Expression of inducible cAMP early repressor is coupled to the cAMP-protein kinase A signaling pathway in osteoblasts

We previously showed that parathyroid hormone (PTH) induces inducible cAMP early repressor (ICER) in osteoblastic cells and mouse calvariae. PTH signaling in osteoblastic cells is transduced by PTH receptor 1, which is coupled to cAMP-protein kinase A (PKA), protein kinase C (PKC), and calcium signaling pathways. In the present study, we examined the role of these pathways in mediating PTH-induced ICER mRNA and protein expression in osteoblastic MC3T3-E1 cells. Using RT-PCR, we found that PTH(1-34), forskolin (FSK), and 8-bromo-cAMP (8Br-cAMP) induced ICER expression, while phorbol myristate acetate (PMA), ionomycin, and PTH(3-34) did not. Similar results were found for the induction of ICER protein. PKA inhibition by H89 markedly reduced PTH- and FSK-induced ICER expression, while PKC depletion by PMA had little effect. We also tested ICER induction by other osteotropic signaling agonists. Other cAMP-PKA pathway activators, such as PTH-related protein (PTHrP), induced ICER expression, while agents that signal through other pathways did not. PTHrP maximally induced ICER mRNA at 2-4 h, which then returned to baseline by 10 h. Finally, PTH, FSK, and PTHrP induced ICER in cultured mouse calvariae and osteoblastic ROS 17/2.8, UMR-106, and Pyla cells. We conclude that ICER expression in osteoblasts requires activation of the cAMP-PKA signaling pathway.     

Prevalence of skeletal and dental anomalies and normal variants seen in cephalometric and other radiographs of orthodontic patients.

Pretreatment cephalometric radiographs may contain important incidental findings that require attention before orthodontic therapy. A review of the cephalometric and dental radiographs of 325 consecutive healthy orthodontic patients revealed 431 notable findings of the skull, cervical spine, and maxillofacial complex. Most of these findings were nonpathologic anomalies or normal variants. If recognized as such by the orthodontist, no further evaluation would be required, thus avoiding unnecessary costs and patient anxiety. However, there were 15 findings (3.5%) that required additional evaluation by physicians or oral and maxillofacial surgeons before or concurrent with the initiation of orthodontic therapy. Familiarity with the appearance and prevalence of skeletal and dental anomalies and normal variants seen in cephalometric radiographs, and the ability to separate those that require follow-up from those that do not, is an important facet of orthodontic practice.     

Periodontal disease and bisphosphonates induce osteonecrosis of the jaws in the rat

Bisphosphonates (BPs) are medications used commonly to treat primary and metastatic bone cancer, as well as osteoporosis. Although BPs improve bone mineral density, reduce fracture risk, and reduce hypercalcemia of malignancy, some patients develop BP‐related osteonecrosis of the jaws (BRONJ). This devastating complication is defined as clinically exposed bone in the maxillofacial region for more than 8 weeks. Despite an increasing number of BRONJ cases since first reported, the disease pathophysiology remains largely unknown. Since published studies suggest a significant role for dental disease in the pathophysiology of BRONJ, we developed a BRONJ animal model where aggressive periodontal disease is induced by ligature placement around the crown of the right maxillary first molar in the presence of vehicle (veh) or zoledronic acid (ZA), a potent BP. Ligature placement induced significant alveolar bone loss, which was attenuated by ZA treatment. Osteonecrosis was observed associated with ligature‐induced periodontitis in the ZA‐treated group. This was seen as sequestration and extensive periosteal alveolar bone formation on micro–computed tomography (µCT) in the ligated site of BP‐treated animals. Histologic examination confirmed these findings, seen as necrotic bone with diffuse loss of osteocytes and empty lacunae, rimming of the necrotic bone by squamous epithelium and inflammation, and exposure to the oral cavity. Importantly, the rat lesions were strikingly similar to those of BRONJ patients. Our data suggest that dental disease and potent BP therapy are sufficient for BRONJ development in the rat. © 2011 American Society for Bone and Mineral Research