Orthodontic correction of a transposed maxillary canine and first premolar in the permanent dentition.

The patient was a 16-year-old Japanese girl whose chief complaints were crowding and transposition of the maxillary canine and first premolar. A setup model was used to preoperatively align the teeth in their transposed positions. The amount of postoperative reshaping was estimated for the occlusal surfaces of the teeth. However, the patient did not wish to have her teeth reduced by reshaping or to have composite materials for restorative camouflage. Because she strongly expected alignment of her teeth in the correct intra-arch position, her transposed teeth were corrected without extraction of the transposed teeth. Cone-beam computed tomography was used to obtain more detailed information about the transposition, and the direction of tooth movement was examined. Although the duration of the treatment was long, both the crowns and the roots of the transposed teeth were aligned correctly.

Orthodontic treatment including autotransplantation of a mature tooth.

The patient was a 24-year-old Japanese female. The chief complaints were crowding and masticatory dysfunction due to the missing right first molar. Her maxillary first premolars had been extracted when she was a primary school student. We planned orthodontic treatment with extraction of the mandibular first premolars and transplantation of the mandibular left first premolar into the maxillary right first molar area. We made a diagnostic setup model to initiate an appropriate treatment plan for the discrepancy in tooth size ratio. Following the diagnostic setup model, the space in the maxillary right first molar area was closed by a small amount of tooth movement, and a good occlusion was achieved. The patient had been in retention for 7 years, and the occlusion has been maintained very well during this time. In the follow-up, 10 years after autotransplantation, no signs of inflammatory or replacement root resorption were found, and marginal bone support appeared similar to that of neighboring teeth.

Transforming growth factor-beta signaling at the tumor-bone interface promotes mammary tumor growth and osteoclast activation.

Understanding the cellular and molecular changes in the bone microenvironment is important for developing novel therapeutics to control breast cancer bone metastasis. Although the underlying mechanism(s) of bone metastasis has been the focus of intense investigation, relatively little is known about complex molecular interactions between malignant cells and bone stroma. Using a murine syngeneic model that mimics osteolytic changes associated with human breast cancer, we examined the role of tumor-bone interaction in tumor-induced osteolysis and malignant growth in the bone microenvironment. We identified transforming growth factor-beta receptor 1 (TGF-betaRI) as a commonly upregulated gene at the tumor-bone (TB) interface. Moreover, TGF-betaRI expression and activation, analyzed by nuclear localization of phospho-Smad2, was higher in tumor cells and osteoclasts at the TB interface as compared to the tumor-alone area. Furthermore, attenuation of TGF-beta activity by neutralizing antibody to TGF-beta or TGF-betaRI kinase inhibitor reduced mammary tumor-induced osteolysis, TGF-betaRI expression and its activation. In addition, we demonstrate a potential role of TGF-beta as an important modifier of receptor activator of NF-kappaB ligand (RANKL)-dependent osteoclast activation and osteolysis. Together, these studies demonstrate that inhibition of TGF-betaRI signaling at the TB interface will be a therapeutic target in the treatment of breast cancer-induced osteolysis.

IGF2 modulates the microenvironment for osteoclastogenesis.

We previously reported that hypoxic stress enhanced osteoclast differentiation via increasing insulin-like growth factor 2 (IGF2) production. However, the mechanisms underlying IGF2 stimulation remains unknown. In this study, we investigated the molecular mechanisms of osteoclastogenesis by IGF2 treatment. Primary mouse bone marrow cells were cultured with IGF2. Total RNAs were applied to a DNA microarray analysis, and quantitative RT-PCR was then used to confirm the microarray data and clarify which cells expressed the relative genes. The most interesting findings were the upregulations of CXC chemokine ligand 7 (CXCL7) expression in stromal cells and stromal cell-derived factor 1 (SDF1) expression in osteoblastic cells with IGF2 treatment. The addition of exogenous SDF1 to CXCL7 increased the number of osteoclasts and promoted the formation of giant osteoclasts. These results suggest that IGF2 modulates the microenvironment around osteoclast precursor cells. SDF1 together with CXCL7 may promote the formation of giant osteoclasts.

Transforming growth factor beta derived from bone matrix promotes cell proliferation of prostate cancer and osteoclast activation-associated osteolysis in the bone microenvironment.

Metastatic prostate tumors in the bone microenvironment stimulate bone resorption, resulting in release of growth factors from the bone matrix that play important roles in tumor growth and osteoclast induction. Transforming growth factor beta (TGFbeta) is one of the most abundantly stored cytokines in bone matrix, regulating diverse biological activities. Here we evaluate its involvement in prostate tumor growth in the bone microenvironment, comparing with tumor growth in the subcutaneous microenvironment as a control. Rat prostate tumors were transplanted onto the cranial bone and into the subcutis of F344 male rats. Tumor cell proliferation, apoptosis, and TGFbeta signal transduction were compared between the tumor-bone interface and the tumor-subcutaneous interface. Effects of TGFbeta on osteoclast differentiation were also evaluated in vitro. Inhibitory effects of TGFbeta receptor 1 antisense oligonucleotide on TGFbeta signaling, osteolysis, osteoblasts, and tumor growth were examined in vivo. Osteolytic changes were extensively observed at the tumor-bone interface, where the TGFbeta level, TGFbeta signal transduction, and tumor cell proliferation were higher than at the tumor-subcutaneous interface. In vitro treatment with receptor activator of nuclear factor-kappaB ligand induced osteoclast differentiation of bone marrow stromal cells, and additional exposure to TGFbeta exerted promotive effects on osteoclast induction. Intratumoral injection of TGFbeta receptor 1 antisense oligonucleotide significantly reduced TGFbeta signal transduction, osteolysis, induction of osteoclast and osteoblast, and tumor cell proliferation. Thus, we experimentally show that TGFbeta derived from bone matrix promotes cell proliferation of rat prostate cancer and osteoclast activation-associated osteolysis in the bone microenvironment.