Identification of COL2A1 mutations in platyspondylic skeletal dysplasia, Torrance type.
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Collagen Type II↗
Biomedical subjects
A Mabuchi
Publications and source records attributed to A Mabuchi.
Novel mutation in exon 18 of the cartilage oligomeric matrix protein gene causes a severe pseudoachondroplasia.
Pseudoachondroplasia (PSACH) is a common skeletal dysplasia characterized by disproportionate short stature, early-onset osteoarthrosis, and dysplasia of the spine, epiphysis, and metaphysis. Multiple epiphyseal dysplasia (MED) is a similar but less severe disorder characterized by dysplasia of the epiphysis. Both disorders are caused by mutations in the cartilage oligomeric matrix protein (COMP) gene. COMP mutations cluster in a region of the gene that encodes calmodulin-like repeats (CLRs) and correlate closely with disease severity. Typically, mutations in exon 13 that composes the seventh CLR produce severe PSACH phenotypes, whereas mutations found elsewhere in the gene produce mild PSACH or MED phenotypes. We have identified a PSACH patient carrying a novel mutation in exon 18 of COMP that composes the C-terminal globular domain. This mutation produced a severe PSACH phenotype with marked short stature and deformities of the spine and extremities. Our results extend the range of disease-causing mutations within the COMP gene and demonstrate the importance of the additional domain of COMP protein in its in vivo function.
Achondroplasia↗
Long-term results of rotational acetabular osteotomy in patients with slight narrowing of the joint space on preoperative radiographic findings.
Between 1975 and 1984, we performed rotational acetabular osteotomy in 22 female patients with painful hip dysplasia. At the time of surgery, the patients were in their twenties, and radiographs showed slight narrowing of the joint space. Of these patients, 15 were followed-up for 15 to 22 years (average, 19.8 years) after surgery. The preoperative severity of coxarthrosis in all 15 hips was graded as stage II, according to the classification of coxarthrosis advocated by the Japanese Orthopaedic Association. All 15 patients available for follow-up had had no additional operations on the operated side during the follow-up period. At the time of follow-up, the patients were aged 41 to 48 years (average, 44.3 years). Of the 15 patients, 12 had little or no pain and 14 could walk for more than 30 min without a cane; the severity of coxarthrosis was graded stage I in 3 hips, stage II in 4 hips, stage III in 5 hips, and stage IV in 3 hips. We conclude that rotational acetabular osteotomy is efficacious for patients who have preoperative radiographic findings of slight narrowing of the joint space.
Acetabulum↗
Identification of sequence polymorphisms in two sulfation-related genes, PAPSS2 and SLC26A2, and an association analysis with knee osteoarthritis.
Osteoarthritis (OA) is one of the most common musculoskeletal disorders and is characterized by degeneration of articular cartilage. Sulfation of extracellular matrix proteins in articular cartilage is an important step in maintaining normal cartilage metabolism. Two sulfation-related genes have been reported as the causal genes of severe chondrodysplasias: mutations in PAPSS2 (3'-phosphoadenosine 5'-phosphosulfate synthase 2) cause spondylo-epimetaphyseal dysplasia (SEMD), and mutations in SLC26A2 (solute carrier family 26, member 2) cause diastrophic dysplasia. Given their critical roles in cartilage metabolism and the severe phenotypes that result from mutations in these genes, we examined PAPSS2 and SLC26A2 as candidate susceptibility loci for OA. We identified sequence polymorphisms in the coding and core promoter regions of these genes and analyzed their potential association with knee OA within the Japanese population. Ten sequence polymorphisms were detected in PAPSS2 and five in SLC26A2. An association analysis showed suggestive association of one minor polymorphism in the promoter region of SLC26A2. This 4-bp adenine deletion allele, del4A, was over-represented in knee OA (P = 0.043, odds ratio = 3.43) and is thought to confer a minor susceptibility to knee OA within the Japanese population. Haplotype analysis showed no evidence of association with the two genes, however, excluding them as major susceptibility loci for knee OA.
Anion Transport Proteins↗
Identification of sequence polymorphisms of the COMP (cartilage oligomeric matrix protein) gene and association study in osteoarthrosis of the knee and hip joints.
Osteoarthrosis (OA) is a common cause of musculoskeletal disability characterized by late-onset degeneration of articular cartilage. Although several candidate genes have been reported, susceptibility genes for OA remain to be determined. Hereditary osteochondral dysplasias produce severe, early-onset OA and hence are models for common idiopathic OA. Among them are pseudoachondroplasia and multiple epiphyseal dysplasia, both of which are caused by mutations in the cartilage oligomeric matrix protein (COMP) gene. Therefore, COMP may be a susceptibility gene for OA. We screened for polymorphisms by direct sequencing of all exons of the COMP gene with their flanking intron sequences and the promoter region. We identified 16 polymorphisms, of which 12 were novel. Using six polymorphisms spanning the entire COMP gene, we examined the association of COMP in Japanese patients with OA of the knee and hip joints. Genotype and allele frequencies of the polymorphisms were not significantly different between OA and control groups, and there was no significant difference in haplotypes. These results do not support an association between COMP and OA in the Japanese population.
Cartilage↗
Unresponsiveness of intrahepatic lymphocytes to bacterial superantigen: rapid development of suppressive Mac-1(high) cells in the mouse liver.
We previously found that a small dose (2 microg per mouse) of staphylococcal enterotoxin B (SEB) induced early emerging unresponsiveness in intrahepatic-lymphocyte populations (IHLs). The purpose of this study was to reveal the inducing role of accessory cells involved in IHLs in this phenomenon. IHLs prepared at 3 to 24 hours after SEB injection failed to proliferate in response not only to SEB but also to SEA, representing ligand-nonspecific unresponsiveness, whereas spleen cells (SPCs) and mesenteric lymph-node cells showed transient proliferation. Unresponsiveness in IHLs was related to a deficit of their accessory cell function as measured by coculture of irradiated IHLs and antigen-specific, type 1 T-helper (Th1) clone cells. High levels of nitrite were detected in the culture supernatant. Supplement of N(G)-monomethyl-L-arginine lowered nitrite levels and concurrently restored the proliferative response of Th1 cells, indicating the involvement of nitric oxide in suppression. Adherent cells prepared from IHLs well reproduced these results. As shown by flow cytometry, Mac-1(high) Ia(+) cells, which mainly included F4/80(+) cells (macrophages) and a minor population of CD11c(+) cells (dendritic cells), increased in proportion in IHLs but not in SPCs at 6 to 24 hours. Depletion of Mac-1(high) cells from IHLs with antibody-coated magnetic beads recovered the proliferative response. Depleted Mac-1(high) cells had a monocytoid appearance. In immunostained sections, Kupffer cells came to highly express both Mac-1 and Ia at 12 hours. These results indicate that Mac-1(high)Ia(+) adherent cells, largely Kupffer cells activated by SEB, nonspecifically suppress the proliferation of Th1 cells via nitric oxide production before manifestation of ligand-specific unresponsiveness.
Animals↗
Cultured murine parenchymal liver cells induce differentiation of bone marrow cells to macrophage-like cells which present antigen to Th1 clones but inhibit their proliferation by nitric oxide and prostaglandins.
Suppressor cells were developed from nylon wool nonadherent CD4(-)8(-)TCRbeta(-) bone marrow cells cocultured with parenchymal liver cells for 2.5 days. The major suppressor cell population consisted of nylon wool/plastic dish-adherent, phagocytic Mac-1(+) CD3(-)4(-)8(-) cells (Ad cells), with 34% of the Ad cells being F4/80(+). These Ad cells suppressed the antigen-specific proliferation of Th1 clones in an MHC-nonrestricted manner. They showed a dose-dependent increase in suppressive activity, with both NO and PGE(2) levels in the culture supernatant rising with Ad cell concentration. OVA-pulsed Ad cells (OVA-Ad cells) were found to stimulate IFN-gamma production, resulting in an elevation of the NO and PGE(2) levels in wells containing OVA-specific Th1 clones. No DNA synthesis by these clones was detected in the absence of N(G)-monomethyl-l-arginine and indomethacin, yet the proliferation of the clone was induced in the presence of these chemicals. As proliferation is inhibited by NO and PGE(2) the Ad cells give the impression that they have no antigen-presenting function. This function is MHC-class-II-restricted. If cells such as Ad cells did actually exist in the hepatic sinusoid, they could by their nature play a major role in inducing the early emerging unresponsiveness of T cells in the liver which we reported in a previous paper.
Animals↗
Role of the liver in T cell differentiation--generation of CD3-CD4+/CD8+TCRbeta- cells and CD3-4-8-TCRbeta+ cells from CD4-8-TCRbeta- athymic nude bone marrow cells by culture with parenchymal liver cells.
To investigate the influence of the liver on differentiation of hematopoietic stem cells/pro-T cells, TN-NWP-BMC (athymic nude bone marrow cells that were treated with anti-TCRbeta, anti-CD4, and anti-CD8 Abs plus complement and then passed through a nylon wool column) were cultured on parenchymal liver cells. After culture for 2.5 days, CD3-4-8-TCRbeta+ cells and CD3-CD4+/CD8+TCRbeta- cells were developed from TN-NWP-BMC. TCRVbeta8+ cells comprised 19.9% of CD3-4-8-TCRbeta+ cells, and Vbeta8 mRNA was detected in the CD3-4-8-TCRbeta+ cells by reverse transcriptase-polymerase chain reaction. The CD3-CD4+/CD8+TCRbeta- cells contained not only single-positive cells but also CD4+8+ double-positive cells. The CD8 protein consisted of 88.9% CD8alpha+beta-, 10.1% CD8alpha+beta+, and 1% CD8alpha-beta+ molecules. From these results and the finding of co-expressed antigens, CD3-4-8-TCRbeta+ cells and CD3-CD4+/CD8+TCRbeta- cells appear to be immature cells not committed to a certain cell lineage.
Animals↗
Production of B cell differentiation factors by mouse parenchymal liver cells.
Previously we reported that most antibody secreting cells secreted IgA in the liver. Here we assessed the possibility that parenchymal liver cells (PLC) produced factors, transforming growth factor (TGF)-beta and IL-5, which participate in the differentiation of B cells to IgA-secreting cells. We showed that TGF-beta activity was present in the culture supernatant of PLC, and IL-5 activity was in the lysate of PLC. Moreover, it was confirmed that IL-5 protein produced by PLC was mainly localized in the cell membrane by histochemical staining. The findings that both TGF-beta and IL-5 were produced by PLC should provide useful information concerning the fact that IgA-secreting cells were dominant in the liver.
Animals↗
A unique response to staphylococcal enterotoxin B by intrahepatic lymphocytes and its relevance to the induction of tolerance in the liver.
It has been reported that the intrahepatic lymphocyte (IHL) population is somewhat differently constituted from lymphocytes in other lymphoid tissues. Staphylococcal enterotoxin B (SEB) is a superantigen which can induce T-cell tolerance in mice. The authors investigated the in vitro and in vivo responses of mouse IHL to SEB. An intravenous injection of SEB did not result in the augmentation of the proliferative response of IHL, while mesenteric and splenic lymphocytes (mLNC and SPC, respectively) had augmented responses. Interleukin-2 (IL-2) mRNA was clearly detected in mLNC and SPC by reverse transcriptase-polymerase chain reaction (RT-PCR) shortly after the administration of SEB, but it was scarcely expressed in IHL. The expression of CD25 (IL-2 receptor) was also augmented in mLNC and SPC in the early period, while it was not changed in IHL. These findings suggested that the time required for tolerance induction is different locally and that the loss of augmentation of IL-2 and IL-2 receptor production by IHL may be relevant to the rapid induction of T-cell tolerance in the liver.
Animals↗
Interleukin 7 receptor-deficient mice lack gammadelta T cells.
The interleukin 7 receptor (IL-7R) plays a crucial role in early B- and T-cell development. It consists of a unique a chain and a common gamma chain [IL-2 receptor gamma chain (IL-2Rgamma)]. Gene inactivation of IL-7, IL-7R, and IL-2Rgamma resulted in severe impairment of B and T lymphopoiesis in mice. In addition, IL-2Rgamma-deficient mice lack gammadelta T cells in the skin and have the impaired development of natural killer (NK) cells and intraepithelial lymphocytes. To explore the role of IL-7/IL-7R system in gammadelta T- and NK-cell development, we have generated and analyzed IL-7R-deficient mice. gammadelta T cells were absent from skin, gut, liver, and spleen in the deficient mice. In contrast, alphabeta T and B cells were detected in reduced, but certain, numbers, and NK cells developed normally. The gammadelta T-cell development in fetal and adult thymus was also completely blocked. These results clearly demonstrate that the signal from IL-7R is indispensable for gammadelta T-cell development in both thymic and extrathymic pathways. On the contrary, it is suggested that NK-cell development requires cytokine(s) other than IL-7.
Animals↗
Characteristic immunological tolerance in intrahepatic lymphocytes induced by bacterial superantigen SEB.
We have reported that the liver is closely associated with the hematolymphoid system and that the liver, as a lymphoid organ, may play an important role in the differentiation of lymphocytes and oral tolerance. To investigate the relevance of the liver to immunological tolerance, we compared the response pattern to Staphylococcus enterotoxin B (SEB) in intrahepatic lymphocytes (IHL) with those of spleen cells (SPC) and mesenteric lymph node cells (mLNC) during tolerance induction. Tolerance was induced by i.v. injections of SEB in all three organs. IHL had a distinct pattern from the other cells in the induction of unresponsiveness to SEB. While SPC and mLNC have a proliferation phase before the reduction of DNA synthesis, IHL become tolerant immediately without this phase. When IHL became tolerant in the early period after SEB injection, their nylon-wool column non-adherent (NW-NA) IHL were not recovered from unresponsiveness in vitro in spite of the addition of irradiated normal SPC as accessory cells. NW-NA IHL did not secrete IL-2 during this process, indicating that NW-NA IHL were in a state of functional anergy soon after the i.v. administration of SEB. Phenotypic analysis revealed that the characteristic changes of IHL during the induction of unresponsiveness might be associated with the kinetic modulation of CD4+ V beta 8+ T cells. These results suggest that the liver may hold a different mechanism for the induction of tolerance to SEB from that of SPC and mLNC.
Animals↗
Production of interleukin-1 by primary cultured parenchymal liver cells (hepatocytes).
The production of interleukin-1 (IL-1) by cultured parenchymal liver cells was revealed by a biological assay with an IL-1-dependent cell line, Northern blot analysis, and in situ hybridization. Inhibition experiments on the IL-1 activity with anti IL-1 alpha antibody also support the presence of IL-1 alpha in the supernatant of cultured parenchymal liver cells. Based on these results, we discuss the possibility of IL-1 production by parenchymal liver cells in vivo.
Animals↗
[Modification of surface phenotype and function in intrahepatic lymphocytes during liver regeneration after partial hepatectomy].
In the intrahepatic lymphocyte fraction (IHL) of mice whose livers have been perfused by Ca+2 and Mg+2 free Hank's balance salt solution, flow cytometric analysis reveals various cells similar to those found in the spleen (CD3+ cell, CD4+ cell, CD8+ cell, alpha beta TCR+ cell, gamma delta TCR+ cell, Thy1.2+ cell, B220+ cell and asialo-Gm1+ cell). The cytotoxic activity against YAC-1 cells in IHL is significantly higher than that in spleen cells. Furthermore, IHL has cytolytic activity against syngeneic thymoma BW5147 cells which is not found in spleen cells. Both cytotoxic activities of IHL are greatly weakened by the pretreatment of IHL with anti asialo-Gm1 Ab and rabbit complement. During liver regeneration after a partial hepatectomy, the percentages of lymphocyte subsets of IHL such as alpha beta TCR+ cells, gamma delta TCR+ cells and asialo-Gm1+ cells transiently increase 2 days after the partial hepatectomy and their cytotoxic activities against YAC-1 and BW5147 cells also reach a peak at that time. It is well known that the peak of mitotic index in regenerating parenchymal liver cells peaks 2 days after a partial hepatectomy and that the number of Pit cells peaks 10 to 14 days after. Compared with the time for reaching the highest mitotic index in regenerating parenchymal liver cells, the proliferation of Pit cells comes very late. It has not been clear which proliferation process in parenchymal liver cells is suppressed by activated Pit cells. Our findings in this paper reveal that the percentages and the cytotoxic activities of asialo-Gm1+ cells in IHL reach their peak 2 days after an operation.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Growth control of primary culture hepatocytes by nonparenchymal liver cells. Role of interferon produced by liver sinusoidal cells.
Using the primary culture of liver cells, we showed that interferon produced by nonparenchymal liver cells inhibits the proliferation of cultured parenchymal liver cells. DNA synthesis of parenchymal liver cells was suppressed not only by their coculture with nonparenchymal liver cells but also by the addition of the culture supernatant of nonparenchymal liver cells. The suppressive activity of the supernatant correlated closely with the interferon (alpha + beta) level in the supernatant and was reduced by anti interferon (alpha + beta) serum. Furthermore, purified interferon (alpha + beta) also suppressed parenchymal liver cell proliferation in a dose-dependent manner and the suppression was released by anti interferon (alpha + beta) serum. The interferon level of the supernatant necessary for suppressing parenchymal liver cell proliferation, however, was extraordinarily low compared with purified interferon. The possibility exists that IFN in the culture supernatant of nonparenchymal liver cells works synergistically with other factors in the supernatant to suppress the cell proliferation.
Animals↗
Adhesive interaction between lymphocytes and sinusoidal liver cells.
Since sinusoidal liver cells directly interact with circulating hemopoietic cells and lymphocytes, Kupffer cells may have the capacity to trap and activate these cells in the liver microcirculation. In order to investigate the adhesion mechanism of Kupffer cells to other lymphoid cells, mouse sinusoidal liver cells were isolated by a collagenase perfusion followed by differential centrifugations. By in vitro adhesion assay of lymphocytes to sinusoidal liver cells and staining of adhered lymphocytes with FITC/peroxidase labeled peanut agglutinin (PNA), the following observations were made: 1) Lymphocytes from various lymphoid organs including the liver itself adhered to Kupffer cells. 2) After an incubation period, DNA synthesis of the adhered lymphocytes increased. 3) A high percentage of the adhered lymphocytes were PNA+ cells. 4) D-Galactose, a PNA specific carbohydrate, inhibited the lymphocyte binding and the total DNA synthesis of the adhered lymphocytes decreased proportionally with their decrease in number. Our results suggest that sinusoidal liver cells may have the ability to trap and to activate PNA+ cells.
Animals↗
Production of macrophage colony-stimulating factor by adult murine parenchymal liver cells (hepatocytes).
The activity of macrophage colony-stimulating factor (M-CSF) was found in the culture supernatant of mouse parenchymal liver cell fractions in a bone marrow colony-forming assay. The activity of an M-CSF-like substance purified by a four-step procedure was neutralized by goat anti-mouse M-CSF antiserum. M-CSF mRNA was detected in cellular RNA prepared from cultured parenchymal liver cell fractions by Northern blot analysis and also in cultured parenchymal liver cells by in situ hybridization. These results indicate that parenchymal liver cells have the capacity to produce M-CSF. We discuss the role of M-CSF in hematopoiesis, the immune response, and other biological phenomena.
Acrylic Resins↗
The liver and the hematolymphoid system: I. The regulation of nylon-passed spleen cell proliferation by active factors released from syngeneic nonparenchymal liver cells.
Nylon-passed spleen cells were found to proliferate when cultured with syngeneic nonparenchymal adherent liver cells and their culture supernatants. The supernatants contained IL-1, IL-6, GM-CSF, and IFN (alpha + beta) activities but not IL-2 and IL-3 activities. The IFN level was higher in early culture sup (2-24 hr) than in later culture sup (48-72 hr). Proliferation was greatly increased by anti-IFN (alpha + beta) serum in the spleen cells cultured in the earlier sup. This antiserum increased the spleen cell proliferation only slightly in the later culture sup. This suggests that nonparenchymal liver cells produce two factors, one having a suppressor, and the other an enhancer action, with IFN being one of the suppressor factors. With culture time, DNA synthesis of spleen cells increased and IL-2 and IL-3 activities were generated in the culture sup. Cells proliferated during culture were found to be morphologically lymphocytes, granulocytes, and macrophages. The mechanisms by which nonparenchymal liver cells regulate the hematolymphoid system are discussed based on our observations.
Animals↗