Aging is a progressive process associated with declining tissue function over time. Kynurenine, an oxidized metabolite of the essential amino acid tryptophan that increases in abundance with age, drives cellular processes of aging and dysfunction in many tissues, and recent work has focused on understanding the pathways involved in the harmful effects of kynurenine on bone. In this study, we sought to investigate the effects of controlled kynurenine administration on osteoblast bioenergetics, in vivo osteoblast abundance, and marrow fat accumulation. Additionally, as an extension of earlier studies with dietary administration of kynurenine, we investigated the effects of kynurenine on Hdac3 and NCoR1 expression and enzymatic deacetylase activity as potential mechanistic contributors to the effects of kynurenine on osteoblasts. Kynurenine administration suppressed cellular metabolism in osteoblasts at least in part through impaired mitochondrial respiration, and suppressed osteoblastic numbers in vivo with no concurrent effects on marrow adiposity. Deleterious effects of kynurenine treatment on osteoblasts were more pronounced in female models as compared to males. However, kynurenine treatment did not inhibit Hdac3's enzymatic deacetylase activity nor its repression of downstream glucocorticoid signaling. As such, future work will be necessary to determine the mechanisms by which increased kynurenine contributes to aging bone bioenergetics. The current study provides novel further support for the idea that kynurenine contributes to impaired osteoblastic function, and suggests that impaired matrix production by kynurenine-affected osteoblasts is attributed in part to impaired osteoblastic bioenergetics. As circulating kynurenine levels in increase with age, and human bone density inversely correlates with the serum kynurenine to tryptophan ratio, these mechanisms may have important relevance in the etiology and pathogenesis of osteoporosis in humans.

中文翻译：

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犬尿氨酸抑制体外成骨细胞能量和体内成骨细胞数量。

衰老是一个渐进过程，与组织功能随时间下降有关。犬尿氨酸是一种必需氨基酸色氨酸的氧化代谢物，随着年龄的增长而增加，它会驱动许多组织中的衰老和功能障碍的细胞过程，最近的工作重点是了解犬尿氨酸对骨骼产生有害影响的途径。在这项研究中，我们试图研究受控犬尿氨酸给药对成骨细胞生物能量学、体内成骨细胞丰度和骨髓脂肪积累的影响。此外，作为犬尿氨酸饮食给药早期研究的延伸，我们研究了犬尿氨酸对 Hdac3 和 NCoR1 表达和酶促脱乙酰酶活性的影响，作为犬尿氨酸对成骨细胞影响的潜在机制贡献者。犬尿氨酸给药至少部分通过线粒体呼吸受损来抑制成骨细胞的细胞代谢，并抑制体内成骨细胞数量，同时对骨髓肥胖没有影响。与男性相比，犬尿氨酸治疗对成骨细胞的有害影响在女性模型中更为明显。然而，犬尿氨酸处理既不抑制 Hdac3 的酶促脱乙酰酶活性，也不抑制其对下游糖皮质激素信号传导的抑制。因此，未来的工作将有必要确定增加的犬尿氨酸导致骨生物能量老化的机制。目前的研究为犬尿氨酸导致成骨细胞功能受损的观点提供了新的进一步支持，并表明受犬尿氨酸影响的成骨细胞基质产生受损部分归因于成骨细胞生物能学受损。由于循环犬尿氨酸水平随着年龄的增长而增加，并且人体骨密度与血清犬尿氨酸与色氨酸的比率呈负相关，这些机制可能与人类骨质疏松症的病因和发病机制具有重要关联。