Can occlusal evaluation of children with unilateral cleft lip and palate help determine future maxillofacial morphology?

Objective : To investigate the change in occlusal evaluations from the 5-year-olds' index to the Goslon Yardstick and to compare the relationship between the evaluations and maxillofacial growth in patients with complete unilateral cleft lip and palate (UCLP). Design : A prospective longitudinal study. Subjects : The sample consisted of 85 patients with complete UCLP who underwent surgery from 1969 to 1994 and were treated at the Kyushu University Hospital in Fukuoka, Japan. Subjects had two serial dental casts performed at the ages of 5 and 10 years. Furthermore, each patient had lateral cephalographs taken at the age of 5 years, 76 of 85 subjects had films taken at the age of 10 years, and 54 subjects also had lateral cephalograms taken after the age of 15 years. Methods : Every dental cast was evaluated by the 5-year-olds' index and the Goslon Yardstick, respectively. The lateral cephalographs were traced and digitized, and angular dimensions were calculated. Outcomes were compared using Spearman's rank-order correlation analysis and the Kruskal-Wallis analysis. Results and Conclusion : Dental arch relationships were evaluated and rated as 2.96 in the 5-year-olds' index and 2.85 in the Goslon Yardstick, respectively. Both groupings showed a significant relationship, and they showed no change in 36 out of 85 subjects (42.3%), significant improvement in 30 (35.3%), and deterioration in 19 (22.3%). Two occlusal groupings and maxillofacial morphology on the cephalographs indicated that the grouping reflected the anteroposterior position of the mandible. Moreover, both groupings showed some relation to previous maxillofacial growth, but they did not show any relationship with future growth. The Goslon Yardstick may not predict maxillofacial morphology in adulthood.

Vicious cycle between myeloma cell binding to bone marrow stromal cells via VLA-4-VCAM-1 adhesion and macrophage inflammatory protein-1alpha and MIP-1beta production.

Multiple myeloma (MM) cell adhesion to stromal cells via very late antigen (VLA)-4 and vascular cell adhesion molecule (VCAM)-1 interaction causes enhanced secretion of osteoclastogenic activity by MM cells. We have reported that MM cell-derived macrophage inflammatory protein (MIP)-1alpha and MIP-1beta are responsible for most of the osteoclastogenic activity in MM. Thus, adhesion-mediated osteoclastogenesis may be caused by enhanced production of MIP-1 via VLA-4-VCAM-1 interaction. The present study was undertaken to clarify whether MM cell-derived MIP-1 plays a role in VLA-4-VCAM-1 adhesion-mediated osteoclastogenesis. Adhesion of MM cells to VCAM-1 upregulated MIP-1alpha and MIP-1beta production from MM cells and enhanced production of osteoclastogenic activity by MM cells. Blockade of MIP-1alpha and MIP-1beta actions not only abrogated elaboration of osteoclastogenic activity, but also suppressed spontaneous MM cell adhesion to VCAM-1. These results demonstrate that MM cell adhesion to VCAM-1 upregulates MIP-1 production by MM cells to cause enhancement of osteoclastogenesis. In addition, the results suggest that the increased production of MIP-1 further enhances MM cell binding to stromal cells via stimulation of VLA-4-VCAM-1 adhesion, forming a "vicious cycle" between MM cell adhesion to stromal cells and MIP-1 production via VLA-4-VCAM-1 interaction.

Malignant B-lymphoid cells with bone lesions express receptor activator of nuclear factor-kappaB ligand and vascular endothelial growth factor to enhance osteoclastogenesis.

PURPOSE: Receptor activator of nuclear factor-kappaB ligand (RANKL) is a key mediator of osteoclastogenesis. Because certain types of tumor cells aberrantly express RANKL, and because bone destruction also develops in B-cell lymphomas of bone origin, we investigated RANKL expression and the mechanisms of osteoclastogenesis in B-lymphoid neoplasms. EXPERIMENTAL DESIGN AND RESULTS: Immunohistochemistry of bone specimens resected from patients with primary B-cell lymphoma of bone with bone destruction revealed that lymphoma cells express RANKL as well as vascular endothelial cell growth factor (VEGF). The tumor cells isolated from the bone specimens enhanced osteoclastogenesis in vitro. In contrast, B-cell lymphoma infiltrating to the bone marrow without bone destruction did not express RANKL. Both RANKL and VEGF were expressed by a portion of B-lymphoid cell lines, including Daudi and IM-9. These RANKL-expressing tumor cells enhanced osteoclastogenesis from RAW264.7 cells and human monocyte-derived preosteoclasts in the absence of stromal cells/osteoblasts in a RANKL-dependent manner. Furthermore, conditioned media from Daudi cells enhanced transmigration of preosteoclasts that was inhibited by anti-VEGF antibody, suggesting that tumor cell-derived VEGF mediates recruitment of osteoclast precursors. Moreover, cocultures of B-lymphoid cell lines with osteoclasts enhanced the growth of B-lymphoid cells. CONCLUSIONS: Some malignant B cells aberrantly express functional RANKL as well as VEGF to enhance osteoclastogenesis. The coexpression of RANKL and VEGF may also contribute to the close cellular interactions with osteoclastic cells, thereby forming a vicious cycle between osteoclastic bone destruction and tumor expansion in bone.

A soluble form of fibroblast growth factor receptor 2 (FGFR2) with S252W mutation acts as an efficient inhibitor for the enhanced osteoblastic differentiation caused by FGFR2 activation in Apert syndrome.

Apert syndrome is an autosomal dominant disease characterized by craniosynostosis and bony syndactyly associated with point mutations (S252W and P253R) in the fibroblast growth factor receptor (FGFR) 2 that cause FGFR2 activation. Here we investigated the role of the S252W mutation of FGFR2 on osteoblastic differentiation. Osteoblastic cells derived from digital bone in two Apert patients with the S252W mutation showed more prominent alkaline phosphatase activity, osteocalcin and osteopontin mRNA expression, and mineralized nodule formation compared with the control osteoblastic cells derived from two independent non-syndromic polydactyly patients. Stable clones of the human MG63 osteosarcoma cells (MG63-Ap and MG63-IIIc) overexpressing a splice variant form of FGFR2 with or without the S252W mutation (FGFR2IIIcS252W and FGFR2IIIc) showed a higher RUNX2 mRNA expression than parental MG63 cells. Furthermore MG63-Ap exhibited a higher osteopontin mRNA expression than did MG63-IIIc. The enhanced osteoblastic marker gene expression and mineralized nodule formation of the MG63-Ap was inhibited by the conditioned medium from the COS-1 cells overexpressing the soluble FGFR2IIIcS252W. Furthermore the FGF2-induced osteogenic response in the mouse calvarial organ culture system was blocked by the soluble FGFR2IIIcS252W. These results show that the S252W mutation in the FGFR2 gene enhances the osteoblast phenotype in human osteoblasts and that a soluble FGFR2 with the S252W mutation controls osteoblast differentiation induced by the S252W mutation through a dominant negative effect on FGFR2 signaling in Apert syndrome.

Osteoclasts enhance myeloma cell growth and survival via cell-cell contact: a vicious cycle between bone destruction and myeloma expansion.

Multiple myeloma (MM) expands in the bone marrow and causes devastating bone destruction by enhancing osteoclastic bone resorption in its vicinity, suggesting a close interaction between MM cells and osteoclasts (OCs). Here, we show that peripheral blood mononuclear cell-derived OCs enhanced growth and survival of primary MM cells as well as MM cell lines more potently than stromal cells, and that OCs protected MM cells from apoptosis induced by serum depletion or doxorubicin. OCs produced osteopontin (OPN) and interleukin 6 (IL-6), and adhesion of MM cells to OCs increased IL-6 production from OCs. In addition, IL-6 and OPN in combination enhanced MM cell growth and survival. However, the effects of OCs on MM cell growth and survival were only partially suppressed by a simultaneous addition of anti-IL-6 and anti-OPN antibodies and were completely abrogated by inhibition of cellular contact between MM cells and OCs. These results demonstrate that OCs enhance MM cell growth and survival through a cell-cell contact-mediated mechanism that is partially dependent on IL-6 and OPN. It is suggested that interactions of MM cells with OCs augment MM growth and survival and, thereby, form a vicious cycle, leading to extensive bone destruction and MM cell expansion.

Expression of RANK is dependent upon differentiation into the macrophage/osteoclast lineage: induction by 1alpha,25-dihydroxyvitamin D3 and TPA in a human myelomonocytic cell line, HL60.

Receptor activator of nuclear factor (RANK) is a member of the tumor necrosis factor receptor superfamily indispensable for osteoclast differentiation. However, little is known about the regulatory mechanism of RANK expression. In the present study, RANK expression during macrophage/osteoclast differentiation was investigated using a human myelomonocytic cell line, HL60, capable of differentiating into mature osteoclasts under appropriate conditions. RANK mRNA expression was barely detectable in growing HL60 cells. We found that treatment with 1alpha,25-dihydroxyvitamin D(3) and TPA resulted in an apparent induction of RANK mRNA and protein in association with differentiation into the macrophage/osteoclast lineage. Induction of RANK was time and dose dependent and lineage specific. Moreover, RANK induction was blocked by an RNA polymerase II inhibitor, suggesting an involvement of a transcriptional mechanism. The induced RANK was functional as it was able to bind RANK ligand and activate NF-kappaB. In the induced HL60 cells expressing both c-Fms and RANK, RANK mRNA expression was further enhanced by RANKL, but not by macrophage colony-stimulating factor. These results suggest a positive feedback regulation of RANK expression by its own intracellular signaling. The in vitro system described here may be a useful model to elucidate the regulatory mechanism of RANK expression and its role in human osteoclastogenesis.

Prognostic implications of nasal cavity and cleft morphology in secondary bone grafting.

OBJECTIVE: To examine the prognostic significance of the skeletal morphology around the nasal cavity and the alveolar cleft in secondary bone grafting (SBG). DESIGN AND SETTING: Fifty-one alveolar clefts in 41 patients (10 bilateral and 31 unilateral cleft lips and palates) registered in the Tokushima University Dental Hospital were examined in this study. METHOD: Evaluation of the bony bridge after SBG using dental radiographs at 1 year after surgery. The clefts were divided into two groups: group I (54.9%) in which the upper border of the bony bridge was preferably maintained on or above the horizontal reference line (RL) constructed at the level of the root apex of the upper central incisor adjacent to the cleft, and group II (45.1%) in which the bone level was lower than the RL. Presurgical cleft width was determined by the dental radiographs. The cleft/nasal cavity ratio; the value of the cleft width divided by the nasal cavity width on the cleft side, which was analyzed by frontal cephalograms before the SBG; and the cleft/apertura piriformis ratio, the value analyzed by computed tomography, were used. RESULTS AND CONCLUSION: The age, sex, and eruptive stage of the canine teeth at the time of the SBG showed no significant difference between groups. The presurgical cleft width also showed no significant difference between group I (6.6 +/- 3.1 mm) and group II (7.9 +/- 3.3 mm). The cleft/nasal cavity ratio showed a significant difference between groups I and II (0.42 +/- 0.14, 0.75 +/- 0.25; p < .05). Furthermore, the cleft/apertura piriformis ratio also showed a significant difference between groups I and II (0.32 +/- 0.12, 0.65 +/- 0.26; p < .05). These results suggested that measurements of the skeletal morphology around the nasal cavity and alveolar cleft might aid in predicting the stability of the bony bridge after SBG.

Role for macrophage inflammatory protein (MIP)-1alpha and MIP-1beta in the development of osteolytic lesions in multiple myeloma.

Multiple myeloma (MM) cells cause devastating bone destruction by activating osteoclasts in the bone marrow milieu. However, the mechanism of enhanced bone resorption in patients with myeloma is poorly understood. In the present study, we investigated a role of C-C chemokines, macrophage inflammatory protein (MIP)-1alpha and MIP-1beta, in MM cell-induced osteolysis. These chemokines were produced and secreted by a majority of MM cell lines as well as primary MM cells from patients. Secretion of MIP-1alpha and MIP-1beta correlated well with the ability of myeloma cells to enhance osteoclastic bone resorption both in vitro and in vivo as well as in MM patients. In osteoclastogenic cultures of rabbit bone cells, cocultures with myeloma cells as well as addition of myeloma cell-conditioned media enhanced both formation of osteoclastlike cells and resorption pits to an extent comparable to the effect of recombinant MIP-1alpha and MIP-1beta. Importantly, these effects were mostly reversed by neutralizing antibodies against MIP-1alpha and MIP-1beta, or their cognate receptor, CCR5, suggesting critical roles of these chemokines. We also demonstrated that stromal cells express CCR5 and that recombinant MIP-1alpha and MIP-1beta induce expression of receptor activator of nuclear factor-kappaB (RANK) ligand by stromal cells, thereby stimulating osteoclast differentiation of preosteoclastic cells. These results suggest that MIP-1alpha and MIP-1beta may be major osteoclast-activating factors produced by MM cells.

Correction of a deformed thumb by distraction of the phalanx.

We used distraction osteogenesis to correct six deformed thumbs in four patients ranging in age from 4 to 7 years. Two of the patients had Apert syndrome (syndromic craniosynostosis with symmetrical syndactyly) and two had polydactyly. We used a small fixator with a ball joint and successfully corrected the angular deformity after lengthening the proximal phalanx by distraction. This single inclusive procedure was extremely useful. We found the optimal distraction regimen for the digital phalanx was a one day waiting period and lengthening at 1 mm/day. The mean healing indexes were 37.2 days/cm (range 24.2 to 41.5) in those with Apert syndrome and 64.3 days/cm in those with polydactyly (62.5 and 66.0). Our results suggest that osteogenesis at the distraction site may be quicker in patients with Apert syndrome than in those with polydactyly.