Osteoclasts, the multinucleated cells primarily responsible for dissolution of bone tissue, form by fusion of precursors that circulate in the bloodstream. A variety of factors have been shown to affect the mature osteoclast and its progenitor cell, such as calcium‐regulating hormones, products of the immune system, and constituents of the arachidonic acid cascade. To date, however, the osteoclast precursor has not been identified. Furthermore, there is limited information on the factors that influence osteoclast development and regulation, reflecting (...) in part the paucity of data on the osteoclast cell surface. Recent progress in understanding osteoclasts formation and function is discussed. (shrink)

Development of gene transfer systems provides a key tool for understanding gene function. Exciting and often unexpected consequences from embryo manipulations are yielding insights into molecular mechanisms underlying development under normal and pathogenic states, and are providing animal models for diseases. Contributing to this progress is the elegant work on c‐fos(1), where Wagner and coworkers identify this proto‐oncogene as a primary factor which directs cell differentiation along the osteoclast/macrophage lineages, and thus regulates bone remodeling. Their studies support a link (...) between skeletogenesis, marrow formation and hematopoiesis, and may help to delineate mechanisms underlying the oncogenic transformation of skeletal and hematopoietic cells. (shrink)

As life extended into eukaryota, a great host of strategies emerged in the pursuit of cellular life. Some cells have been successful in solitude, some moved into cooperatives (i.e., multicellular organisms), but one additional strategy emerged. Throughout eukaryotes, many of the diverse multicellular cooperatives took life in partnership one step further. These cells came together and lost their singularity in the expanse of syncytial life. Recently in our search for this elusive “how”, we discovered the intriguing peculiarity of a nuclear, (...) RNA‐binding protein living a second life as a fusion manager at the surface of developing osteoclasts, ushering them into syncytia 1. It is from here that we will develop several thoughts about the advantages of multinucleated cells and discuss how these fusing cells pass through several hallmarks of cell death. We will propose that cell fusion shares much with cell death because cell fusion is a death of sorts for the cells that undergo it – a death of the life that was and the beginning of new life in a community without borders. (shrink)

Rheumatoid arthritis (RA) may not be a multifactorial disease; it can be hypothesized that RA is developed through a series of events following a triggering event, which is the emergence of a chemokine for neutrophils in the synovium. IL‐17A, secreted by infiltrated neutrophils, stimulates synoviocytes to produce CCL20, which attracts various CCR6‐expressing cells, including Th17 cells. Monocytes (macrophages) appear after neutrophil infiltration according to the natural course of inflammation and secrete IL‐1β and TNFα. Then, IL‐17A, IL‐1β, and TNFα stimulate synoviocytes (...) to produce CCL20, amplifying the inflammation. Varieties of chemokines secreted by infiltrating cells accumulate in the synovium and induce synoviocyte proliferation by binding to the corresponding G protein‐coupled receptors, thus expanding the synovial tissue. CCL20 in this tissue attracts circulating monocytes that express both CCR6 and receptor activator of NF‐κB (RANK), which differentiate into osteoclasts in the presence of RANKL. In this way, pannus is formed, and bone destruction begins. (shrink)

Although many regulators of skeletogenesis have been functionally characterized, one current challenge is to integrate this information into regulatory networks. Here, we discuss how the canonical Wnt and Smad‐dependent BMP pathways interact together and play antagonistic or cooperative roles at different steps of osteogenesis, in the context of the developing vertebrate embryo. Early on, BMP signaling specifies multipotent mesenchymal cells into osteochondroprogenitors. In turn, the function of Wnt signaling is to drive these osteochondroprogenitors towards an osteoblastic fate. Subsequently, both pathways (...) promote osteoblast differentiation, albeit with notable mechanistic differences. In osteocytes, the ultimate stage of osteogenic differentiation, the Wnt and BMP pathways exert opposite effects on the control of bone resorption by osteoclasts. We describe how the dynamic molecular wiring of the canonical Wnt and Smad‐dependent BMP signaling into the skeletal cell genetic programme is critical for the generation of bone‐specific cell types during development. (shrink)

The cause of Paget's disease is still unknown, despite many years of intensive study. During this time, evidence has sporadically emerged to suggest that the disease may result from a slow viral infection by one or more of the Paramyxoviruses. More recently, epidemiologic and molecular studies have suggested that the canine paramyxovirus, canine distemper virus, is the virus responsible for the disease. If true, then along with rabies, this would be a further example of a canine virus causing human disease. (...) Studies in the natural host have now supported these findings. Further investigations have proposed that the bony abnormalities seen in Paget's disease are due to the effects of the virus on osteoclastic interleukin‐6 and c‐FOS production, possibly via the transcription factor NF‐kB. (shrink)

Osteons are cylindrical structures of bone created by matrix resorbing osteoclasts, followed by osteoblasts that deposit new bone. Osteons align with the principal loading direction and it is thought that the osteoclasts are directed by osteocytes, the mechanosensitive cells that reside inside the bone matrix. These osteocytes are presumably controlled by interstitial fluid flow, induced by the physiological loading of bones. Here I consider the stimulation of osteocytes while the osteon is closed by osteoblasts. In a conceptual finite element model, (...) bone is considered a poro‐elastic material and subjected to locomotion‐induced loading conditions. It appears that the magnitude of flow is constant along the closing cone, while shear strain rate in the bone matrix diminishes linearly with the deposition of bone. This suggests that shear strain rate, rather than fluid flow, is the physical cue that controls osteocytes and bone deposition in newly formed osteons. (shrink)

Conserved upstream open reading frames (uORFs) are found within many eukaryotic transcripts and are known to regulate protein translation. Evidence from genetic and bioinformatic studies implicates disturbed uORF‐mediated translational control in the etiology of human diseases. A genetic mouse model has recently provided proof‐of‐principle support for the physiological relevance of uORF‐mediated translational control in mammals. The targeted disruption of the uORF initiation codon within the transcription factor CCAAT/enhancer binding protein β (C/EBPβ) gene resulted in deregulated C/EBPβ protein isoform expression, associated (...) with defective liver regeneration and impaired osteoclast differentiation. The high prevalence of uORFs in the human transcriptome suggests that intensified search for mutations within 5′ RNA leader regions may reveal a multitude of alterations affecting uORFs, causing pathogenic deregulation of protein expression. (shrink)