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Periodontal disease is characterized by inflammation of the periodontal tissue and subsequent destruction of the alveolar bone. It is one of the most common infectious diseases in humans, being the leading cause of tooth loss in adults. Recently, it has been shown that the receptor activator of NF-κB ligand (RANKL) produced by osteoblasts and periodontal ligament fibroblasts critically contributes to the bone destruction caused by periodontal disease. Activation of the immune system plays an important role in the induction of RANKL during periodontal inflammation. Here we discuss the molecular mechanisms of periodontal bone destruction by focusing on the osteoimmune molecule RANKL.

Osteoporosis is a disease in which the density and quality of bone is reduced, leading to an increase in fragility fractures. Osteoporosis is a major health threat affecting more than 10 million people in Japan. Emerging evidence has shown that anti-resorptive drugs such as bisphosphonates and raloxifene efficiently increase bone mass and prevent osteoporotic fractures by maintaining bone homeostasis. In addition, anabolic drugs such as parathyroid hormone and novel anti-resorptive drugs such as anti-RANKL drugs and cathepsin K inhibitors, which directly target osteoclasts are under development. In this review, we would like to summarize the current status of the development of anti-osteoporotic drugs.

Fracture healing is a process comprising of a local bleeding followed by inflammation and differentiation of mesenchymal cells that lead to formation of soft extracellular matrix tissue, cartilage and bone. This pathway includes endo-chondral bone formation and in part intra-membranous bone formation. During this process several sets of cytokines are involved in the regulation of the progress in fracture healing. This paper reviews the molecules involved in fracture healing.

Parathyroid hormone (PTH) has been applied to postmenopausal women and several studies revealed that intermittent PTH treatment significantly increases lumbar bone mineral density and reduces fracture risk. However, the mechanism of PTH anabolic function on bone is not fully understood yet. PTH receptors (PPR) are expressed in osteoblasts and PPR stimulates multiple intracellular signal pathways, including those mediated by cAMP-PKA signaling pathway and PLC-PKC signaling pathway. Several studies demonstrate that the PKA signaling through G-proteins in osteoblasts play important roles in regulating gene expression and osteogenesis by PTH.

Osteoprotegerin (OPG) has been identified as a novel cytokine that specifically inhibits osteoclastogenesis. OPG acts as a soluble decoy receptor that inhibits the binding of receptor activator of NF-kappaB ligand (RANKL) to its receptor RANK and thus inhibits the proliferation and activation of osteoclasts. Human serum OPG can now be easily measured using a sandwich-type ELISA kit, and the roles of OPG in various diseases have been revealed by clinical studies. These clinical studies have demonstrated that OPG plays an important role in not only metabolic bone diseases but also other diseases such as coronary artery disease, vascular calcification, chronic renal failure and malignancy. Furthermore, OPG may be a useful and novel marker related to the progression or mechanisms of these diseases.

Multiple myeloma is characterized by accumulation of monoclonal plasma cells in the bone marrow and progression of lytic bone lesions. Myeloma cells enhance bone resorption by triggering a coordinated increase in RANK ligand and decrease in osteoprotegerin in the bone marrow. Macrophage inflammatory protein (MIP)-1alpha and MIP-1beta are secreted by myeloma cells, and play a major role in the enhancement of bone resorption by myeloma cells. Furthermore, the growth and survival of myeloma cells are enhanced by contact with osteoclasts, suggesting the presence of a vicious cycle between bone destruction and myeloma cell expansion. In addition, myeloma cells secrete soluble Wnt inhibitors, dickkopf (Dkk)-1 and secreted Frizzled-related protein (sFRP)-2, to suppress bone formation. Thus, myeloma cells closely interact with bone cells in the bone marrow microenvironment to enhance bone resorption and concomitantly suppress bone formation, which causes the formation of destructive bone lesions and a rapid loss of bone. Disruption of the pathognomonically skewed cellular interactions in myeloma bone marrow microenvironment may ameliorate bone destruction along with myeloma expansion.

Malignancy-associated hypercalcemia (MAH) is caused by tumor over-production of parathyroid hormone-related protein (PTHrP), or by locally enhanced bone resorption in metastatic lesions of solid cancers. Medical treatment of MAH includes hydration by saline infusion, loop diuretics to promote urinary calcium excretion and anti-resorptives such as calcitonin and bisphosphonates. Particularly, bisphosphonates are the current mainstay for MAH treatment : they not only inhibit osteoclastic bone resorption to ameliorate hypercalcemia but can also alleviate bone pain and can even prevent cancer cell expansion in bone metastatic lesions.

Osteoporosis is a systemic skeletal disease characterized by low bone mass and the microarchitectural deterioration of bone tissue. The pathophysiology of osteoporosis is complex, involving a broad spectrum of endogenous and environmental factors. Recently, molecular and genetic approaches are revealing that genetic backgrounds are important for the pathophysiology of osteoporosis. We discuss about recent findings of osteoporosis and osteopenia caused by monogenic mutations in humans and mice.

The discovery of receptor activator of nuclear factor-kappaB ligand (RANKL) elucidates the mechanism of osteoclast differentiation and function regulated by osteoblasts. Osteoprotegerin (OPG), a soluble decoy receptor of RANKL, inhibits both differentiation and function of osteoclasts. OPG-deficient (OPG-/-) mice exhibited severe osteoporosis caused by enhanced osteoclastic bone resorption. Deficiency of OPG in human has been shown to result in juvenile Paget's disease. Blood alkaline phosphatase activity of OPG-/- mice was about four times as high as that of wild-type mice. These results suggest that osteoclastic bone resorption coincidentally induces osteoblastic bone formation by an unknown factor (called coupling factor). Collagen sponge disks containing bone morphogenetic protein-2 (rhBMP-2) were implanted into the dorsal muscle pouches in OPG-/- mice and wild-type mice, and bone mineral density (BMD) of the collagen sponge disks was determined every week for 3 weeks. No significant difference in BMD of the disc was observed between OPG-/- mice and wild-type mice. These results suggest that bone formation is accurately coupled with bone resorption at local sites in OPG-/- mice.

Vascular calcification, such as coronary and aortic calcification, is a significant feature of vascular pathology. Two distinct forms of vascular calcification are well recognized. One is medial calcification, which occurs between the cell layers of smooth muscle cells, and is related to aging, diabetes and chronic renal failure. The other is atherosclerotic calcification, which occurs in the intima during the development of atheromatous disease. It has been shown that statins inhibit the progression of calcification in the aortic valve and the coronary artery. We have found that statins inhibit calcification of human aortic smooth muscle cells, which is induced by incubating the cells in high-phosphate medium. We also found that this is mediated by inhibiting cellular apoptosis, an essential mechanism for calcification, not by inhibiting inorganic phosphate (Pi) uptake by sodium-dependent phosphate cotransporter (NPC). Besides apoptosis and Pi uptake, such proteins as osteoprotegerin (OPG), matrix Gla protein (MGP), Klotho, fetuin-A, and apoE have been shown to negatively affect vascular calcification. Many previous reports suggest that vascular calcification appears to be regulated by promoting factors, such as Pi, apoptosis, modified LDL, advanced glycation end products, oxidative stress, vitaminD3, glucocorticoid, cbfa-1, osteopontin, and inhibitory factors, such as OPG, MGP, Klotho, fetuin-A, PTH/PTHrP, pyrophosphate, statins, and bisphosphonates. The precise mechanism of vascular calcification is of interest.

Identification of RANKL/ODF (receptor activator of NF-kappaB ligand/osteoclast differentiation factor), RANK(receptor activator of NF-kappaB) and OPG/OCIF(osteoprotegerin/ osteoclastogenesis inhibitory factor) revealed the mechanisms regulating osteoclast differentiation and function. RANKL-RANK signaling is essential for the physiological osteoclast development and plays a major role in the pathological bone destruction. OPG and anti-RANKL antibody act as a specific inhibitor of RANKL and are useful and applicable to osteoporosis and rheumatoid arthritis.

Osteoclastogenesis inhibitory factor (OCIF) is a novel member of the Tumor Necrosis Factor Receptor superfamily and identical with Osteoprotegerin (OPG) discovered by Amgen researchers. OCIF/OPG is a decoy receptor (a soluble receptor that acts as an antagonist) that binds to osteoblast cells via Receptor Activator of NF-kappa B Ligand (RANKL) involved in the signal transduction between osteoblast cells and osteoclastic progenitor cells, eventually suppressing differentiation of the progenitor cells into osteoclasts. The balance between the OCIF/OPG and RANKL is regulated by cytokines and hormones. Studies on OCIF/OPG-RANKL system have provided important insights into the pathogenesis of human metabolic bone diseases, leading to the expectation of OCIF/OPG as a novel candidate for a therapeutic agent for metabolic bone diseases.

The pathogenesis of adynamic bone disease (ABD) attributes to calcium overload, active vitamin D (VD) metabolism, increase in inactive PTH (parathyroid hormone) fragments, or derangement of bone metabolism regulation factors. In particular, increased Ca overload plays a critical role in the development of ABD. Thus, alleviated Ca load by sevelamer hydrochloride and appropriate VD administration could be effective on not only prevention, and also treatment of ABD.

Certain types of cancers have a strong propensity to metastasize to bone, which requires combination of multiple factors responsible for the different steps of metastasis. Bone metabolic markers are now widely used in clinical practice and give useful information on the ongoing bone metabolism, reflecting the activity of bone-resorbing osteoclasts and bone-forming osteoblasts. Bone markers have a potential as diagnostic tools for bone metastasis, and are useful in monitoring the response to anticancer as well as antiresorptive therapies. Since bone metabolic markers alone are insufficient for the diagnosis and assessment of bone metastasis, it is important to combine bone markers with tumor-related markers and imaging studies such as scintigraphy and MRI. More recently, soluble receptor activator of nuclear factor-kappaB ligand (RANKL) and osteoprotegerin (OPG) have been implicated as markers for osteoclastogenic activity. Serum levels of these factors and/or their ratios may provide additional information on the severity of bone disease and the prognosis.

In randomized clinical trials, parathyroid hormone (PTH) showed potent anabolic effects on the lumbar spine and decreased the risk of incident vertebral fractures dramatically. Although the anabolic effect of PTH on cortical bone in the femoral neck is still unclear, it should be demonstrated in further clinical studies. Concurrent or sequential therapies of PTH and anti-resorptive agents will be one of the major issues of treatment for osteoporosis in the future.

Patients with end-stage renal disease have greatly elevated risks of atherosclerotic disease. Vascular calcification in advanced atherosclerosis is a common feature in ESRD patients. Risk factors of atherosclerosis in ESRD patients are coronary risk factors such as hypertension, diabetes and hyperlipidemia and hyperphosphatemia. Bone associated proteins including osteopontin, matrix Gla protein and osteoprotegerin may be involved in the progression of atherosclerosis.

Bone destruction in rheumatoid arthritis is characterized as 'the defective control of bone metabolism by the immune system'. During the course of our study to investigate the mechanism of arthritic bone destruction, we have explored a new field called' osteo-immunology'. Here we summarize the regulation of the bone metabolism by signalling cross-talk between RANKL and IFNs, focusing on the T cell-mediated regulation of osteoclastogenesis by IFN-gamma. The better understanding of the interactions between bone and immune cells will provide further insights into the both fields.

The abnormal metabolism of calcium and bone is one of the most common complications seen in chronic dialysis patients. The activity of PTH has been mainly assessed by intact PTH assay; however, recent data suggest that this assay may overestimate PTH activity by detecting 7-84 PTH fragments in addition to 1-84 PTH molecules(whole PTH). Another issue in this field is that higher levels of PTH are needed to maintain normal bone turnover in uremic patients. Accumulated osteoprotegerin in uremic serum may be responsible for this skeletal resistance to PTH.

A novel cytokine termed osteoclastogenesis inhibitory factor (OCIF) was purified to homogeneity from conditioned medium of human embryonic lung fibroblasts. OCIF is a heparin-binding basic glycoprotein with Mr of 60 kDa for a monomer and 120 kDa for a homodimer. OCIF specifically inhibits osteoclastogenesis in vitro and increases bone mineral density and bone volume in normal rats. The cloning of OCIF cDNA revealed that OCIF is a soluble member of the tumor necrosis factor receptor (TNFR) superfamily consisting of four cystein-rich domains, two death domain homologous regions (DDHs), and C-terminal basic domain. Mutational analysis of OCIF revealed that N-terminal portion of OCIF consisting of four cystein-rich domains is sufficient to inhibit osteoclastogenesis. OCIF inhibits osteoclastogenesis by binding to the sites expressed on osteoblastic cells and interrupting cell-to-cell signaling between osteoblastic cells and osteoclast progenitors.