Osteoclasts are specialized cells derived from the monocyte/macrophage haematopoietic lineage that develop and adhere to bone matrix, then secrete acid and lytic enzymes that degrade it in a specialized, extracellular compartment. Discovery of the RANK signalling pathway in the osteoclast has provided insight into the mechanisms of osteoclastogenesis and activation of bone resorption, and how hormonal signals impact bone structure and mass. Further study of this pathway is providing the molecular basis for developing therapeutics to treat osteoporosis and other diseases of bone loss.

Osteoclast differentiation and activation

The study of extracellular vesicles (EVs) has the potential to identify unknown cellular and molecular mechanisms in intercellular communication and in organ homeostasis and disease. Exosomes, with an average diameter of ~100 nanometers, are a subset of EVs. The biogenesis of exosomes involves their origin in endosomes, and subsequent interactions with other intracellular vesicles and organelles generate the final content of the exosomes. Their diverse constituents include nucleic acids, proteins, lipids, amino acids, and metabolites, which can reflect their cell of origin. In various diseases, exosomes offer a window into altered cellular or tissue states, and their detection in biological fluids potentially offers a multicomponent diagnostic readout. The efficient exchange of cellular components through exosomes can inform their applied use in designing exosome-based therapeutics.

The biology, function, and biomedical applications of exosomes

Osteoporosis is a disorder in which loss of bone strength leads to fragility fractures. This review examines the fundamental pathogenetic mechanisms underlying this disorder, which include: (a) failure to achieve a skeleton of optimal strength during growth and development; (b) excessive bone resorption resulting in loss of bone mass and disruption of architecture; and (c) failure to replace lost bone due to defects in bone formation. Estrogen deficiency is known to play a critical role in the development of osteoporosis, while calcium and vitamin D deficiencies and secondary hyperparathyroidism also contribute. There are multiple mechanisms underlying the regulation of bone remodeling, and these involve not only the osteoblastic and osteoclastic cell lineages but also other marrow cells, in addition to the interaction of systemic hormones, local cytokines, growth factors, and transcription factors. Polymorphisms of a large number of genes have been associated with differences in bone mass and fragility. It is now possible to diagnose osteoporosis, assess fracture risk, and reduce that risk with antiresorptive or other available therapies. However, new and more effective approaches are likely to emerge from a better understanding of the regulators of bone cell function.

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Pathogenesis of osteoporosis: concepts, conflicts, and prospects

Osteoclasts are the principal, if not exclusive, bone-resorbing cells, and their activity has a profound impact on skeletal health. So, disorders of skeletal insufficiency, such as osteoporosis, typically represent enhanced osteoclastic bone resorption relative to bone formation. Prevention of pathological bone loss therefore depends on an appreciation of the mechanisms by which osteoclasts differentiate from their precursors and degrade the skeleton. The past five years have witnessed important insights into osteoclast formation and function. Many of these discoveries have been made through genetic experiments that involved the rare hereditary disorder osteopetrosis.

Genetic regulation of osteoclast development and function

Functions of RANKL/RANK/OPG in bone modeling and remodeling.

Bone resorption by osteoclasts is coupled with bone formation by osteoblasts, and this balanced process continuously remodels and adapts the skeleton. The receptor activator of nuclear factor kappaB ligand (RANKL) has been identified as an essential cytokine for the formation and activation of osteoclasts. The effects of RANKL are physiologically counterbalanced by the decoy receptor osteoprotegerin (OPG). Estrogen deficiency, glucocorticoid exposure, T-cell activation (eg, rheumatoid arthritis), and skeletal malignancies (eg, myeloma, metastases) enhance the ratio of RANKL to OPG and, thus, promote osteoclastogenesis, accelerate bone resorption, and induce bone loss. Moreover, alterations of the OPG/RANKL/RANK system have been implicated in vascular diseases. RANKL blockade (using OPG or RANK fusion proteins or RANKL antibodies) has prevented bone loss caused by osteoporosis, chronic inflammatory disorders, and malignant tumors in animal models and may emerge as a therapy in humans based on studies in postmenopausal osteoporosis, myeloma bone disease, and osteolytic metastases. This review summarizes the clinical implications of the OPG/RANKL/RANK system for bone and vascular diseases.

Clinical Implications of the Osteoprotegerin/RANKL/RANK System for Bone and Vascular Diseases

Osteoprotegerin (OPG) regulates osteoclast and immune functions and appears to represent a protective factor for the vascular system. However, the role of OPG in human atherosclerosis has not been evaluated. In this study, we assessed OPG serum levels in 522 age-matched men who, on the basis of coronary angiography, had either absence of coronary artery disease (CAD) or presence of single-vessel disease, double-vessel disease, or severe triple-vessel disease. OPG serum levels were positively correlated with age (r = 0.28; P < 0.001) and were higher in men with diabetes mellitus (P < 0.01). OPG serum levels in men without CAD were 5.4 +/- 2.0 pmol/liter, compared with 6.1 +/- 2.1 pmol/liter in single-vessel disease (P < 0.005), 5.9 +/- 2.4 in double-vessel disease (P < 0.05), and 6.3 +/- 2.3 pmol/liter in triple-vessel disease (P < 0.001). Moreover, OPG serum levels were positively correlated with the severity of CAD as determined by a CAD scoring system (r = 0.17; P < 0.01). In conclusion, our data underline that OPG serum levels are associated with the severity of CAD and are increased in elderly men and patients with diabetes mellitus. We conclude that increased OPG serum levels may reflect advanced cardiovascular disease in men.

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Increased Osteoprotegerin Serum Levels in Men with Coronary Artery Disease

Patients with osteoporosis frequently suffer from vascular calcification, which was shown to predict both cardiovascular morbidity/mortality and osteoporotic fractures. Various common risk factors and mechanisms have been suggested to cause both bone loss and vascular calcification, including aging, estrogen deficiency, vitamin D and K abnormalities, chronic inflammation and oxidative stress. Major breakthroughs in molecular and cellular biology of bone metabolism and the characterization of knockout animals with deletion of bone-related genes have led to the concept that common signaling pathways, transcription factors and extracellular matrix interactions may account for both skeletal and vascular abnormalities. For example, mice that lack the cytokine decoy receptor osteoprotegerin or the hormone Klotho display a combined osteoporosis-arterial calcification phenotype. In this review, we summarize the current data and evaluate potential mechanisms of the osteoporosis-arterial calcification syndrome. We propose a unifying hypothesis of vascular calcification that combines both active and passive mechanisms of vascular mineralization with aspects of bone resorption and age-related changes.

Vascular calcification and osteoporosis--from clinical observation towards molecular understanding.

Vascular calcification may occur at different areas of the vessel wall, including the intima in atherosclerosis and the media in Monckeberg's sclerosis Medial calcification of arteries is common in patients with diabetes mellitus or chronic renal failure Osteoprotegerin (OPG) and receptor activator of nuclear factor-kappaB ligand are essential modulators of bone homeostasis and may be involved in the process of vascular calcification In this study we investigated arteries from patients with Monckeberg's sclerosis and atherosclerosis Apoptosis, which precedes vascular calcification in vitro, was assessed by an in situ ligation assay and was localized to the medial layer of arteries (Monckeberg's sclerosis) and the neointima (atherosclerosis) Immunohistochemistry and in situ hybridization revealed OPG immunoreactivity and mRNA expression surrounding calcified areas in the medial layer (Monckeberg's sclerosis), whereas OPG was mainly expressed adjacent to calcified neointimal lesions (atherosclerosis) Receptor activator of nuclear factor-kappaB ligand protein and mRNA were barely or not detectable Of note, TNF-related apoptosis-inducing ligand, an inducer of apoptosis that is also blocked by OPG, displayed a similar spatial distribution as OPG In summary, we demonstrate enhanced apoptosis adjacent to vascular calcification, and the concurrent expression of regulators of apoptosis and osteoclastic differentiation, TNF-related apoptosis-inducing ligand and OPG, suggesting their involvement in the pathogenesis of vascular calcification

Localization of Osteoprotegerin, Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand, and Receptor Activator of Nuclear Factor-κB Ligand in Mönckeberg’s Sclerosis and Atherosclerosis

Michael Schoppet

Papers

Clinical Implications of the Osteoprotegerin/RANKL/RANK System for Bone and Vascular Diseases

Increased Osteoprotegerin Serum Levels in Men with Coronary Artery Disease

Vascular calcification and osteoporosis--from clinical observation towards molecular understanding.

Localization of Osteoprotegerin, Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand, and Receptor Activator of Nuclear Factor-κB Ligand in Mönckeberg’s Sclerosis and Atherosclerosis

Osteoprotegerin deficiency and juvenile Paget's disease.