Cell adhesion molecules in human osteoblasts: structure and function

Osteoblasts and bone lining cells form a near continuous layer covering the bone surface and interactions between these cells and the organic matrix of bone are important determinants of osteoblast proliferation and differentiation. In addition, cells of the osteoblast-lineage form functional communications with each other, with the extra-cellular matrix and with osteocytes through cytoplasmic processes extending through canaliculi in the bone. Together, these cells form a network of putative importance in the regulation of skeletal homeostasis. Cell-cell and cell-matrix interactions are mediated by members of several families of cell adhesion molecules, and knowledge of their interactions will be of fundamental importance in understanding the role of osteoblast in skeletal turnover. Here, the expression pattern of members of the major families of cell adhesion molecules by cells of the osteoblast lineage is reviewed. Special emphasis has been placed on human tissues. In addition, the possibility that cells at progressive stages of the osteoblast lineage have different profiles of cell adhesion molecule expression is explored, and the putative significance of cell-matrix interactions in human skeletal disease briefly discussed.     

Osteoimmunology: The correlation between osteoclasts and the Th17/Treg balance in osteoporosis

Osteoporosis is a bone disease that is caused by disorder of the skeletal microenvironment, and it characterized by a high disability rate and the occurrence of low energy fractures. Studies on osteoporosis and related treatment options have always been hot spots in the field of bone biology. In the past, the understanding of osteoporosis has been rather limited; research has only shown that osteoporosis involves the imbalance of bone resorption and bone formation, and recent studies have not provided cutting‐edge theories of the basic understanding of osteoporosis. Recent studies have shown crosstalk between bone and immune responses. RANKL, an essential factor for osteoclasts (OCs), is associated with the immune system. T helper (Th17)/regulatory T (Treg) cells are two different kinds of T cells that can self‐interact and regulate the differentiation and formation of OCs. Therefore, understanding the correlation between the skeletal and immune systems and further revealing the roles and the cooperation between RANKL and the Th17/Treg balance will help to provide new insights for the treatment of osteoporosis.     

Osteoimmunology: memorandum for rheumatologists

Rapid progress has been made in exploring the connections between the skeletal system and the immune system over the past decade. Bone tissue forms developmental niches for hematopoietic stem cells, and activated immune cells are involved in bone metabolism regulation and are potent mediators of osteoporosis and bone erosion under pathological conditions. The interdisciplinary field of osteoimmunology has emerged to pool the knowledge of the interdependence of these two systems, including the shared ligands and receptors, their crosstalk and interaction, and common intracellular signaling pathways with bidirectional influence. The receptor activator of nuclear factor-kappa B(RANK)/RANK ligand(RANKL)/osteoprotegerin(OPG) triad is the key vinculum, with multifaceted potency, being not only essential for osteoclastogenesis but also critical for lymph node organogenesis and lymphopoiesis as well as for immune regulation. In this review, we summarize the progress in this area, focusing on those aspects of interest concerning rheumatic diseases.     

TGF-beta1 on osteoimmunology and the bone component cells

TGF-β1 is an immunoregulatory cytokine that regulates immune cell proliferation, survival, differentiation, and migration. Compelling evidence has demonstrated a strong association between the immune and skeletal systems (so called Osteoimmunology), such as the critical role of TGF-β1 in the development and maintenance of the skeletal tissue. This review provides an overview of the mechanisms in which TGF-β1 interacts with bone component cells, such as osteoblasts, osteoclasts, chondrocytes, mesenchymal stem cells, and hematopoietic stem cells, in concert with other cytokines and hormones.     

Osteoimmunology: interactions of the immune and skeletal systems

Bone is a dynamic tissue that provides mechanical support, physical protection, and enables movement. Bone also serves as a storage site for minerals and is where blood cells are produced. Bone homeostasis is regulated by the balance between bone formation and resorption, and involves the coordinated action of osteoblasts and osteoclasts. Osteoblasts are bone-forming cells that secrete organic matrix molecules, while osteoclasts are derived from hematopoietic precursors and resorb bone matrix. Although osteoblasts and osteoclasts are the major regulators of bone metabolism and are regulated by the local microenvironment, it has recently come to be appreciated that skeletal system homeostasis is greatly influenced by components of the immune system. For example, some pathological bone resorption observed under inflammatory conditions has been shown to be due, in part, to direct and indirect effects of activated T cells on osteoclasts. In this regard, we would like to review current progress and perspectives in "osteoimmunology", an interdisciplinary research principle governing the cross-talk between the bone and immune systems. Better understanding of how the osteoimmune system operates in normal and pathological situations is likely to lay the groundwork for future therapies for the variety of diseases that affect both bone and the immune system.     

Skeletal remodeling in health and disease

The use of genetically manipulated mouse models, gene and protein discovery and the cataloguing of genetic mutations have each allowed us to obtain new insights into skeletal morphogenesis and remodeling. These techniques have made it possible to identify molecules that are obligatory for specific cellular functions, and to exploit these molecules for therapeutic purposes. New insights into the pathophysiology of diseases have also enabled us to understand molecular defects in a way that was not possible a decade ago. This review summarizes our current understanding of the carefully orchestrated cross-talk between cells of the bone marrow and between bone cells and the brain through which bone is constantly remodeled during adult life. It also highlights molecular aberrations that cause bone cells to become dysfunctional, as well as therapeutic options and opportunities to counteract skeletal loss.     

Bone cell interactions through Eph/ephrin

Bones cannot properly form or be maintained without cell-cell interactions through ephrin ligands and Eph receptors. Cell culture analysis and evaluation of genetic mouse models and human diseases reveal various ephrins and Eph functions in the skeletal system. Migration, attachment and spreading of mesenchymal stem cells are regulated by ephrinB ligands and EphB receptors. ephrinB1 loss-of-function is associated with craniofrontonasal syndrome (CFNS) in humans and mice. In bone remodeling, ephrinB2 is postulated to act as a “coupling stimulator.” In that case, bidirectional signaling between osteoclastic ephrinB2 and osteoblastic EphB4 suppresses osteoclastic bone resorption and enhances osteoblastic bone formation, facilitating the transition between these two states. Parathyroid hormone (PTH) induces ephrinB2 in osteoblasts and enhances osteoblastic bone formation. In contrast to ephrinB2, ephrinA2 acts as a “coupling inhibitor,” since ephrinA2 reverse signaling into osteoclasts enhances osteoclastogenesis and EphA2 forward signaling into osteoblasts suppresses osteoblastic bone formation and mineralization. Furthermore, ephrins and Ephs likely modulate pathological conditions such as osteoarthritis, rheumatoid arthritis, multiple myeloma and osteosarcoma. This review focuses on ephrin/Eph-mediated cell-cell interactions in bone biology.     

Semaphorin 4D Promotes Skeletal Metastasis in Breast Cancer

Bone density is controlled by interactions between osteoclasts, which resorb bone, and osteoblasts, which deposit it. The semaphorins and their receptors, the plexins, originally shown to function in the immune system and to provide chemotactic cues for axon guidance, are now known to play a role in this process as well. Emerging data have identified Semaphorin 4D (Sema4D) as a product of osteoclasts acting through its receptor Plexin-B1 on osteoblasts to inhibit their function, tipping the balance of bone homeostasis in favor of resorption. Breast cancers and other epithelial malignancies overexpress Sema4D, so we theorized that tumor cells could be exploiting this pathway to establish lytic skeletal metastases. Here, we use measurements of osteoblast and osteoclast differentiation and function in vitro and a mouse model of skeletal metastasis to demonstrate that both soluble Sema4D and protein produced by the breast cancer cell line MDA-MB-231 inhibits differentiation of MC3T3 cells, an osteoblast cell line, and their ability to form mineralized tissues, while Sema4D-mediated induction of IL-8 and LIX/CXCL5, the murine homologue of IL-8, increases osteoclast numbers and activity. We also observe a decrease in the number of bone metastases in mice injected with MDA-MB-231 cells when Sema4D is silenced by RNA interference. These results are significant because treatments directed at suppression of skeletal metastases in bone-homing malignancies usually work by arresting bone remodeling, potentially leading to skeletal fragility, a significant problem in patient management. Targeting Sema4D in these cancers would not affect bone remodeling and therefore could elicit an improved therapeutic result without the debilitating side effects.     

Expression of differentiated functions in heterokaryons between skeletal myocytes,adrenal cells,fibroblasts and glial cells

The regulation of both muscle and adrenal functions was examined in heterokaryons formed by fusing differentiated chick skeletal myocytes to Y1 mouse adrenal cells. Mouse fast skeletal myosin light chain one (LC1) synthesis was induced and acetylcholine receptor expression was maintained at muscle control levels. Steroid secretion, although reduced compared with Y1 × Y1 adrenal homokaryon control fusions, was nonetheless maintained at relatively high levels. Steroid secretion in the myocyte × adrenal heterokaryons was constitutively expressed and was not increased by exposure to either adrenocorticotrophic hormone or db-cAMP. The population of heterokaryons was thus simultaneously expressing both muscle and adrenal functions. The steroid secretion in these heterokaryons was compared to that in heterokaryons formed by fusing Y1 adrenal cells to either chick skin fibroblasts or rat C6 glial cells. Both of these sets of heterokaryons exhibited low baseline levels of steroid secretion that were inducible to control values by ACTH. These results extend previous observations showing that heterokaryons are functionally very different than cell hybrids, and exhibit a variety of phenotypic interactions. Although fibroblasts suppress muscle functions in heterokaryons, they are permissive for adrenal functions. C6 glial cells are permissive for both adrenal and muscle functions, and along with several other neurectodermal derivatives contain an inducible skeletal myosin light chain gene. Finally, myocytes and Y1 adrenal cells are mutually permissive for their differentiated functions, and Y1 adrenal cells contain an inducible myosin light chain gene.     

The dynamic interplay between osteoclasts and the immune system

Investigation into arthritis, as well as numerous bone phenotypes found in mice lacking immune-related genes, has highlighted the importance of the interplay between the bone and immune systems, which has led to the emergence and evolution of the field of osteoimmunology. RANKL stimulates osteoclastogenesis through nuclear factor of activated T cells (NFAT) c1, which is also a crucial regulator of immunity. In rheumatoid arthritis, bone destruction is caused by the enhanced activity of osteoclasts, which is mainly dependent on interleukin-17-producing helper T cells (T_H17). The scope of osteoimmunology has been extended to encompass a wide range of molecular and cellular interactions. The framework of osteoimmunology will provide a scientific basis for future therapeutic approaches to diseases related to both of these systems.     

Osteoimmunology: shared mechanisms and crosstalk between the immune and bone systems

Osteoimmunology is an interdisciplinary research field focused on the molecular understanding of the interplay between the immune and skeletal systems. Although osteoimmunology started with the study of the immune regulation of osteoclasts, its scope has been extended to encompass a wide range of molecular and cellular interactions, including those between osteoblasts and osteoclasts, lymphocytes and osteoclasts, and osteoblasts and haematopoietic cells. Therefore, the two systems should be understood to be integrated and operating in the context of the 'osteoimmune' system, a heuristic concept that provides not only a framework for obtaining new insights by basic research, but also a scientific basis for the discovery of novel treatments for diseases related to both systems.     

The roles of bone‐derived exosomes and exosomal microRNAs in regulating bone remodelling

Pathological destructive bone diseases are primarily caused by the failure of a lifelong self‐renewal process of the skeletal system called bone remodelling. The mechanisms underlying this process include enhanced osteoclast activity and decreased generation of the osteoblast lineage. Intercellular interaction and crosstalk among these cell types are crucial for the maintenance of bone remodelling, either through the secretion of growth factors or direct cell–cell physical engagement. Recent studies have revealed that exosomes derived from bone cells, including osteoclasts, osteoblasts and their precursors, play pivotal roles on bone remodelling by transferring biologically active molecules to target cells, especially in the processes of osteoclast and osteoblast differentiation. Here, we review the contents of bone‐derived exosomes and their functions in the regulatory processes of differentiation and communication of osteoclasts and osteoblasts. In addition, we highlight the characteristics of microRNAs of bone‐derived exosomes involved in the regulation of bone remodelling, as well as the potential clinical applications of bone‐derived exosomes in bone remodelling disorders.     

Bone cell interactions through Eph/ephrin: Bone modeling,remodeling and associated diseases

Bones cannot properly form or be maintained without cell-cell interactions through ephrin ligands and Eph receptors. Cell culture analysis and evaluation of genetic mouse models and human diseases reveal various ephrins and Eph functions in the skeletal system. Migration, attachment and spreading of mesenchymal stem cells are regulated by ephrinB ligands and EphB receptors. ephrinB1 loss-of-function is associated with craniofrontonasal syndrome (CFNS) in humans and mice. In bone remodeling, ephrinB2 is postulated to act as a “coupling stimulator.” In that case, bidirectional signaling between osteoclastic ephrinB2 and osteoblastic EphB4 suppresses osteoclastic bone resorption and enhances osteoblastic bone formation, facilitating the transition between these two states. Parathyroid hormone (PTH) induces ephrinB2 in osteoblasts and enhances osteoblastic bone formation. In contrast to ephrinB2, ephrinA2 acts as a “coupling inhibitor,” since ephrinA2 reverse signaling into osteoclasts enhances osteoclastogenesis and EphA2 forward signaling into osteoblasts suppresses osteoblastic bone formation and mineralization. Furthermore, ephrins and Ephs likely modulate pathological conditions such as osteoarthritis, rheumatoid arthritis, multiple myeloma and osteosarcoma. This review focuses on ephrin/Eph-mediated cell-cell interactions in bone biology.     

Impact of cytokines and T lymphocytes upon osteoclast differentiation and function

Historically, the osteoblast has been considered the master cell in the control of osteoclast development and, therefore, bone resorption. Now the interactions between cells of the immune system and bone cells have redefined our thinking on the regulation of bone resorption. Moreover, the crosstalk between these cell types has special significance in inflammatory conditions such as rheumatoid arthritis. This report highlights the contribution that T lymphocytes make in regulating osteoclast formation and bone resorption.     

Invariant natural killer T cells: bridging innate and adaptive immunity

Cells of the innate immune system interact with pathogens via conserved pattern-recognition receptors, whereas cells of the adaptive immune system recognize pathogens through diverse, antigen-specific receptors that are generated by somatic DNA rearrangement. Invariant natural killer T (iNKT) cells are a subset of lymphocytes that bridge the innate and adaptive immune systems. Although iNKT cells express T cell receptors that are generated by somatic DNA rearrangement, these receptors are semi-invariant and interact with a limited set of lipid and glycolipid antigens, thus resembling the pattern-recognition receptors of the innate immune system. Functionally, iNKT cells most closely resemble cells of the innate immune system, as they rapidly elicit their effector functions following activation, and fail to develop immunological memory. iNKT cells can become activated in response to a variety of stimuli and participate in the regulation of various immune responses. Activated iNKT cells produce several cytokines with the capacity to jump-start and modulate an adaptive immune response. A variety of glycolipid antigens that can differentially elicit distinct effector functions in iNKT cells have been identified. These reagents have been employed to test the hypothesis that iNKT cells can be harnessed for therapeutic purposes in human diseases. Here, we review the innate-like properties and functions of iNKT cells and discuss their interactions with other cell types of the immune system.     

Stem cell regulation via dynamic interactions of the nervous and immune systems with the microenvironment

Physiological interactions between the nervous and immune systems with components of the local microenvironment are needed to maintain homeostasis throughout the body. Dynamic regulation of bone remodeling, hematopoietic stem cells, and their evolving niches via neurotransmitter signaling are part of the host defense and repair mechanisms. This crosstalk links activated leukocytes, neuronal, and stromal cells, which combine to directly and indirectly regulate hematopoietic stem cells. Together, interactions between diverse systems create a regulatory "brain-bone-blood triad," contributing an additional dimension to the concept of the hematopoietic stem cell niche.     

Effects of immune cells on mesenchymal stem cells during fracture healing

In vertebrates, bone is considered an osteoimmune system which encompasses functions of a locomotive organ, a mineral reservoir, a hormonal organ, a stem cell pool and a cradle for immune cells. This osteoimmune system is based on cooperatively acting bone and immune cells, cohabitating within the bone marrow. They are highly interdependent, a fact that is confounded by shared progenitors, mediators, and signaling pathways. Successful fracture healing requires the participation of all the precursors, immune and bone cells found in the osteoimmune system. Recent evidence demonstrated that changes of the immune cell composition and function may negatively influence bone healing. In this review, first the interplay between different immune cell types and osteoprogenitor cells will be elaborated more closely. The separate paragraphs focus on the specific cell types, starting with the cells of the innate immune response followed by cells of the adaptive immune response, and the complement system as mediator between them. Finally, a brief overview on the challenges of preclinical testing of immune-based therapeutic strategies to support fracture healing will be given.     

Cellular and molecular interactions regulating skeletogenesis

Skeletal development involves complex coordination among multiple cell types and tissues. In long bones, a cartilage template surrounded by the perichondrium is first laid down and is subsequently replaced by bone marrow and bone, during a process named endochondral ossification. Cells in the cartilage template and the surrounding perichondrium are derived from mesenchymal cells, which condense locally. In contrast, many cell types that make up mature bone and in particular the bone marrow are brought in by the vasculature. Three tissues appear to be the main players in the initiation of endochondral ossification: the cartilage, the adjacent perichondrium, and the invading vasculature. Interactions among these tissues are synchronized by a large number of secreted and intracellular factors, many of which have been identified in the past 10 years. Some of these factors primarily control cartilage differentiation, while others regulate bone formation and/or angiogenesis. Understanding how these factors operate during skeletal development through the analyses of genetically altered mice depends on being able to distinguish the effect of these molecules on the different cell types that comprise the skeleton. This review will discuss the complexity of skeletal phenotypes, which arises from the tightly regulated, complex interactions among the three tissues involved in bone development. Specific examples illustrate how gene functions may be further assessed using new approaches including genetic and tissue manipulations.     

Immune and nonimmune components orchestrate the pathogenesis of inflammatory bowel disease

Inflammatory bowel disease (IBD) pathogenesis is driven by the interactions between the innate and the adaptive immune system. Both systems are actually expressed not only by immune cells, but also by essentially all types of nonimmune cells. Nonimmune cells have classically been considered as simple targets of the aberrant inflammatory process occurring in IBD. However, the discovery that many of the functions traditionally attributed to immune cells are also performed by nonimmune cells has caused a shift to a multidirectional hypothesis in which nonimmune cells and even acellular elements are considered active players of IBD pathogenesis. The aim of this review is to summarize the current role played by each cell type in IBD pathogenesis.