戸松 瑛介

OBJECTIVES: Phosphate (Pi) induces differentiation of arterial smooth muscle cells to the osteoblastic phenotype by inducing the type III Na-dependent Pi transporter Pit-1/solute carrier family member 1. This induction can contribute to arterial calcification, but precisely how Pi stress acts on the vascular wall remains unclear. We investigated the role of extracellular Pi in inducing microstructural changes in the arterial wall. METHODS: Aortae of Pit-1-overexpressing transgenic (TG) rats and their wild-type (WT) littermates were obtained at 8 weeks after birth. The thoracic descending aorta from WT and TG rats was used for the measurement of wall thickness and uniaxial tensile testing. Structural and ultrastructural analyses were performed using light microscopy and transmission electron microscopy. Gene expression of connective tissue components in the aorta was quantified by quantitative real-time polymerase chain reaction. RESULTS: Aortic wall thickness in TG rats was the same as that in WT rats. Uniaxial tensile testing showed that the circumferential breaking stress in TG rats was significantly lower than that in WT rats (p<0.05), although the longitudinal breaking stress, breaking strain, and elastic moduli in both directions in TG rats were unchanged. Transmission electron microscopy analysis of the aorta from TG rats showed damaged formation of elastic fibers in the aortic wall. Fibrillin-1 gene expression levels in the aorta were significantly lower in TG rats than in WT rats (p<0.05). CONCLUSIONS: Pi overload acting via the arterial wall Pit-1 transporter weakens circumferential strength by causing elastic fiber malformation, probably via decreased fibrillin-1 expression.

38歳男性。全身の骨痛、歩行・起立障害を主訴に前医を受診した。腫瘍性骨軟化症(TIO)が疑われ、精査加療目的に当院へ紹介となった。FGF23の全身静脈サンプリングと68Ga-DOTATOC-PET/CTにより右鼻腔内の腫瘤がTIOの原因腫瘍であると診断し、内視鏡下に右鼻腔腫瘍摘出術が施行された。その結果、病理組織学的に鼻腔原発リン酸塩尿性間葉系腫瘍と診断され、術後5日で全身の骨痛は完全消失し、立位保持・歩行ともに可能となった。術後1年経過現在、腫瘍の再発や骨痛の再燃はなく、FGF23も正常範囲内である。

AIMS: Although skin manifestations are common in diabetic patients, its characteristics are poorly identified. This study explored the differentiation process of keratinocytes in type 2 diabetes mellitus (T2DM) in vivo. METHODS: Back skin of T2DM model KKAy/TaJcl mice (KKAy) and C57BL/6JJcl mice (control) aged 8 and 12 weeks was used. The mRNA expression of differentiation markers of keratinocytes was measured by quantitative real-time polymerase chain reaction (qRT-PCR). The expression of each marker in situ was examined immunohistochemically. RESULTS: KKAy mice showed hyperglycemia versus control mice. The histological findings showed increased thickness and structural impairment of epidermal tissue in KKAy mice. The qRT-PCR revealed that the expression of integrin beta 1 and keratin 14 in KKAy and control mice was identical. However, the expression of involucrin at 8 weeks, keratin 10 at 12 weeks, and filaggrin and loricrin at 8 and 12 weeks was decreased in KKAy mice. Immunohistochemical findings showed that filaggrin was markedly decreased in KKAy mice, though Ki-67 remained unchanged. CONCLUSION: The terminal differentiation process was impaired in the diabetic skin, while keratinocyte proliferation was preserved. Damaged terminal differentiation of keratinocytes may contribute to impairment of the skin barrier function in diabetic dermatoses.

Osteoporosis patients with chronic kidney disease (CKD) are becoming common in our superaging society. Renal dysfunction causes phosphorus accumulation in the circulating plasma and leads to the development of CKD-mineral bone disorder (MBD). We have previously reported that type III Pi transporter-overexpressing transgenic (Pit-1 TG) rats manifest phosphate (Pi)-dependent podocyte injury. In the present study, we explored the effect of risedronate on Pi-induced podocyte injury in vivo. Pit-1 TG rats and wild-type rats at 5 weeks old were divided into a risedronate-treated group and an untreated group. We subcutaneously administered 5 μg/kg body weight of risedronate or saline twice a week during the experimental period. Risedronate did not alter serum creatinine levels at 5, 8, and 12 weeks of age. However, electron microscopy images showed that thickening of the glomerular basement membrane was improved in the risedronate treatment group. Furthermore, immunostaining for podocyte injury markers revealed that both desmin- and connexin43-positive areas were smaller in the risedronate-treated group than in the untreated group, suggesting that bisphosphonates could rescue Pi-induced podocyte injury. In conclusion, our findings suggest that risedronate could maintain glomerular barrier function by rescuing Pi-induced podocyte injury.

Autoimmune thyroid diseases (AITDs), including Graves' diseases (GD) and Hashimoto's thyroiditis (HT), are the most common autoimmune diseases, and are mainly mediated by T cells that produce cytokines and chemokines in abnormal amounts. Few reports have described the circulating chemokines active in AITDs. Recently, we used a new multiplex immunobead assay to simultaneously measure cytokines and chemokines in small volume serum samples from patients with AITDs. We measured 23 selected serum chemokines in patients with GD (n=45) or HT (n=26), and healthy controls (n=9). GD patients were further classified as either untreated, intractable, or in remission, while HT patients were classified as either hypothyroid or euthyroid. Of the 23 serum chemokines assayed, only the serum level of IP-10 (CXCL10/interferon-γ-inducible protein 10) was elevated, depending on disease activity, in GD or HT compared with healthy controls. However, the serum level of IP-10 was also increased in both untreated GD patients and hypothyroid HT patients, suggesting that levels of this cytokine may not be affected by disease specificity. In conclusion, autoimmune inflammation in patients with AITD is closely related to the level of the serum chemokine, IP-10. Therefore, IP-10 might be a good biomarker for tissue inflammation in the thyroid, but not a useful biomarker for predicting disease specific activity, the progression of AITDs, or responsiveness to treatment because of its independence from thyroid function or disease specificity.