Osteoimmunology: Cross-talk between Bone and Immune Cells

The complexity of skeletal system has long been appreciated for its roles in support and regulation of mineral homeostasis. However, with increasing knowledge of the intercommunication among the various cell types associated with bone, a deeper appreciation of the dynamic role of the skeleton has unfolded. The cells of bone were classically identified as the bone forming osteoblasts, the osteocytes embedded in the mineral matrix, and the bone resorbing osteoclasts. As more information became available regarding the origin of these cells, it became increasingly apparent that there were not only important control mechanisms within the skeletal system, but also with the immune system.

Although the term “osteoimmunology” was first used in a published commentary by Aaron and Choi in 2000, observations that cells of the immune system could be involved in the regulation of bone cell action date back to 1972 (Aaron & Choi, 2000). This study by Horton et al. (1972) noted that a soluble mediator present in supernatant fluid from cultures of human peripheral blood leukocytes that were stimulated by phytohemagglutinin, or by antigenic material found in human dental plaque, could increase the number of active osteoclasts and stimulate bone resorption in fetal rat bone organ cultures.

This factor was initially called osteoclast-activating factor (OAF) but was later identified as the cytokine, IL-1 beta (Dewhirst et al., 1985). IL-1 is now recognized as a major player in the regulation of osteoclastic as well as osteoblastic mediated responses particularly in inflammatory conditions. Since then, a number of cytokines and chemokines produced by a variety of cells associated with the immune system have been identified as modulators of bone cells. The article by Souza & Lerner (2013) in this thematic issue provides a comprehensive review of the wide variety of the factors produced in inflammatory processes that have both positive and negative effects on osteoclastic cell formation and activity. Souza and Lerner also provide an extensive discussion of the mechanism of action of RANKL and highlights the studies on the role of this cytokine in bone remodeling (Souza & Lerner, 2013).

RANKL, a member of the TNF superfamily, was first isolated and cloned based on its regulation of the interactions between T-lymphocytes and dendritic cells (Wong et al, 1997a, 1997b). However, after its original description, it was soon found to be a critical signal for osteoclastogenesis by its activation of the receptor activator of nuclear factor β (RANK) on osteoclast progenitor cells. RANKL is produced not only by osteoblasts/osteocytes in bone, stromal cells in bone marrow, synovial fibroblasts and periodontal ligament cells, but also expressed by T-, B- and NK-cells, further emphasizing a connection between immune cells and bone cells. Knowledge of the interactions of the RANK/RANKL system with a multitude of cytokines as well as transcription factors and several immunomodulatory molecules in the regulation of bone metabolism has widened our understanding of the critical interconnections between various cell types in both the skeletal and immune systems.

The article by D’Amelio (2013) reiterates the importance of the RANK/RANKL systems and the repertoire of cytokines discussed by Souza and Lerner (2013) in bone regulation with emphasis on role of estrogen and the immune system. She discusses the recent data that point to a relationship between estrogen deficiency and the immune system with its consequences of resulting bone loss leading to postmenopausal osteoporosis. The data suggest that estrogen depletion increases osteoclast formation and activity, both directly and indirectly, through T and B cell activation and cytokine production by these cells. The studies to date have important implications for the development of new therapeutic approaches for post-menopausal osteoporosis.

Resorption and net loss of bone can also occur as a result of inflammation in chronic infectious disease such as periodontitis. This oral condition that has been shown to be related to systemic conditions such as cardiovascular and respiratory diseases, diabetes, and osteoporosis, is a bacteria-driven inflammation of the periodontium that results in resorption of the alveolar bone. Myneni, Setthem, and Sharma’s article in this issue (Myneni et al., 2013) reviews the role of Toll-like receptors (TLRs) in the interaction between cells of the immune system and osteoclastic cells and the nature of the inflammatory responses in periodontitis. The article discusses how innate and adaptive immunity play critical roles in periodontal disease and provides a working model of how Th2 can lead to net bone loss.

As the interest in regulation of bone remodeling and the potential interconnections with factors produced by both immune cells and osseous cells continues, studies with agents not typically considered osteogenic or osteolytic have yielded potentially new approaches for development of novel therapeutics for bone loss. The review on sphingosine-1-phosphate (S1P) and lysophosphatidic acid (LPA) by Dziak (2013) focuses on the emerging roles of these lysophospholipids as autocrine and paracrine modulators of bone remodeling. Both S1P and LPA, produced by a variety of cell types, including immune cells, appear to have unique effects on osteoblastic and osteoclastic cell actions via specific receptors. Since compromised lysophospholipids signaling has been implicated in the etiology of disorders, such as inflammatory and autoimmune diseases, studies on the effects of S1P and LPA on bone formation and bone resorptive cells further strengthen the concept of osteoimmunology as a important approach to embrace further studies in these areas.

The review by Horwood (2013) brings the concept of osteoimmunology full circle and discusses studies that suggest that immune cells not only have effects on bone cells, but that bone cells can control the precursors of immune cells. She presents exciting studies on the emerging role of osteoblastic and osteoclastic cells in the hematopoietic stem cell niche, the specific microenvironment in the bone marrow, and discusses how regulatory signals from bone cells in this niche appear to be critical for regulation of hematopoietic stem cell survival and self-renewal.

When I began my career in bone biology in the mid 1970s, the cutting edge research was focused on isolation of homogeneous bone cell preparations in order to study how osteoblastic and osteoclastic cells might respond to factors known to have effects on bone. After the initial bone cell isolation of osteoblastic cells from fetal rat calvaria using collagenase digestion by Peck et al. (1964), there followed a series of modifications of this technique yielding more enriched preparations (Dziak & Brand, 1974; Wong & Cohn, 1974). Although these methods yielded cells that generated important results on mechanisms of action of various hormones and agents, the studies of Chambers in the mid 1980s emphasized that in order to fully understand mechanisms of actions on bone as it occurs in vivo, one has to appreciate the interactions of the various cell types that are naturally present in the tissue (McSheehy & Chambers, 1986). For example, the classical bone resorptive agent, PTH, did not result in resorption of devitalized bone sections in the presence of osteoclastic cells unless these cells were co-incubated with osteoblastic cells (McSheehy & Chambers, 1986).

It became evident that studies on bone had to be extended beyond the approach with homogeneous or enriched preparations of only osteoblastic or osteoclastic cells. We now know from studies discussed thoroughly in this thematic issue, that interactions among not only the mature osseous cells and their precursors at various stages of development, but also cells of the immune system are critical to the regulation of bone. Likewise, bone cells are intimately involved in the regulation of immune cells via maintenance of the hematopoietic stem cell niche. Osteoimmunology is a growing field that encompasses many different technological approaches and is yielding exciting information critical to both the skeletal and the immune system. I wish to thank Dr. Kate Rittenhouse-Olson, Editor of Immunological Investigations, and the contributing authors to this issue for the opportunity to serve as guest editor and help disseminate the advancements in this area of bone and immunological research.