Bone homeostasis depends on the resorption of bones by osteoclasts and formation of bones by the osteoblasts. Imbalance of this tightly coupled process can cause diseases such as osteoporosis. Thus, the mechanisms that regulate communication between osteoclasts and osteoblasts are critical to bone cell biology. It has been shown that osteoblasts and osteoclasts can communicate with each other through direct cell-cell contact, cytokines, and extracellular matrix interaction. Osteoblasts can affect osteoclast formation, differentiation, or apoptosis through several pathways, such as OPG/RANKL/RANK, RANKL/LGR4/RANK, Ephrin2/ephB4, and Fas/FasL pathways. Conversely, osteoclasts also influence formation of bones by osteoblasts via the d2 isoform of the vacuolar (H+) ATPase (v-ATPase) V0 domain (Atp6v0d2), complement component 3a, semaphorin 4D or microRNAs. In addition, cytokines released from the resorbed bone matrix, such as TGF-β and IGF-1, also affect the activity of osteoblasts. Drugs could be developed by enhancing or restricting some of these interactions. Several reviews have been performed on the osteoblast-osteoclast communication. However, few reviews have shown the research advances in the recent years. In this review, we summarized the current knowledge on osteoblast-osteoclast communication.

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Osteoblast–osteoclast interactions

The immune and skeletal systems share a variety of molecules, including cytokines, chemokines, hormones, receptors, and transcription factors. Bone cells interact with immune cells under physiological and pathological conditions. Osteoimmunology was created as a new interdisciplinary field in large part to highlight the shared molecules and reciprocal interactions between the two systems in both heath and disease. Receptor activator of NF-κB ligand (RANKL) plays an essential role not only in the development of immune organs and bones, but also in autoimmune diseases affecting bone, thus effectively comprising the molecule that links the two systems. Here we review the function, gene regulation, and signal transduction of osteoimmune molecules, including RANKL, in the context of osteoclastogenesis as well as multiple other regulatory functions. Osteoimmunology has become indispensable for understanding the pathogenesis of a number of diseases such as rheumatoid arthritis (RA). We review the various osteoimmune pathologies, including the bone destruction in RA, in which pathogenic helper T cell subsets [such as IL-17-expressing helper T (Th17) cells] induce bone erosion through aberrant RANKL expression. We also focus on cellular interactions and the identification of the communication factors in the bone marrow, discussing the contribution of bone cells to the maintenance and regulation of hematopoietic stem and progenitors cells. Thus the time has come for a basic reappraisal of the framework for understanding both the immune and bone systems. The concept of a unified osteoimmune system will be absolutely indispensable for basic and translational approaches to diseases related to bone and/or the immune system.

Osteoimmunology: The Conceptual Framework Unifying the Immune and Skeletal Systems

Tumor necrosis factor (TNF) superfamily member 11 (TNFSF11, also known as RANKL) regulates multiple physiological or pathological functions, including osteoclast differentiation and osteoporosis. TNFRSF11A (also called RANK) is considered to be the sole receptor for RANKL. Herein we report that leucine-rich repeat-containing G-protein-coupled receptor 4 (LGR4, also called GPR48) is another receptor for RANKL. LGR4 competes with RANK to bind RANKL and suppresses canonical RANK signaling during osteoclast differentiation. RANKL binding to LGR4 activates the Gαq and GSK3-β signaling pathway, an action that suppresses the expression and activity of nuclear factor of activated T cells, cytoplasmic, calcineurin-dependent 1 (NFATC1) during osteoclastogenesis. Both whole-body (Lgr4(-/-)) and monocyte conditional knockout mice of Lgr4 (Lgr4 CKO) exhibit osteoclast hyperactivation (including elevation of osteoclast number, surface area, and size) and increased bone erosion. The soluble LGR4 extracellular domain (ECD) binds RANKL and inhibits osteoclast differentiation in vivo. Moreover, LGR4-ECD therapeutically abrogated RANKL-induced bone loss in three mouse models of osteoporosis. Therefore, LGR4 acts as a second RANKL receptor that negatively regulates osteoclast differentiation and bone resorption.

LGR4 is a receptor for RANKL and negatively regulates osteoclast differentiation and bone resorption.

Src kinase (Src) is a tyrosine protein kinase that regulates cellular metabolism, survival, and proliferation. Many studies have shown that Src plays multiple roles in macrophage-mediated innate immunity, such as phagocytosis, the production of inflammatory cytokines/mediators, and the induction of cellular migration, which strongly implies that Src plays a pivotal role in the functional activation of macrophages. Macrophages are involved in a variety of immune responses and in inflammatory diseases including rheumatoid arthritis, atherosclerosis, diabetes, obesity, cancer, and osteoporosis. Previous studies have suggested roles for Src in macrophage-mediated inflammatory responses; however, recently, new functions for Src have been reported, implying that Src functions in macrophage-mediated inflammatory responses that have not been described. In this paper, we discuss recent studies regarding a number of these newly defined functions of Src in macrophage-mediated inflammatory responses. Moreover, we discuss the feasibility of Src as a target for the development of new pharmaceutical drugs to treat macrophage-mediated inflammatory diseases. We provide insights into recent reports regarding new functions for Src that are related to macrophage-related inflammatory responses and the development of novel Src inhibitors with strong immunosuppressive and anti-inflammatory properties, which could be applied to various macrophage-mediated inflammatory diseases.

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The Role of Src Kinase in Macrophage-Mediated Inflammatory Responses

Understanding the mechanisms of the pharmacological effects of herbal formulae from traditional Chinese medicine (TCM) is important for their appropriate application. However, this understanding has been impeded by the complex nature of herbal formulae. A herbal formula is a mixture of hundreds of chemical ingredients with multiple potential targets. The effects produced by an entire herbal formula cannot be adequately explained by considering separately each ingredient in it. This is a recognised problem that remains in need of methods to solve it. Here we introduce a holistic analysis method to decipher the molecular mechanisms of herbal formulae. This method combines chemical and therapeutic properties with network pharmacology, using a novel approach to evaluate the importance of the targets and ingredients of herbal formulae. We used the Liu-Wei-Di-Huang (LWDH) pill, a classic herbal formula, as an example to illustrate our method and validated some results by a following experiment. We revealed the core molecular targets and bioprocess network of the pharmacological effects of LWDH and inferred its therapeutic indications. This method provides a novel strategy to understand the mechanisms of herbal formulae in a holistic way and implies new applications of classic herbal formulae.

A novel network pharmacology approach to analyse traditional herbal formulae: the Liu-Wei-Di-Huang pill as a case study.

Activation of NF-κB and MAPK/activator protein 1 (AP-1) signaling pathways by receptor activator NF-κB ligand (RANKL) is essential for osteoclast activity Targeting NF-κB and MAPK/AP-1 signaling to modulate osteoclast activity has been a promising strategy for osteoclast-related diseases In this study we examined the effects of maslinic acid (MA), a pentacyclic triterpene acid that is widely present in dietary plants, on RANKL-induced osteoclastogenesis, osteoclast function, and signaling pathways by in vitro and in vivo assay systems In mouse bone marrow monocytes (BMMs) and RAW2647 cells, MA inhibited RANKL-induced osteoclastogenesis in a dose-dependent manner within nongrowth inhibitory concentration, and MA decreased osteoclastogenesis-related marker gene expression, including TRACP, MMP9, c-Src, CTR, and cathepsin K Specifically, MA suppressed osteoclastogenesis and actin ring formation at early stage In ovariectomized mice, administration of MA prevented ovariectomy-induced bone loss by inhibiting osteoclast activity At molecular levels, MA abrogated the phosphorylation of MAPKs and AP-1 activity, inhibited the IκBα phosphorylation and degradation, blocked NF-κB/p65 phosphorylation, nuclear translocation, and DNA-binding activity by downregulating RANK expression and blocking RANK interaction with TRAF6 Together our data demonstrate that MA suppresses RANKL-induced osteoclastogenesis through NF-κB and MAPK/AP-1 signaling pathways and that MA is a promising agent in the treatment of osteoclast-related diseases such as osteoporosis

Yu Ma

Papers

LGR4 is a receptor for RANKL and negatively regulates osteoclast differentiation and bone resorption.

Maslinic acid suppresses osteoclastogenesis and prevents ovariectomy‐induced bone loss by regulating RANKL‐mediated NF‐κB and MAPK signaling pathways