顎関節におけるHIF-1αの役割

Objective: Temporomandibular joint osteoarthritis (TMJ-OA) is a degenerative disease characterized by permanent cartilage loss. Articular cartilage is maintained in a low-oxygen environment. The chondrocyte response to hypoxic conditions involves expression of hypoxia inducible factor 1α (HIF-1α), which induces chondrocytes to increase expression of vascular endothelial growth factor (VEGF). Here, we investigated the role of HIF-1α in mechanical load effects on condylar cartilage and subchondral bone in heterozygous HIF-1α-deficient mice (HIF-1α+/-). Design: Mechanical stress was applied to the TMJ of C57BL/6NCr wild-type (WT) and HIF-1α+/- mice with a sliding plate for 10 days. Histological analysis was performed by HE staining, Safranin-O/Fast green staining, and immunostaining specific for articular cartilage homeostasis. Results: HIF-1α+/- mice had thinner cartilage and smaller areas of proteoglycan than WT controls, without and with mechanical stress. Mechanical stress resulted in prominent degenerative changes with increased expression of HIF-1α, VEGF, and the apoptosis factor cleaved Caspase-3 in condylar cartilage. Conclusion: Our results indicate that HIF-1a may be important for articular cartilage homeostasis and protective against articular cartilage degradation in the TMJ under mechanical stress condition, therefore HIF-1α could be an important new therapeutic target in TMJ-OA

口唇裂・口蓋裂患者の歯数異常に関する調査

口唇裂・口蓋裂患者は，軟組織や骨の癒合不全だけでなく，永久歯の先天欠如や過剰などの歯数異常が認められ，歯科矯正学的対応に苦慮することも多い．そこで，口唇裂・口蓋裂患者における永久歯の歯数異常の実態を明らかにすることを目的として，1995年1月から2011年12月までの17年間に出生し，徳島大学病院矯正歯科を受診した口唇裂・口蓋裂患者（症候群を含まない）を対象とした調査を行い，以下の結果を得た． 1．調査資料が揃っている患者101名の男女比は，1：1.02であった． 2．顎裂保有者82名の顎裂部位は，1 ▼ 3の型が最も多く，次いで1 ▼23の型であった．（▼は顎裂部位を示す） 3．永久歯における歯数異常の発現率は63.4％であり，歯の欠如のみを有するものが50.5％，過剰歯のみを有するものは8.9％，歯の欠如と過剰歯をともに有するものは4.0％であった． 4．歯の欠如の歯種別頻度は，側切歯が最も多く，次いで第二小臼歯の順であった． 5．顎裂保有者のみを対象とすると，歯の欠如の発現頻度は披裂側で59.8％，非披裂側で24.3％であった． 以上のことから，口唇裂・口蓋裂患者での先天欠如歯の発現率は高いため，治療計画立案時に補綴治療を含めた包括的歯科治療の必要性が示唆された

A New Light on the Evolution and Propagation of Prehistoric Grain Pests: The World's Oldest Maize Weevils Found in Jomon Potteries, Japan

Three Sitophilus species (S. granarius L., S. oryzae L., and S. zeamais Mots.) are closely related based on DNA analysis of their endosymbionts. All are seed parasites of cereal crops and important economic pest species in stored grain. The Sitophilus species that currently exist, including these three species, are generally believed to be endemic to Asia's forested areas, suggesting that the first infestations of stored grain must have taken place near the forested mountains of southwestern Asia. Previous archaeological data and historical records suggest that the three species may have been diffused by the spread of Neolithic agriculture, but this hypothesis has only been established for granary weevils in European and southwestern Asian archaeological records. There was little archeological evidence for grain pests in East Asia before the discovery of maize weevil impressions in Jomon pottery in 2004 using the “impression replica” method. Our research on Jomon agriculture based on seed and insect impressions in pottery continued to seek additional evidence. In 2010, we discovered older weevil impressions in Jomon pottery dating to ca. 10 500 BP. These specimens are the oldest harmful insects in the world discovered at archaeological sites. Our results provide evidence of harmful insects living in the villages from the Earliest Jomon, when no cereals were cultivated. This suggests we must reconsider previous scenarios for the evolution and propagation of grain pest weevils, especially in eastern Asia. Although details of their biology or the foods they infested remain unclear, we hope future interdisciplinary collaborations among geneticists, entomologists, and archaeologists will provide the missing details

Cannabinoid CB2 Receptor Gene and Environmental Interaction in the Development of Psychiatric Disorders

CB2 cannabinoid receptor (CB2R) gene is associated with depression. We investigated the gene-environment interaction between CB2R function and diverse stressors. First, anxiety-like behavior during chronic-mild-stress (CMS) was evaluated in C57BL/6JJmsSlc mice following treatment with CB2R agonist JWH015 or inverse-agonist AM630. Second, locomotor activity and anxiety-like behavior were measured following exposure to an immune poly I:C stressor. Gene expressions of HPA axis related molecules, Fkbp5, Nr3c1 and Crf and pro-inflammatory cytokine Il-1b, as well as Bdnf as a key neurotrophin that supports neuron health, function, and synaptic plasticity, were determined in hippocampus of Cnr2 knockout mice, as indicators of stressful environment. CMS-induced anxiety-like behavior was enhanced by AM630 and reduced by JWH015 and fluvoxamine. Poly I:C reduced locomotor activity and increased anxiety-like behavior, and these effects were pronounced in the heterozygote than in the wild type mice. Fkbp5 and Nr3c1 expression were lower in the Cnr2 heterozygotes than in the wild type mice with Poly I:C treatment. These findings indicate that interaction between CB2R gene and stressors increases the risk of depression-like behaviors that may be linked with neuro-immune crosstalk. Further studies in human subjects are necessary to determine the role of CB2R and environmental interaction in the development of depression

C-type natriuretic peptide facilitates autonomic Ca²⁺ entry in growth plate chondrocytes for stimulating bone growth

骨を長く伸ばす仕組みの一端を解明 --C型ナトリウム利尿ペプチド（CNP）は軟骨細胞内Ca2+シグナルを活性化して骨伸長を促す--. 京都大学プレスリリース. 2022-03-16.Pumping calcium for bigger bones. 京都大学プレスリリース. 2022-05-13.The growth plates are cartilage tissues found at both ends of developing bones, and vital proliferation and differentiation of growth plate chondrocytes are primarily responsible for bone growth. C-type natriuretic peptide (CNP) stimulates bone growth by activating natriuretic peptide receptor 2 (NPR2) which is equipped with guanylate cyclase on the cytoplasmic side, but its signaling pathway is unclear in growth plate chondrocytes. We previously reported that transient receptor potential melastatin-like 7 (TRPM7) channels mediate intermissive Ca²⁺ influx in growth plate chondrocytes, leading to activation of Ca²⁺/calmodulin-dependent protein kinase II (CaMKII) for promoting bone growth. In this report, we provide evidence from experiments using mutant mice, indicating a functional link between CNP and TRPM7 channels. Our pharmacological data suggest that CNP-evoked NPR2 activation elevates cellular cGMP content and stimulates big-conductance Ca²⁺-dependent K⁺ (BK) channels as a substrate for cGMP-dependent protein kinase (PKG). BK channel-induced hyperpolarization likely enhances the driving force of TRPM7-mediated Ca²⁺ entry and seems to accordingly activate CaMKII. Indeed, ex vivo organ culture analysis indicates that CNP-facilitated bone growth is abolished by chondrocyte-specific Trpm7 gene ablation. The defined CNP signaling pathway, the NPR2-PKG-BK channel–TRPM7 channel–CaMKII axis, likely pinpoints promising target proteins for developing new therapeutic treatments for divergent growth disorders

Experimental Evidence for the Involvement of PDLIM5 in Mood Disorders in Hetero Knockout Mice

<div><p>Background</p><p>Reports indicate that PDLIM5 is involved in mood disorders. The <i>PDLIM5</i> (PDZ and LIM domain 5) gene has been genetically associated with mood disorders; it’s expression is upregulated in the postmortem brains of patients with bipolar disorder and downregulated in the peripheral lymphocytes of patients with major depression. Acute and chronic methamphetamine (METH) administration may model mania and the evolution of mania into psychotic mania or schizophrenia-like behavioral changes, respectively.</p> <p>Methods</p><p>To address whether the downregulation of PDLIM5 protects against manic symptoms and cause susceptibility to depressive symptoms, we evaluated the effects of reduced <i>Pdlim5</i> levels on acute and chronic METH-induced locomotor hyperactivity, prepulse inhibition, and forced swimming by using <i>Pdlim5</i> hetero knockout (KO) mice.</p> <p>Results</p><p>The homozygous KO of <i>Pdlim5</i> is embryonic lethal. The effects of METH administration on locomotor hyperactivity and the impairment of prepulse inhibition were lower in <i>Pdlim5</i> hetero KO mice than in wild-type mice. The transient inhibition of PDLIM5 (achieved by blocking the translocation of protein kinase C epsilon before the METH challenge) had a similar effect on behavior. <i>Pdlim5</i> hetero KO mice showed increased immobility time in the forced swimming test, which was diminished after the chronic administration of imipramine. Chronic METH treatment increased, whereas chronic haloperidol treatment decreased, <i>Pdlim5</i> mRNA levels in the prefrontal cortex. Imipramine increased <i>Pdlim5</i> mRNA levels in the hippocampus.</p> <p>Conclusion</p><p>These findings are partially compatible with reported observations in humans, indicating that PDLIM5 is involved in psychiatric disorders, including mood disorders.</p> </div