Although best known for its role in T lymphocyte activation, the calcineurin/nuclear factor of activated T cells (NFAT) signaling pathway is also known to be involved in a wide range of other biological responses in a variety of different cell types. Here we have investigated the role of the calcineurin/NFAT signaling pathway in the regulation of osteoclast differentiation. Osteoclasts are bone-resorbing multinucleated cells that are derived from the monocyte/macrophage cell lineage after stimulation with a member of the tumor necrosis factor family of ligands known as receptor activator of nuclear factor-B ligand (RANKL). We now report that inhibition of calcineurin with either the immunosuppressant drugs cyclosporin A and FK506, or the retrovirally mediated ectopic expression of a specific calcineurin inhibitory peptide, all potently inhibit the RANKL-induced differentiation of the RAW264.7 monocyte/macrophage cell line into mature multinucleated osteoclasts. In addition, we find that NFAT family members are expressed in RAW264.7 cells and that their expression is up-regulated in response to RANKL stimulation. Most importantly, we find that ectopic expression of a constitutively active, calcineurin-independent NFATc1 mutant in RAW264.7 cells is sufficient to induce these cells to express an osteoclast-specific pattern of gene expression and differentiate into morphologically distinct, multinucleated osteoclasts capable of inducing the resorption of a physiological mineralized matrix substrate. Taken together, these data define calcineurin as an essential downstream effector of the RANKL-induced signal transduction pathway leading toward the induction of osteoclast differentiation and furthermore, indicate that the activation of the NFATc1 transcription factor is sufficient to initiate a genetic program that results in the specification of the mature functional osteoclast cell phenotype.Bone is a dynamic tissue that is under a constant state of remodeling or homeostasis. This remodeling process is a delicate balance between the activities of osteoblasts, the cells that deposit bone, and osteoclasts, the cell type that is responsible for bone resorption (1, 2). Interference with this delicate balance can result in very serious human pathologies that affect bone integrity, such as osteoporosis and osteopetrosis. Accordingly, the molecular signaling pathways that regulate osteoblast and osteoclast differentiation and function have come under intense scrutiny.Osteoclasts, the cells that resorb bone, are hematopoietically derived, multinucleated cells that arise from the monocyte/ macrophage lineage (3). It is now clear that osteoclast differentiation is dependent upon the intimate cellular interaction of myeloid preosteoclast precursors with either osteoblasts or stromal cells and is influenced by a wide range of local factors (4, 5). In fact, a wealth of data has indicated that a member of the tumor necrosis factor family of ligands known as receptor activator of nuclear factor-B (NF-B) 1 ligand (RANKL; also known...

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Objective First bite syndrome, characterized by pain in the parotid region after the first bite of each meal, predominantly develops in patients who have had head and neck surgery. Idiopathic parotid pain (IPP) that mimics first bite syndrome may present in patients without a history of surgery or evidence of an underlying tumor, but its clinical features are unclear. This study characterized the clinical characteristics of IPP in patients with diabetes. Study Design A retrospective case review involving the clinical findings and pain characteristics of nine patients with IPP and diabetes who presented to our department between 2013 and 2016. Results All the patients were men diagnosed with type 2 diabetes (median age, 43 years). IPP developed unilaterally in seven patients and bilaterally in two. The median intensity of the first bite pain was 8 on a numerical rating scale of 0–10. The trigger factor was gustatory stimuli, and the trigger area was the posterior section of the tongue. Postprandial pain occurred within 1–10 min after meals in six patients. Conclusions IPP may be considered a separate disorder, in which the pain characteristics are similar to those of first bite syndrome but the clinical features and pathophysiology are different.

Activin A, a member of the TGF-b superfamily, is abundant in bone matrix, but little is known about its physiological role in bone metabolism. The present study was undertaken to determine whether topical activin A can increase the bone mass of isografted bone. The tibiae were bilaterally dissected from a donor C3H/HeJ mouse and transplanted subcutaneously in the dorsal region of a recipient mouse. One isografted tibia was topically infused for either 1, 2, 3, or 4 weeks with activin A, using an osmotic minipump at a dose of 0.02, 0.2, or 2 ng/hr. The other tibia was infused with 0.9% NaCl (control). The following results were obtained: (1) Topical activin A (2 ng/hr) stimulated periosteal bone formation after 2 or 3 weeks. The bone area in a standardized transverse section averaged 1.3 fold that in the control. (2) Numerous cuboidal or conical osteoblasts appeared on the surface of newly formed bone after the infusion of activin A for 2 or 3 weeks. Autoradiographic studies using 3H-proline revealed that the surface area of newly formed bone labelled with autoradiographic silver grains was greater in activin A-treated bone than in the control, suggesting an increased synthesis and secretion of collagen by osteoblasts. (3) Topical activin A increased the number of osteoclasts after 2 to 4 weeks. Furthermore, enhanced or increased bone resorption was observed in the projected anterior site of activin A-treated bone after 4 weeks. These results suggest that topical activin A increases the bone mass of isografted bone by increasing bone turnover.

Background/Aim Road traffic accidents (RTAs) are a common cause of maxillofacial injuries. The aim of this retrospective multicentre study was to investigate the characteristics of maxillofacial fractures and dental injuries that occurred in RTAs in Miyagi, Japan. Materials and Methods The records of 404 patients with maxillofacial injuries treated at the Oral and Maxillofacial Surgery Departments of four different institutions over a period of 12 years were analysed. Ninety‐nine of these patients had suffered these injuries in an RTA. RTA‐related cases were divided according to age, gender, presentation month, presentation day of the week, transportation mode, time of accident, fracture sites and fracture mechanism. Results There were 72 males and 27 females who suffered injuries as the result of an RTA, for a male‐to‐female ratio of 2.7:1.0, with a mean age of 35.3 years (range, 1‐86 years old). Most of the accidents occurred in June and on a Wednesday, and most of the affected patients were riding a bicycle at the time. The number of patients with maxillofacial injuries related to bicycle riding showed an increasing trend in recent years. Mandible fractures were the most prevalent, followed by dental injuries and maxilla fractures. In cases with a single fracture of the mandible, the symphysis was the most frequent site, while in those with multiple fractures, the association of symphysis and bi‐lateral condyle fractures was the greatest. For bicycle‐related accidents, a single fracture in the mandible occurred more often than multiple fractures. Conclusions The number of RTA‐related injuries while bicycle riding showed an increasing trend with mandible fractures commonly seen in those cases. Efforts to reduce maxillofacial injuries related to bicycle accidents are needed.

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Statins, lipid-lowering drugs, have been reported to influence bone metabolism. However, the available information about their effects on bone formation and resorption in vivo is still limited. The present study was undertaken to determine whether the topical administration of mevastatin could increase the bone mass of isografted bone. The tibiae were bilaterally dissected from a donor MRL/MpJ mouse and transplanted subcutaneously in the dorsal region of a recipient mouse. One grafted tibia was topically infused for either 1, 2, 3, or 4 weeks with mevastatin, using an osmotic minipump at a dose of 2.5 pmol/hr. The other tibia was infused with 0.9% NaCl (control). Our three results were: (1) Topical mevastatin stimulated bone formation and numerous cuboidal osteoblasts appeared on the surface of newly formed bone. Bone mineral density and bone area in mevastatin-treated bone were significantly increased. (2) Topical mevastatin increased the number of osteoclasts. (3) The expression of bone morphogenetic protein-2 (BMP-2) mRNA and receptor activator of NF-kB ligand (RANKL) mRNA were upregulated in mevastatin-treated bone. These results suggest that the topical infusion of mevastatin increases bone mass of isografted bone by increasing bone turnover and, at least in part, by promoting the expression of BMP-2 and RANKL mRNA.

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