林 宏栄

Fibroblast growth factor-23 (FGF23) is a bone-derived hormone that promotes urinary phosphate excretion in response to phosphate loading. While essential for phosphate homeostasis, elevated FGF23 increases phosphate concentration in the renal tubular fluid, promoting calcium-phosphate crystal formation and tubular injury. Here we show that bone resorption mobilizes phosphate into the circulation and mimics the pathophysiology of dietary phosphate loading. Enhanced bone resorption, induced by soluble receptor activator of NF-κB ligand (sRANKL) administration or microgravity exposure on the International Space Station, increased circulating FGF23 levels and caused renal tubular injury in mice. Pre-treatment with bisphosphonate, an inducer of osteoclast apoptosis, prevented sRANKL-induced increases in FGF23 and tubular damage. These findings suggest that bone mineral loss may contribute to renal tubular injury in clinical settings, including immobilization, osteoporosis, and chronic kidney disease-mineral bone disorder.

【緒言】顎裂部骨移植術は，唇顎口蓋裂の一連の治療において欠かすことのできない重要な手術である。移植骨は腸骨より採取する方法が標準的であるが，術後は腸骨採取部の疼痛による歩行困難や離床の遅れがしばしば問題となる。腸骨採取部の疼痛コントロールは患者のQOL 向上や患者満足度の観点からも重要である。当科では2013 年より顎裂部骨移植術の腸骨採取部に長時間作用型局所麻酔薬であるロピバカイン塩酸塩を使用しており，今回，われわれはその有効性について検討した。【方法】2006 年4 月から2019 年3 月までに自治医科大学附属病院歯科口腔外科･矯正歯科で顎裂部骨移植術を施行した患者101 名（男性60 名，女性41 名），111 顎裂を対象とした。腸骨採取は前腸骨より行い，採取後にロピバカイン塩酸塩を使用しなかった群をNR 群（24 例），ロピバカイン塩酸塩を使用した群をR 群（87 例）として，術後の初回鎮痛薬使用開始時間，歩行開始時期，術後在院日数について検討した。【結果】鎮痛薬の初回平均投与時間はNR 群8.3 時間，R 群8.2 時間であった。また，全体のうち鎮痛薬の内服を必要とした患者割合はNR 群70.8 %，R 群56.3 % であった。平均歩行開始時期はNR 群42.9 時間，R 群23.5時間で，R 群で有意に術後早期の歩行が可能であった。術後在院日数はNR 群5.5 日，R 群2.9 日で，R 群で有意に在院日数が短く，重回帰分析においてもロピバカイン塩酸塩の使用の有無が術後在院日数に有意に影響する結果となった。【考察】アセトアミノフェンやNSAIDs（非ステロイド性抗炎症薬）などの全身的な鎮痛薬投与のみでは体動時の十分な鎮痛が得られず，離床の遅れにつながることがある。今回，腸骨採取後にロピバカイン塩酸塩を使用することで，術後早期の離床と在院日数の短縮が可能であることが示された。ロピバカイン塩酸塩は，持続性のある鎮痛効果が期待でき，腸骨採取部の疼痛コントロールに有効 であるといえた。

ABSTRACT Background Double‐hit lymphoma shows a poor prognosis, necessitating early diagnosis to improve prognosis. Case Presentation A 68‐year‐old Japanese woman presented with pain and a click in the right temporomandibular joint. The right side of her neck was acutely swollen. A biopsy of a mass lesion and lymph node suggested diffuse large B‐cell lymphoma; chromosomal analyses revealed MYC and BCL2 rearrangements. Complete response was achieved with chemotherapy. Peripheral blood stem cell transplantation was performed, but the patient relapsed. She died due to respiratory failure. Conclusion Double‐hit lymphoma is often accompanied by cervical lymphadenopathy. Lymph node biopsy is useful for early diagnosis.

The Western pattern diet is rich not only in fat and calories but also in phosphate. The negative effects of excessive fat and calorie intake on health are widely known, but the potential harms of excessive phosphate intake are poorly recognized. Here, we show the mechanism by which dietary phosphate damages the kidney. When phosphate intake was excessive relative to the number of functioning nephrons, circulating levels of FGF23, a hormone that increases the excretion of phosphate per nephron, were increased to maintain phosphate homeostasis. FGF23 suppressed phosphate reabsorption in renal tubules and thus raised the phosphate concentration in the tubule fluid. Once it exceeded a threshold, microscopic particles containing calcium phosphate crystals appeared in the tubule lumen, which damaged tubule cells through binding to the TLR4 expressed on them. Persistent tubule damage induced interstitial fibrosis, reduced the number of nephrons, and further boosted FGF23 to trigger a deterioration spiral leading to progressive nephron loss. In humans, the progression of chronic kidney disease (CKD) ensued when serum FGF23 levels exceeded 53 pg/mL. The present study identified calcium phosphate particles in the renal tubular fluid as an effective therapeutic target to decelerate nephron loss during the course of aging and CKD progression.

Kidney calcification increases the risk of chronic kidney disease. However, to date, renal calcium phosphate crystallization, a main initiating and driving factor of kidney calcification, has not been explored as a drug target. Pre-clinical drug development is hampered by limited knowledge on the broad range of kidney calcification disorders, characterized by a multifactorial process of disease progression. In this work, we first established an in vitro calcification profiling platform to accelerate pre-clinical drug discovery. The image-based profiling assay allowed the rapid testing of several ionic stimuli and/or inhibitory molecules. We then leveraged a previously established library of inositol hexakisphosphate analogues to identify a renal calcium phosphate inhibitor. A lead compound showed in vitro and in vivo efficacy to prevent calcium phosphate-induced kidney damage. In conclusion, this work reports a renal calcium phosphate inhibitor that could efficiently reduce kidney damage and emphasizes the utility and translational value of the in vitro calcification platform.

Fibroblast growth factor-23 (FGF23) is a hormone indispensable for maintaining phosphate homeostasis. In response to phosphate intake, FGF23 is secreted from osteocytes/osteoblasts and acts on the kidney to increase urinary phosphate excretion. However, the mechanism by which these cells sense phosphate intake remains elusive. Calciprotein particles are nanoparticles of calcium-phosphate precipitates bound to serum protein fetuin-A and are generated spontaneously in solution containing calcium, phosphate, and fetuin-A to be dispersed as colloids. In cultured osteoblastic cells, increase in either calcium or phosphate concentration in the medium induced FGF23 expression, which was dependent on calciprotein particle formation. When transition of calcium-phosphate precipitates from the amorphous phase to the crystalline phase was blocked by bisphosphonate, the calciprotein particle size was reduced and FGF23 expression was augmented, suggesting that small calciprotein particles containing amorphous calcium-phosphate precipitates function as a more potent FGF23 inducer than larger calciprotein particles containing crystalline calcium-phosphate precipitates. In mice, bolus phosphate administration by oral gavage transiently increased circulating calciprotein particle levels followed by a modest increase in FGF23 expression and serum FGF23 levels. However, continuous dietary phosphate load induced robust and persistent increase in circulating calciprotein particles and FGF23 levels. We confirmed by in vivo imaging that calciprotein particles injected intravenously extravasated into the bone marrow and were deposited on the inner surface of the bone, indicating that these particles have direct access to osteoblasts. Thus, we propose that osteoblasts induce FGF23 expression and secretion when they sense an increase in extracellular calciprotein particles following phosphate ingestion.

65歳の男性。繰り返す口内炎を主訴に，近医から当科を紹介され受診した。初診時，口腔内には多数のアフタを認めたが，偽膜形成は認めなかった。細菌培養検査にてカンジダ陽性であったため抗真菌薬を使用したが症状を繰り返した。外陰部潰瘍を認めていたことから内科に対診したところ，HIV感染が判明した。その後，HIV治療が開始され，現在は口腔内症状も改善し経過観察を行っている。

口腔内に見られるアミロイドーシスは，全身性アミロイドーシスの一部分症として発現する場合があり，多発性骨髄腫の場合は約10％に口腔内にアミロイドーシスが出現すること言われている。今回，左側舌背部に潰瘍を認め，病理組織学的にアミロイドーシスと診断され，その後の全身精査の結果，多発性骨髄腫が明らかとなった1例について報告する。

Angioleiomyoma is a form of subcutaneous vascular leiomyoma that usually occurs in the extremities. Leiomyoma of the oral cavity represents only 0.4% of soft tissue neoplasms and 0.06% of leiomyomas. Isolated cases of angioleiomyoma have been reported in the knee and lower thigh, gastrointestinal tract, genital and renal tract, and brain. Histopathologic examination by biopsy is necessary to establish a diagnosis, and immunohistochemical staining, along with conventional hematoxylin-eosin staining, is important. The differential diagnosis includes hemangioma and angiosarcoma. At present, surgical resection is the standard therapy for leiomyoma, and recurrence is extremely rare. We report a rare case of angioleiomyoma of the cheek in a 45-year-old man. The postoperative course was uneventful, without complications.