Advances in tooth agenesis and tooth regeneration.

The lack of treatment options for congenital (0.1%) and partial (10%) tooth anomalies highlights the need to develop innovative strategies. Over two decades of dedicated research have led to breakthroughs in the treatment of congenital and acquired tooth loss. We revealed that by inactivating USAG-1, congenital tooth agenesis can be successfully ameliorated during early tooth development and that the inactivation promotes late-stage tooth morphogenesis in double knockout mice. Furthermore, Anti- USAG-1 antibody treatment in mice is effective in tooth regeneration and can be a breakthrough in treating tooth anomalies in humans. With approximately 0.1% of the population suffering from congenital tooth agenesis and 10% of children worldwide suffering from partial tooth loss, early diagnosis will improve outcomes and the quality of life of patients. Understanding the role of pathogenic USAG-1 variants, their interacting gene partners, and their protein functions will help develop critical biomarkers. Advances in next-generation sequencing, mass spectrometry, and imaging technologies will assist in developing companion and predictive biomarkers to help identify patients who will benefit from tooth regeneration.

Anti-USAG-1 therapy for tooth regeneration through enhanced BMP signaling.

Uterine sensitization-associated gene-1 (USAG-1) deficiency leads to enhanced bone morphogenetic protein (BMP) signaling, leading to supernumerary teeth formation. Furthermore, antibodies interfering with binding of USAG-1 to BMP, but not lipoprotein receptor-related protein 5/6 (LRP5/6), accelerate tooth development. Since USAG-1 inhibits Wnt and BMP signals, the essential factors for tooth development, via direct binding to BMP and Wnt coreceptor LRP5/6, we hypothesized that USAG-1 plays key regulatory roles in suppressing tooth development. However, the involvement of USAG-1 in various types of congenital tooth agenesis remains unknown. Here, we show that blocking USAG-1 function through USAG-1 knockout or anti-USAG-1 antibody administration relieves congenital tooth agenesis caused by various genetic abnormalities in mice. Our results demonstrate that USAG-1 controls the number of teeth by inhibiting development of potential tooth germs in wild-type or mutant mice missing teeth. Anti-USAG-1 antibody administration is, therefore, a promising approach for tooth regeneration therapy.

Association of Education and Depressive Symptoms with Tooth Loss.

Previous evidence suggests the association of lower educational attainment and depressive symptoms with tooth loss. The hypothesis of this study was that these factors may exacerbate the effect on tooth loss beyond the sum of their individual effects. We aimed to clarify the independent and interactive effects of educational attainment and depressive symptoms on the number of missing teeth among community residents. Cross-sectional data of 9,647 individuals were collected from the general Japanese population. Dental examination was conducted by dentists. Educational attainment was categorized into 3 levels based on the number of educational years: ≤9, >9 to ≤12, and >12 y. The Center for Epidemiologic Studies Depression Scale (CES-D) was used to assess depressive symptoms; a total score of ≥16 and/or the use of medications for depression indicate the presence of depressive symptoms. In the multivariate analysis with adjustment for conventional risk factors, educational attainment was identified as a determinant of the number of missing teeth (>9 to ≤12 y of education: coefficient = 0.199, 95% confidence interval [CI], 0.135 to 0.263, P < 0.001; ≤9 y of education: coefficient = 0.318, 95% CI, 0.231 to 0.405, P < 0.001: reference, >12 y of education). An analysis that included interaction terms revealed that the relationship between "≤9 y of education" and the number of missing teeth differed depending on the depressive symptoms, indicating a positive interactive association (coefficient for interaction = 0.198; 95% CI, 0.033 to 0.364, P for interaction = 0.019: reference, >12 y of education). Our study suggests the presence of a significant association between educational attainment and tooth loss, as well as a partial interactive association between "≤9 y of education" and "depressive symptoms" in the general Japanese population.

Third Dentition Is the Main Cause of Premolar Supernumerary Tooth Formation.

While the prevalence of supernumerary teeth (ST) is high in permanent dentition, the etiology of ST in humans remains unclear. However, multiple murine models of ST have elaborated on dated mechanisms traditionally ascribed to ST etiology: one involves the rescue of rudimental teeth, and the second considers the contribution of odontogenic epithelial stem cells. It remains unclear whether these mechanisms of ST formation in mice are applicable to humans. The third dentition is usually regressed apoptotic-that is, the teeth do not completely form in humans. Recently, it was suggested that ST result from the rescue of regression of the third dentition in humans. The present investigation evaluates the proportion of collected general ST cases that evinced a third dentition based on the clinical definition of ST derived from the third dentition. We also investigated the contribution of SOX2-positive odontogenic epithelial stem cells to ST formation in humans. We collected 215 general ST cases from 15,008 patients. We confirmed that the general characteristics of the collected ST cases were similar to the results from previous reports. Of the 215 cases, we narrowed our analysis to the 78 patients who had received a computed tomography scan. The frequency of ST considered to have been derived from the third dentition was 26 out of 78 cases. Evidence of a third dentition was especially apparent in the premolar region, was more common in men, and was more likely among patients with ≥3 ST. SOX2-positive odontogenic epithelial stem cells within the surrounding epithelial cells of developing ST were observed in non-third dentition cases and not in third dentition cases. In conclusion, the third dentition is the main cause of ST in humans. The odontogenic epithelial stem cells may contribute to ST formation in cases not caused by a third dentition.

Everolimus Rescue Treatment for Chronic Rejection After Pediatric Living Donor Liver Transplantation: 2 Case Reports.

Chronic rejection (CR) remains a challenging complication after liver transplantation. Everolimus, which is a mammalian target of rapamycin inhibitor, has an anti-fibrosis effect. We report here the effect of everolimus on CR. Case 1 was a 7-year-old girl who underwent living donor liver transplantation (LDLT) shortly after developing fulminant hepatitis at 10 months of age. Liver function tests (LFTs) did not improve after transplantation despite treatment with tacrolimus + mycophenolate mofetil (MMF). Antithymoglobulin (ATG) and steroid pulse therapy were also ineffective. The patient was diagnosed with CR, and everolimus was started with a target trough level of about 5 ng/mL. LFTs improved and pathological examination showed no progression of hepatic fibrosis. Case 2 was a 10-year-old girl with Alagille syndrome who underwent LDLT at 1 year of age. She had biopsy-proven acute cellular rejection with prolonged LFT abnormalities beginning 3 years after transplantation. She was treated with steroid pulse therapy, followed by MMF, tacrolimus, and prednisolone. Her condition did not improve, even after subsequent ATG administration. CR was suspected based on liver biopsy in the fourth postoperative year, and everolimus was introduced. The target trough level was around 5 ng/mL, but was reduced to 3 ng/mL due to stomatitis. Four years have passed since the initiation of everolimus, and LFTs are stable with no progression of liver biopsy fibrosis. We describe 2 cases in which everolimus was administered for CR. In both cases, LFTs improved and fibrosis did not progress, suggesting that everolimus is an effective treatment for CR after LDLT.

Pulmonary Arterial Pressure Management Based on Oral Medicine for Pediatric Living Donor Liver Transplant With Portopulmonary Hypertension.

Pediatric living donor liver transplantation (LDLT) in patients with advanced portopulmonary hypertension (PoPH) is associated with poor prognoses. Recently, novel oral medications, including endothelin receptor antagonists (ERAs), phosphodiesterase 5 (PDE5) inhibitors, and oral prostacyclin (PGI2) have been used to treat PoPH. Pediatric patients with PoPH who underwent LDLT from 2006 to 2016 were enrolled. Oral pulmonary hypertension (PH) medication was administered to control pulmonary arterial pressure (PAP). Four patients had PoPH. Their ages ranged from 6 to 16 years, and their original diseases were biliary atresia (n = 2), portal vein obstruction (n = 1), and intrahepatic portal systemic shunt (n = 1). For preoperative management, 2 patients received continuous intravenous PGI2 and 2 oral medications (an ERA alone or an ERA and a PDE5 inhibitor), and 2 received only oral drugs (an ERA and a PDE5 inhibitor). One patient managed only with intravenous PGI2 died. In the remaining 3 cases, intravenous PGI2 or NO was discontinued before the end of the first postoperative week. Postoperative medications were oral PGI2 alone (n = 1), an ERA alone (n = 1), or the combination of an ERA and a PDE5 inhibitor (n = 1). An ERA was the first-line therapy, and a PDE5 inhibitor was added if there was no effect. New oral PH medications were effective and safe for use in pediatric patients following LDLT. In particular, these new oral drugs prevent the need for central catheter access to infuse PGI2.

Circulatory CNP Rescues Craniofacial Hypoplasia in Achondroplasia.

Achondroplasia is the most common genetic form of human dwarfism, characterized by midfacial hypoplasia resulting in occlusal abnormality and foramen magnum stenosis, leading to serious neurologic complications and hydrocephalus. Currently, surgery is the only way to manage jaw deformity, neurologic complications, and hydrocephalus in patients with achondroplasia. We previously showed that C-type natriuretic peptide (CNP) is a potent stimulator of endochondral bone growth of long bones and vertebrae and is also a potent stimulator in the craniofacial region, which is crucial for midfacial skeletogenesis. In this study, we analyzed craniofacial morphology in a mouse model of achondroplasia, in which fibroblast growth factor receptor 3 (FGFR3) is specifically activated in cartilage ( Fgfr3ach mice), and investigated the mechanisms of jaw deformities caused by this mutation. Furthermore, we analyzed the effect of CNP on the maxillofacial area in these animals. Fgfr3ach mice exhibited midfacial hypoplasia, especially in the sagittal direction, caused by impaired endochondral ossification in craniofacial cartilage and by premature closure of the spheno-occipital synchondrosis, an important growth center in craniomaxillofacial skeletogenesis. We crossed Fgfr3ach mice with transgenic mice in which CNP is expressed in the liver under the control of the human serum amyloid-P component promoter, resulting in elevated levels of circulatory CNP ( Fgfr3ach/SAP-Nppc-Tg mice). In the progeny, midfacial hypoplasia in the sagittal direction observed in Fgfr3ach mice was improved significantly by restoring the thickness of synchondrosis and promoting proliferation of chondrocytes in the craniofacial cartilage. In addition, the foramen magnum stenosis observed in Fgfr3ach mice was significantly ameliorated in Fgfr3ach/SAP-Nppc-Tg mice due to enhanced endochondral bone growth of the anterior intraoccipital synchondrosis. These results clearly demonstrate the therapeutic potential of CNP for treatment of midfacial hypoplasia and foramen magnum stenosis in achondroplasia.

Fibroadenoma in adolescent females after living donor liver transplantation.

Breast FA is the most common breast tumor diagnosed in young women. Female renal transplant recipients on CsA have an increased risk of developing FA. However, reports of FA after LDLT have not been described. Our objectives were to determine the incidence of FA, analyze risk factors for FA, and evaluate treatment strategies in adolescent females after LDLT. A total of 18 female patients aged 10-19 years who underwent LDLT and survived at least one year after transplantation were enrolled in our study. The incidence of FA was 11.1%. To determine pre- or post-transplant conditions that are associated with FA after transplantation, the patients were divided into two groups according to the presence or absence of FA: FA group (n=2) and non-FA group (n=16). There were no differences in mean age at LDLT, mean age at breast evaluation, and mean duration between transplantation and breast evaluation between the two groups. However, there was a difference in the immunosuppressive regimen between the two groups. The FA group was maintained on CsA, whereas the non-FA group was maintained on tacrolimus. CsA might be implicated in FA development in adolescent females after LDLT.

Impact of Donor-Specific Antibodies on Graft Fibrosis After Pediatric Living Donor Liver Transplantation for Biliary Atresia.

BACKGROUND: Pediatric living donor liver transplant (LDLT) patients sometimes develop graft fibrosis after non-recurrent diseases such as biliary atresia (BA). Donor-specific antibodies (DSA) have recently been shown to play a possible role in graft damage after liver transplantation. We report the impact of DSA on pediatric LDLT for BA patients. METHODS: Patients under age 18 years who received LDLT for BA at our institution and who had at least 5 years' follow-up were identified, and 23 were eventually enrolled in this study. Pathological findings were assessed with the use of the last available biopsy. Patients were divided into 2 groups, DSA-positive and DSA-negative. Graft fibrosis after LDLT was assessed according to DSA groups. RESULTS: The mean patient age at transplant was 2.6 years. The mean time to the last available biopsy after LDLT was 8.2 years (4.8-15.6 years); 6 patients (26%) showed no fibrosis, whereas fibrosis was graded as F1, F2, or F3 in 8 patients (35%), 8 patients (35%), and 1 patient, respectively. DSA were observed in 12 patients (52%). Moderate graft fibrosis (F2 and F3) was found in 7 (58%) of the DSA-positive group, but only 2 (18%) of the DSA-negative group, showing a statistically significant difference (P < .05). Pre-transplant cross-matching was performed in 17 patients. The 2 patients with a positive cross-match were DSA-positive. Six cross-match-negative patients developed de novo DSA after LDLT. CONCLUSIONS: Graft fibrosis was observed after LDLT for BA during long-term follow-up, more commonly in DSA-positive patients. DSA may play a role in fibrosis formation.

Mouth breathing, another risk factor for asthma: the Nagahama Study.

BACKGROUND: Allergic rhinitis, a known risk factor for asthma onset, often accompanies mouth breathing. Mouth breathing may bypass the protective function of the nose and is anecdotally considered to increase asthma morbidity. However, there is no epidemiological evidence that mouth breathing is independently associated with asthma morbidity and sensitization to allergens. In this study, we aimed to clarify the association between mouth breathing and asthma morbidity and allergic/eosinophilic inflammation, while considering the effect of allergic rhinitis. METHODS: This community-based cohort study, the Nagahama Study, contained a self-reporting questionnaire on mouth breathing and medical history, blood tests, and pulmonary function testing. We enrolled 9804 general citizens of Nagahama City in the Shiga Prefecture, Japan. RESULTS: Mouth breathing was reported by 17% of the population and was independently associated with asthma morbidity. The odds ratio for asthma morbidity was 1.85 (95% CI, 1.27-2.62) and 2.20 (95% CI, 1.72-2.80) in subjects with mouth breathing alone and allergic rhinitis alone, which additively increased to 4.09 (95% CI, 3.01-5.52) when mouth breathing and allergic rhinitis coexisted. Mouth breathing in nonasthmatics was a risk for house dust mite sensitization, higher blood eosinophil counts, and lower pulmonary function after adjusting for allergic rhinitis. CONCLUSION: Mouth breathing may increase asthma morbidity, potentially through increased sensitization to inhaled allergens, which highlights the risk of mouth-bypass breathing in the 'one airway, one disease' concept. The risk of mouth breathing should be well recognized in subjects with allergic rhinitis and in the general population.

Disseminated Metastatic Tissue Calcification After Orthotopic Liver Transplantation: A Case Report.

BACKGROUND: Hypercalcemia has been observed in patients after liver transplantation. However, it is rare that the hypercalcemia induced disseminated tissue calcification and heart failure. CASE REPORT: We report a rare case of heart failure caused by disseminated metastatic tissue calcification that involved extensive progressive myocardial calcification after liver transplantation. A 20-year-old man with end-stage liver disease due to biliary atresia underwent ABO-incompatible living donor liver transplantation. After successful transplantation, he suffered from antibody-mediated rejection. Subsequently, ABO-matched cadaveric liver retransplantation was successfully performed. Hypercalcemia developed gradually following the second transplantation. His serum calcium level increased to 18.3 mg/dL with sudden onset of ventricular tachycardia. Although he was resuscitated with a cardiopulmonary support device, he died of heart and liver failure. Histopathologic examination revealed systemic disseminated metastatic tissue calcification, including massive myocardial calcification. CONCLUSION: Progressive worsening of hypercalcemia resulted in disseminated metastatic tissue calcification and massive metastatic myocardial calcification, which led to heart failure after liver transplantation. Because hypercalcemia after liver transplantation can cause fatal tissue calcification, early intervention for hypercalcemia should be considered.

Comparison of human mesenchymal stem cells derived from bone marrow, synovial fluid, adult dental pulp, and exfoliated deciduous tooth pulp.

Populations of pluripotent stem cells were isolated from bone marrow, synovial fluid, adult dental pulp, and exfoliated deciduous teeth and their multipotentiality properties compared. Osteogenic, chondrogenic, adipogenic, and neurogenic differentiation potentials were examined. Bone marrow mesenchymal stem cells (BMMSCs) and synovial fluid-derived cells (SFCs) showed the highest levels of osteogenesis as expressed by alkaline phosphatase (ALP) activity (0.54±0.094 U/mg protein and 0.57±0.039 U/mg protein, respectively; P=0.60) and by osteocalcin (BGLAP; determined by real-time RT-PCR). SFCs showed the highest levels of chondrogenesis as expressed by ALP activity (1.75±0.097 U/mg protein) and of COL2A1 and COL10A1 by real-time PCR. In terms of adipogenesis, lipid vesicles were observed in the BMMSCs and SFCs. Dental pulp stem cells (DPSCs) and stem cells from human exfoliated deciduous teeth (SHED) exhibited neurogenesis potential, as shown by increases in expression of class III ß-tubulin (TUBB3) and microtubule-associated protein 2 (MAP2) on RT-PCR. Variability was found in the differentiation potential corresponding to the tendency of the original tissue to differentiate. It is suggested that the cell type should be selected depending on the regenerative treatment regimen.

Tooth loss and atherosclerosis: the Nagahama Study.

Several epidemiologic studies have suggested that oral disease is a risk factor for cardiovascular disease (CVD). However, whether a clinically significant association exists between the 2 disorders remains controversial. Here, we investigated the association between tooth loss, as an indicator of oral disease, and arterial stiffness, as a marker of atherosclerosis, in Japanese adults. Cross-sectional data were collected for 8,124 persons aged 30 to 75 y with no history of tooth loss for noninflammatory reasons, such as orthodontic treatment, malposition, and trauma. Participants received a comprehensive dental examination and extensive in-person measurements of CVD risk factors, and arterial stiffness was evaluated using the cardio-ankle vascular index (CAVI). We examined the association between CAVI and tooth loss using general linear models with adjustment for age, sex, body mass index, smoking status, hemoglobin A1c, and a history of insulin or hypoglycemic medication depending on the model. In addition, we performed an analysis that included interaction terms of the centered variables tooth loss, sex, and age. The results of the multiple regression analysis that included the interaction terms detected that the relationship between CAVI and tooth loss was dependent on sex, with only men showing a positive correlation (ß for interaction = 0.04; 95% confidence interval, 0.02-0.06). The findings from this study suggest that a linear relationship exists between tooth loss and degree of arterial stiffness and that the association differed depending on sex.

The effect of nicotine on osteoinduction by recombinant human bone morphogenetic protein 2.

Nicotine, one of the constituents of tobacco, is known to have an adverse effect on human health. We sought to clarify the interaction between nicotine and recombinant human bone morphogenetic protein 2 (rhBMP-2) in terms of osteogenesis in vitro and osteoinduction in vivo. Nicotine did not inhibit or stimulate alkaline phosphatase (ALP) activity or the amount of osteocalcin in C2C12 cells in the presence of rhBMP-2 in vitro. Ectopic bone formation using a collagen sponge containing rhBMP-2 was evaluated with and without nicotine after 21 days using radiographic, histological, biochemical, and immunohistochemical analyses. ALP activity in the medium-dose group (2.2±0.9IU/mg protein; P=0.047) and the high-dose group (2.0±0.1IU/mg protein; P=0.03) was significantly lower than in the control group. The calcium content in the medium-dose group (35.4±12.9µg/mg tissue; P=0.0099) and high-dose group (34.8±10.5µg/mg tissue; P=0.006) was significantly lower than in the control group. The number of vascular endothelial growth factor-positive cells in the high-dose group (671.9±57.3cells/mm(2); P=0.03) was significantly lower than in the control group. Results showed that nicotine did not inhibit the stimulatory effect of rhBMP-2 in vitro, but a high dose of nicotine inhibited bone formation in vivo by adversely affecting vascularization.

Phenotypes of CCAAT/enhancer-binding protein beta deficiency: hyperdontia and elongated coronoid process.

OBJECTIVES: This investigation aimed to conduct a case-control study of mandibular morphology and dental anomalies to propose a relationship between mandibular/dental phenotypes and deficiency of CCAAT/enhancer-binding protein beta (CEBPB). MATERIALS AND METHODS: Skulls of CEBPB(-/-), CEBPB(+/-) and CEBPB(+/+) mice were inspected with micro-computed tomography. Mandibular morphology was assessed with a method of Euclidean distance matrix analysis. RESULTS: Elongation of the coronoid process was identified in CEBPB(+/-) (P ≤ 0.046) and CEBPB(-/-) 12-month-olds (P ≤ 0.028) but not in 14-day-olds (P ≥ 0.217) and 0-day-olds (P ≥ 0.189) of either genotype. Formation of supernumerary teeth in CEBPB(-/-) adult mice was demonstrated (χ(2) = 6.00, df = 1, P = 0.014). CONCLUSIONS: CEBPB deficiency was related to elongation of the coronoid process and formation of supernumerary teeth. The mandibular and dental phenotypes of CEBPB deficiency were unseen by the 14th day after birth. Future investigations into the influence of CEBPB on mandibular and dental development are needed.

The effects of C-type natriuretic peptide on craniofacial skeletogenesis.

C-type natriuretic peptide (CNP) is a potent stimulator of long bone and vertebral development via endochondral ossification. In the present study, we investigated the effects of CNP on craniofacial skeletogenesis, which consists of both endochondral and membranous ossification. Morphometric analyses of crania from CNP knockout and transgenic mice revealed that CNP stimulates longitudinal growth along the cranial length, but does not regulate cranial width. CNP markedly increased the length of spheno-occipital synchondrosis in fetal murine organ cultures, and the thickness of cultured murine chondrocytes from the spheno-occipital synchondrosis or nasal septum, resulting in the stimulation of longitudinal cranial growth. Mandibular growth includes endochondral and membranous ossification; although CNP stimulated endochondral bone growth of condylar cartilage in cultured fetal murine mandibles, differences in the lengths of the lower jaw between CNP knockout or transgenic mice and wild-type mice were smaller than those observed for the lengths of the upper jaw. These results indicate that CNP primarily stimulates endochondral ossification in the craniofacial region and is crucial for midfacial skeletogenesis.

Increased incidence of osteonecrosis of the jaw after tooth extraction in patients treated with bisphosphonates: a cohort study.

This study estimated the cumulative incidence and risk ratio for osteonecrosis of the jaw (ONJ) after tooth extraction in patients with and without administration of bisphosphonates (BP) and identified potential risk factors for bisphosphonate-induced osteonecrosis of the jaw (BIONJ). A cohort study was conducted in all patients undergoing tooth extraction at a university hospital in Japan from April 2006 to June 2009. Of 3216 patients, 126 had BP administration, of whom 5 (3.9%, 95% confidence interval (CI): 1.2-9.2) developed ONJ, versus 1 (0.032%, 95% CI: 0.00081-0.18) among 3090 patients without BP administration. BP administration was associated with the development of ONJ after tooth extraction, with an unadjusted risk ratio of 122.6 (95% CI: 14.4-1041.8). When stratified by age and route of BP administration, the risk ratio for ONJ patients aged 65 years or older with intravenous BP administration compared to those without was 200.2 (95% CI: 23.8-1679.4, P<0.001). Patients receiving BP showed a significant association between the incidence of BIONJ and alveolar bone loss score. The risk of ONJ is higher in patients with than without BP administration, particularly intravenous administration. Severe periodontitis might be a risk factor for BIONJ.

Comparison of laser ray-tracing and skiascopic ocular wavefront-sensing devices.

PURPOSE: To compare two wavefront-sensing devices based on different principles. METHODS: Thirty-eight healthy eyes of 19 patients were measured five times in the reproducibility study. Twenty eyes of 10 patients were measured in the comparison study. The Tracey Visual Function Analyzer (VFA), based on the ray-tracing principle and the Nidek optical pathway difference (OPD)-Scan, based on the dynamic skiascopy principle were compared. Standard deviation (SD) of root mean square (RMS) errors was compared to verify the reproducibility. We evaluated RMS errors, Zernike terms and conventional refractive indexes (Sph, Cyl, Ax, and spherical equivalent). RESULTS: In RMS errors reading, both devices showed similar ratios of SD to the mean measurement value (VFA: 57.5+/-11.7%, OPD-Scan: 53.9+/-10.9%). Comparison on the same eye showed that almost all terms were significantly greater using the VFA than using the OPD-Scan. However, certain high spatial frequency aberrations (tetrafoil, pentafoil, and hexafoil) were consistently measured near zero with the OPD-Scan. CONCLUSION: Both devices showed similar level of reproducibility; however, there was considerable difference in the wavefront reading between machines when measuring the same eye. Differences in the number of sample points, centration, and measurement algorithms between the two instruments may explain our results.

Regeneration of articular cartilage defects in the temporomandibular joint of rabbits by fibroblast growth factor-2: a pilot study.

The purpose of this study was to investigate the therapeutic usefulness of fibroblast growth factor-2 (FGF-2) in rabbit temporomandibular joints (TMJ) with osteoarthritis. A 10-mm(3) defect was bored in the surface of the mandibular condyle head. The animals were divided into four groups: two test groups in which the defect was filled with lyophilized collagen containing 0.1 or 1.0microg of FGF-2, and two control groups, in which the defects were filled with lyophilized collagen without FGF-2 or left empty. The defective sites were examined under a light microscope 3 weeks after surgery. Initiation of cartilage formation was observed in the defects filled with 0.1microg of FGF-2, but only a small amount of cartilage was found in the defects of the 1.0-mug FGF-2- treated group. In the control groups, soft-tissue repair only or no tissue repair was found. In vivo, a dose of 0.1microg of FGF-2 can stimulate articular cartilage restoration in defects of the TMJ in rabbits, although determining the effective concentration range of FGF-2 may be difficult. The present results suggest that an optimum concentration of FGF-2 could restore defects of TMJ articular cartilage clinically.

Tissue reaction at the implantation of recombinant human bone morphogenetic protein-2 into the skeletal muscle.

Bone morphogenetic protein (BMP) is a unique cytokine that induces bony tissue in soft tissue. Tissue reactions at and around the implantation of recombinant human BMP-2 (rhBMP-2) into the soft tissue of rats and nonhuman primates were investigated. At the osteoinduced site of rats, massive trabeculae-lined osteoblasts and rich marrow were observed. At and around the nonosteoinduced sites of nonhuman primates, large clear nuclei were observed in reaction to rhBMP-2 implantation. The surrounding area was visually classified into zones 1, 2 and 3. Zone 3 was near the center of the implant. The area of nuclei, the major axis, the minor axis and the ratio of minor axis per major axis were image-analyzed in the histological views. In zones 1, 2 and 3, the nuclear areas were 18.0 (3.1) mean (SD); unit micron2, 33.4 (5.61) and 110.1 (23.7), respectively. The major axes of nuclear ellipses were 7.45 (0.22) (unit micron), 7.76 (0.26), and 13.9 (1.88), respectively. The minor axes were 3.07 (0.53), 5.59 (0.95) and 10.1 (1.35), respectively. The ratios of minor axis per major axis of nuclear ellipses were 0.4 (0.57), 0.72 (0.11) and 0.73 (0.11) in zones 1, 2 and 3, respectively. These results showed that in zones 2 and 3 cell and tissue reactions were marked against rhBMP-2 implantation.