Osteoclastogenesis : The Immunity face unleashed ...

American Journal of Advances in Medical Science www.arnaca.com eISSN: 2347-2766 pISSN: 2454-9061

Review Article Osteoclastogenesis : The Immunity face unleashed Ranjith Raveendran*1 , Sameera G Nath2 1Department

Department of Orthodontics, Kerala State Co-Operative Hospital Complex, Academy of Medical Sciences, Pariyaram Dental College, Kannur-670 001, Kerala, India 2 Department of Periodontics, KMCT Dental College, Mukkom-673602, Kerala, India Abstract Osteoimmunology is a rapidly evolving field of medical science that reveals the relationship between the immune system and bone metabolism. Receptor activator of nuclear factor kappa B ligand (RANKL), its receptor, receptor activator of nuclear factor kappaB (RANK), and a soluble decoy receptor for RANKL, osteoprotegerin (OPG), are three key molecules involved in this system. Understanding osteoimmunology will be central for orthodontic tooth movement related bone metabolism, and for the development of new means to prevent and control pathologic bone loss in diseases such as rheumatoid arthritis, periodontitis etc. This article focuses on the role of Osteoimmunology and its signaling mechanisms in physiologic and pathologic models of bone loss. Key words: Osteoimmunology; orthodontics; periodontics; RANK; RANKL; OPG Cite this article as: Ranjith Raveendran, Sameera G Nath. Osteoclastogenesis- The Immunity face unleashed. American Journal of Advances in Medical Science.2015; 3(4):1-8.

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actively participate both in the inflammatory process and in tissue remodeling processes in the periodontium. Moreover, the outcome of physiological and pathological remodeling processes is also dependent on regulation by systemic hormones, the nervous system, drugs, treatment and genetic traits. There are at least two major pathways that regulate the balance of gingival tissue

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Introduction The maintenance of teeth in the alveolar bone is dependent on remodeling processes in the gingiva, the periodontal ligament and the surrounding jaw bone tissue. Bone tissue is not static but is continuously rebuilt to adapt to external requirements. Cells in the epithelium, gingiva, periodontal ligament and bone are sensitive to signaling molecules that

Conflict of Interest: None declared

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Osteoclastogenesis- The Immunity face unleashed and bone remodeling and the subsequent control of alveolar bone loss. The first involves the interactions with osteoblasts and stroma that couple between bone formation and resorption during physiological bone remodeling processes, like that in orthodontic tooth movements. A network of autocrine and paracrine regulations, a range of growth factors, such as platelet derived growth factor, basic fibroblast growth factor and insulinlike growth factor, exert their activities through their receptors on osteoblasts to stimulate the formation of new bone. In parallel, receptors of endocrine hormones such as thyroid hormone, parathyroid hormone, insulin, progesterone, prolactin, vitamin D3, estrogens and retinoids, are also expressed on osteoblast surfaces to mediate their individual vs. synergistic functions [1,2]. The second pathway deals with the inflammatory or ⁄ and osteoclastogenic cytokines ⁄ mediators that are produced during local tissue inflammation and trauma or systemic assaults and are thus responsible for bone loss under pathological conditions (e.g. stress, inflammation or autoimmunity). However, this homeostasis is perturbed, for example, in inflammatory bone diseases such as periodontal disease and rheumatoid arthritis [3], where bone remodeling becomes imbalanced or dysregulated as a result of increased osteoclast number and activity, resulting in irreversible bone loss, morbidity, perturbation of life quality and even lifethreatening conditions. 4 This pathway may not, by a large degree, necessarily be directly associated with osteoblasts and ⁄ or stromal cell interactions leading to the active bone destruction seen in pathological conditions (such as periodontal infection) where a pool of primed immune cells (e.g. T-cells, B cells and others) and exacerbated immunity (i.e. cytokines released) take predominant control of the scheme in which bone loss occurs [4]. The bone tissue reaction induced by orthodontic treatment is sometimes referred to as a process with resemblances to inflammation-induced remodeling. Movement of teeth induced by orthodontic treatment involves reactions in alveolar


bone, as well as in periodontal ligament, gingiva, blood vessels, and nerves. A prerequisite for the teeth to move in response to orthodontic treatment is osteoclast formation and bone resorption. The osteoclasts appear on both the periodontal ligament side and the bone marrow side. Osteoclasts are the only cells in nature that can degrade mineralized bone tissue and are important for physiological remodeling and modeling processes, calcium homeostasis, tooth eruption, and orthodontic tooth movement. Under normal physiological conditions, the periodontal mechanoreceptors (PMRs) like Ruffini endings remain quiescent, but contain various neuropeptides, such as calcitonin gene-related peptide (CGRP) and substance P (SP) [5,6]. Orthodontic tooth movement alters the neutral state of both mechanoreceptors and nociceptive PDL nerve fibers, effecting the release of biologically active proteins, leading to local neurogenic inflammation and the release of neuropeptides, such as CGRP and SP [6]. Orthodontic tooth movements cause inflammatory reactions in the periodontium and dental pulp, which will stimulate release of various biochemical mediators such as SP [7], prostaglandin E [8], leukotrienes, and cytokines etc causing the sensation of pain. The endothelial cells in the periodontium are probably the first to interact with neuropeptides, which in turn bind circulating leukocytes, facilitating their migration from the capillaries. This triggers the host immune system to react to external stimuli, be it physiological or pathological in nature. The migration of leukocytes in the PDL signifies the onset of an acute inflammation, which is essential for tooth movement into newer locations [9]. Signaling molecules released by these migrating leukocytes (cytokines, growth factors, and colony-stimulating factors) interact with various dental and paradental cells to initiate the tissue remodeling. Monocytes, lymphocytes, and mast cells also express receptors for neuropeptides, which evoke cytokine release, changes in the expression of mediators, or direct release of inflammatory mediators [6].

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and binds to a receptor on pre-osteoclasts known as cFMS, a member of the tyrosine kinase receptor superfamily. The binding of M-CSF to cFMS results in the activation of several transcription factors, including c-fos, which leads to the initiation of osteoclastogenesis. It appears that the main role of M-CSF is to promote the proliferation and survival of preosteoclasts as well as mature osteoclasts [13]. RANKL, its cell surface receptor RANK, and a soluble decoy receptor for RANKL, osteoprotegerin(OPG), are three key molecules that regulate osteoclast differentiation and function [14]. Osteoprotegerin(OPG) prevents binding of RANKL to its receptor RANK expressed on osteoclasts [15]. Differentiation and activation of osteoclast precursors is regulated by the molar ratio of RANKL:OPG in the microenvironment surrounding the osteoclast precursor cells [16]. It is most likely that RANKL is needed also for osteoclast formation during orthodontic treatment and, therefore, an interesting issue is which cells express RANKL and what drives the expression. During normal bone metabolism, RANKL is expressed by osteoblasts. The expression of RANKL is also regulated by other modulators of bone metabolism including parathyroid hormone, vitamin D3 and interleukin-11 [17,18]. While RANKL is considered to be essential for osteoclast-driven bone resorption, tumor necrosis factor has also been reported to be capable of inducing osteoclast bone resorption in the absence of RANKL [19]. However, this finding has been challenged and RANKL is generally accepted as the essential ingredient for osteoclast formation [20]. Osteoprotegerin (OPG) is a natural inhibitor of RANKL. It is a soluble tumor necrosis factor receptor-like molecule that acts as a decoy and blocks the binding of RANKL to RANK and thus prevents osteoclastogenesis. Studies on osteoprotegerin knockout mice have shown the animals to have an osteoporotic phenotype [21]. However, mice that overexpress osteoprotegerin develop osteopetrosis; this is because of a lack of osteoclast formation and hence a lack of bone resorption [22]. Further tumor necrosis factor-mediated bone

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RANK-RANKL-OPG axis in osteoclastogenesis The role of host immune system in bone metabolism and bone resorption has been recognized. The relationship between the immune system and bone metabolism has been termed “Osteoimmunology”, and this is a rapidly evolving field of investigation [10]. Osteoimmunology seeks to define and understand the interactions of immune cells and their cytokines with skeletal cells. Both the immune system and bone share a large number of regulatory cytokines and other molecules in common. It is clear that understanding osteoimmunology will be central for orthodontic tooth movement related bone metabolism, and for the development of new means to prevent and control pathologic bone loss in diseases such as rheumatoid arthritis, periodontitis etc. To date, a number of key regulatory molecules have been identified and these are generally related to the receptor activator of nuclear factor kappaB ligand (RANKL), its receptor, receptor activator of nuclear factor kappaB (RANK), as well as associated signaling molecules and transcription factors. RANKL is a tumor necrosis factor-related cytokine that has been reported to be involved not only in physiological osteoclastogenesis but also in pathological bone loss [11]. Until RANKL was identified as a key osteoclast differentiation factor, osteoblasts and bone marrow stromal cells had been considered the only effector cells which could induce osteoclast differentiation by cell–cell contact with osteoclast precursor cells [12]. Osteoblasts form a cell layer covering all bone surfaces and synthesize an extracellular matrix, consisting of type I collagen fibers and several other proteins,that subsequently mineralize this matrix into bone. In addition, osteoblasts can be regulated to stimulate osteoclast formation and bone resorption by increasing formation of RANKL, thereby, paracrinally induce osteoclast progenitor cell differentiation. Macrophage colony stimulating factor (M-CSF) was one of the earliest signaling molecules identified to play a role in osteoclast development and activation. M-CSF is produced mainly by osteoblasts or bone marrow stromal cells

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Osteoclastogenesis- The Immunity face unleashed destruction can be prevented through the administration of osteoprotegerin, thus reducing the osteoclast numbers [23]. Osteoprotegerin is produced by human periodontal ligament cells, gingival fibroblasts and epithelial cells [24], and its expression is modulated by inflammatory cytokines. Osteoblasts can be regulated to stimulate osteoclast formation and bone resorption by increasing formation of RANKL and decreasing that of OPG and, thereby, paracrinally induce osteoclast progenitor cell differentiation. Some osteoblasts become incorporated into bone matrix and differentiate to dendritic osteocytes, which can sensitize mechanical loading and through decreased sclerostin expression increase Wnt/β-catenin signaling [25] in osteoblasts to enhance bone formation. The osteocytes are also important in bone remodeling, as microcracks damaging old bone causes osteocytic apoptosis and increased RANKL production and, thereby, increased osteoclast formation to resorb the old damaged bone. The resorption process releases coupling factors from the matrix (eg, TGFβ, BMPs), which enhance osteoblastic bone formation and subsequent new bone formation to substitute the resorbed bone, a process denoted bone remodeling. In addition, osteocytes secrete FGF23, a systemic hormone acting on kidneys to regulate phosphate excretion. The molecular mechanism underlying “immune-mediated” osteoclastogenesis was not elucidated until the discovery of RANKL, and by the evidence that RANKL is expressed not only in osteoblasts and bone marrow stromal cells, but also in T cells and B cells [26]. The involvement of RANKL expressed by T cells in pathogenic bone loss was first demonstrated in rheumatoid arthritis in rats. T cells isolated from rheumatoid arthritis synovial fluid expressed RANKL and supported osteoclast differentiation [27]. When RANKL binds to RANK, a number of intracellular signaling pathways are activated for producing factors such as tumor necrosis factor receptor factor-6 and c-Fos, all of which are involved in osteoclast differentiation and activation. All of these pathways are also involved in the induction and activation of nuclear


factor of activated T-cells-1, which is considered to be the master transcription factor for osteoclastogenesis [28]. Importantly, T helper type 1 T cells produce consistently higher levels of RANKL than T helper type 2 T cells [29], ie; RANKL expression induced by T-cell receptor ⁄ CD28 signaling was suppressed in the presence of interleukin-4 [30], suggesting that RANKL can be more abundantly expressed by T helper type 1 lymphocytes than T helper type 2 lymphocytes [30]. Several studies demonstrated that not only T cells, but also B cells, express RANKL in human periodontal diseased gingival tissues [31]. Very few RANKL expressing cells were present in healthy gingival tissues.31 More than 50% of T cells and 90% of B cells expressed RANKL in diseased gingival tissues, whereas