Several factors, such as Osterix (also known as SP7), control the differentiation and proliferation of osteoblasts. Differentiated osteoblasts embedded in the bone matrix are called osteocytes, and they probably have an important function within bone as mechanosensors: that is, they initiate bone remodeling [8].

In the course of different inflammatory diseases, such as RA, psoriatic arthritis and periodontal disease, a confined set of common inflammatory pathways triggers the process of local bone destruction. Since the early 1970s, accumulating evidence has indicated that the immune and the skeletal system share several regulatory factors, such as cytokines, transcription factors and receptors. Furthermore, immune cells and osteoclasts are derived from the same hematopoietic precursor cells and, moreover, hematopoietic stem cells survive in the bone marrow, where they interact with bone cells. Therefore, there is compelling evidence that these two systems influence each another both under physiological and pathological circumstances. The most impressive example is the prolonged and enhanced activation of the immune system in autoimmune diseases such as RA; activation that leads to massive bone destruction caused by the generation of bone resorbing osteoclasts.

During inflammation, the balance between bone formation and bone resorption is disturbed in favor of osteoclast-mediated bone resorption [9]. Mice with defective osteoclast differentiation, such as mice lacking transcription factors (e.g. c-Fos) that are crucial for osteoclastogenesis, develop an inflammatory arthritis that is not associated with bone erosions [3]. In inflammatory arthritis, osteoclasts form the interface between the inflamed synovium and bone, where they mediate the resorption of calcified tissue (Figure 1). Bone resorption depends on the influx of osteoclast precursor cells (OCPs) into the inflamed tissue and their differentiation into mature osteoclasts. Both processes, which are accelerated during an inflammatory reaction, are controlled via a cytokine signaling network formed among cells of the osteoclast lineage, mesenchymal cells and immune cells [5] (Figure 2). The major factor responsible for osteoclast differentiation is the RANK–RANKL system [10]. However, inflammation does not only affect the process of bone resorption, but also disturbs the process of bone formation. Recent evidence has highlighted the impact of inflammation on the Wnt signaling network, which is a major factor during the regulation of osteoblast differentiation and, consequently, the formation of new bone [11]. This review article will focus on the mechanisms of local inflammatory bone loss and highlight new therapeutic strategies for protecting patients from these lesions.

Section snippets

RANKL

The identification of the RANKL–RANK–osteoprotegerin (OPG) system provided a major breakthrough in understanding bone biology. Disruption of the RANKL–RANK–OPG axis leads to an imbalance between bone resorption and bone formation and is responsible for a disturbed bone homeostasis. RANKL, a tumor necrosis factor (TNF) super-family member, is a surface molecule expressed by a large set of different cell types, including activated T cells. Under steady-state conditions, its expression is induced

TNF-α

Inflammatory processes are governed by a complex and hierarchical network of cytokines and chemokines. During the inflammatory response, a whole set of cytokines, such as TNF-α, IL-1, IL-6 and IL-17, is involved in the recruitment, differentiation and activation of osteoclasts (Figure 3). Moreover, cytokines affect the differentiation and function of osteoblasts, thereby influencing the delicate balance between bone formation and bone resorption [36]. A first decisive step during the

Other cytokines

The pro-inflammatory mediator IL-1β is induced by TNF-α and is crucial for the induction of matrix enzyme expression in the synovium, as well as osteoclast formation. Thus, IL-1β induces RANKL expression and thereby promotes osteoclastogenesis. Furthermore, IL-1β is crucial for TNF-α-induced osteoclast development [44]. Although IL-1β appears to be a promising target for blocking bone and cartilage destruction, the anti-inflammatory properties of the recombinant IL-1 receptor antagonist

Wnt signaling

Inflammatory cytokines do not only promote osteoclastogenesis, but also dampen the development of osteoblasts, thereby inhibiting the formation of new bone. One key component is the Wnt-signaling inhibitor Dickkopf 1 (DKK1), which is induced by TNF-α and inhibits bone and cartilage formation [52]. The Wnt/β-catenin signaling pathway is involved in the regulation of diverse and complex processes, such as limb development in Drosophila[53]. Importantly, Wnt proteins also influence bone

Bisphosphonates

Osteoclasts, as the main mediators of inflammatory bone damage, are targeted by the bisphosphonate (Bp) family of drugs, which are widely used in the treatment of different forms of bone loss, including osteoporosis and tumor-associated osteolysis.

Bps are synthetic, non-hydrolyzable analogues of inorganic pyrophosphates. Their specific phosphate-carbon-phosphate structure allows the divalent binding of metal ions such as Ca2+; therefore, Bps are able to bind to mineralized bone surfaces in a

Conclusions

Chronic inflammatory joint diseases such as RA are characterized by systemic and local bone loss. The clinical picture is a composite of inflammatory lesions and structural damage, demonstrating the tight interaction between the immune and the skeletal system. Scientists’ growing knowledge of the cellular and humoral mechanisms involved in alterations of bone metabolism during chronic inflammatory disorders has revealed multiple targets for therapeutic interventions to suppress the

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