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Giant cell arteritis associated with intravenous zoledronic acid administration 与静脉注射唑来膦酸有关的巨细胞动脉炎
IF 3.8 Q1 Medicine Pub Date : 2024-02-14 DOI: 10.1093/jbmrpl/ziae015
M. L. Balbach, Jennifer R Hewlett, R. Wermers, K. Warrington, S. B. Tanner, Erin Y Chew
Bisphosphonates frequently provoke a cytokine-driven acute clinical response (ACR) characterized by fever, chills, arthralgias, and myalgias. More rarely an association between aminobisphosphonates, such as alendronate and zoledronic acid, and rheumatologic and/or immune-mediated syndromes (RIMS) has been described. Herein we report two patients, one with a prior history of rheumatic disease and one without, who developed giant cell arteritis meeting the American College of Rheumatology 2022 criteria following zoledronic acid infusion. We subsequently review existing mechanistic and clinical literature supporting this link. The duration of symptoms and elevation of inflammatory markers may serve as indicators for differentiating between the more common ACR and less frequent but potentially morbid RIMS. Although the benefit of bisphosphonates will outweigh the risk of RIMS for most patients with high fracture risk, clinicians should be aware of this phenomenon to assist earlier diagnosis and treatment in affected individuals.
双膦酸盐经常会引起细胞因子驱动的急性临床反应(ACR),其特点是发热、寒战、关节痛和肌痛。更罕见的是,阿仑膦酸盐和唑来膦酸等氨基双膦酸盐与风湿病和/或免疫介导综合征(RIMS)之间存在关联。在此,我们报告了两名输注唑来膦酸后出现符合美国风湿病学会 2022 年标准的巨细胞动脉炎的患者,其中一人既往有风湿病史,另一人无风湿病史。我们随后回顾了支持这种联系的现有机理和临床文献。症状持续时间和炎症标志物的升高可作为区分更常见的 ACR 和不太常见但可能会导致死亡的 RIMS 的指标。虽然对于大多数骨折风险较高的患者来说,双膦酸盐的益处大于 RIMS 的风险,但临床医生仍应了解这一现象,以帮助对受影响的患者进行早期诊断和治疗。
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引用次数: 0
Romosozumab added to ongoing denosumab in postmenopausal osteoporosis, a prospective observational study 前瞻性观察研究:绝经后骨质疏松症患者在使用地诺单抗的同时使用 Romosozumab
IF 3.8 Q1 Medicine Pub Date : 2024-02-07 DOI: 10.1093/jbmrpl/ziae016
G. Adami, Elisa Pedrollo, Maurizio Rossini, A. Fassio, V. Braga, Emma Pasetto, Francesco Pollastri, C. Benini, O. Viapiana, Davide Gatti
Optimization of sequential and combination treatment is crucial in shaping long-term management of postmenopausal osteoporosis (OP). We conducted a 6-month prospective observational study on postmenopausal women with severe OP receiving treatment with romosozumab either alone (in patients naïve to treatment) or in combination with ongoing long-term denosumab (>2 years) or continuing ongoing denosumab alone (>2 years). We collected serum samples for bone turnover markers, bone modulators and calcium phosphate metabolism at baseline, month 3 and month 6. Bone mineral density was assessed at baseline and after 6 months. Fifty-two postmenopausal women with OP were included in the study. Nineteen received romosozumab alone, 11 received romosozumab combined to ongoing denosumab and 22 continued denosumab alone. BMD increased significantly at all sites at 6 months of follow-up in the romosozumab alone group (femoral neck +8.1%, total hip +6.8% and lumbar spine +7.9%). In contrast, BMD increased significantly only at lumbar spine in the combination group (+7.2%) and in the denosumab group (+1.5%). P1nP increased significantly in romosozumab groups at month 3 (+70.4% in romosozumab alone group and + 99.1% in combination group). Sclerostin levels increased steeply in both romosozumab groups and Dkk1 did not change. Romosozumab added to ongoing denosumab resulted in an increase in P1nP and lumbar spine BMD, but not in femoral neck BMD. For patients on denosumab, using romosozumab as an additional treatment appeared to be useful in terms of bone formation markers and spine BMD versus denosumab alone. Further randomized controlled trials, possibly powered to fracture outcomes, are needed to confirm our results.
优化序贯治疗和联合治疗对于绝经后骨质疏松症(OP)的长期治疗至关重要。 我们对患有严重 OP 的绝经后妇女进行了一项为期 6 个月的前瞻性观察研究,研究对象是单独接受罗莫索单抗治疗(对初次接受治疗的患者)或与正在进行的长期地诺单抗联合治疗(>2 年)或继续单独接受地诺单抗治疗(>2 年)的患者。我们在基线期、第 3 个月和第 6 个月采集了骨转换标志物、骨调节剂和磷酸钙代谢的血清样本,并在基线期和 6 个月后评估了骨矿物质密度。 52名患有OP的绝经后妇女参与了研究。其中 19 人单独接受了罗莫索单抗治疗,11 人在接受罗莫索单抗治疗的同时继续接受地诺单抗治疗,22 人继续单独接受地诺单抗治疗。在 6 个月的随访中,单用罗莫索单抗组所有部位的 BMD 均有明显增加(股骨颈 +8.1%、全髋 +6.8%、腰椎 +7.9%)。相比之下,联合用药组(+7.2%)和地诺单抗组(+1.5%)只有腰椎的 BMD 有明显增加。在第 3 个月时,罗莫索单抗组的 P1nP 显著增加(罗莫索单抗单药组增加 70.4%,联合用药组增加 99.1%)。罗莫索单抗两组的硬骨蛋白水平均急剧上升,而Dkk1则没有变化。 在持续使用地诺单抗的基础上加用 Romosozumab,可增加 P1nP 和腰椎 BMD,但不能增加股骨颈 BMD。对于使用地诺单抗的患者来说,与单独使用地诺单抗相比,使用 Romosozumab 作为额外治疗似乎对骨形成标志物和脊柱 BMD 有帮助。要证实我们的研究结果,还需要进一步的随机对照试验(可能针对骨折结果)。
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引用次数: 0
Romosozumab added to ongoing denosumab in postmenopausal osteoporosis, a prospective observational study 前瞻性观察研究:绝经后骨质疏松症患者在使用地诺单抗的同时使用 Romosozumab
IF 3.8 Q1 Medicine Pub Date : 2024-02-07 DOI: 10.1093/jbmrpl/ziae016
G. Adami, Elisa Pedrollo, Maurizio Rossini, A. Fassio, V. Braga, Emma Pasetto, Francesco Pollastri, C. Benini, O. Viapiana, Davide Gatti
Optimization of sequential and combination treatment is crucial in shaping long-term management of postmenopausal osteoporosis (OP). We conducted a 6-month prospective observational study on postmenopausal women with severe OP receiving treatment with romosozumab either alone (in patients naïve to treatment) or in combination with ongoing long-term denosumab (>2 years) or continuing ongoing denosumab alone (>2 years). We collected serum samples for bone turnover markers, bone modulators and calcium phosphate metabolism at baseline, month 3 and month 6. Bone mineral density was assessed at baseline and after 6 months. Fifty-two postmenopausal women with OP were included in the study. Nineteen received romosozumab alone, 11 received romosozumab combined to ongoing denosumab and 22 continued denosumab alone. BMD increased significantly at all sites at 6 months of follow-up in the romosozumab alone group (femoral neck +8.1%, total hip +6.8% and lumbar spine +7.9%). In contrast, BMD increased significantly only at lumbar spine in the combination group (+7.2%) and in the denosumab group (+1.5%). P1nP increased significantly in romosozumab groups at month 3 (+70.4% in romosozumab alone group and + 99.1% in combination group). Sclerostin levels increased steeply in both romosozumab groups and Dkk1 did not change. Romosozumab added to ongoing denosumab resulted in an increase in P1nP and lumbar spine BMD, but not in femoral neck BMD. For patients on denosumab, using romosozumab as an additional treatment appeared to be useful in terms of bone formation markers and spine BMD versus denosumab alone. Further randomized controlled trials, possibly powered to fracture outcomes, are needed to confirm our results.
优化序贯治疗和联合治疗对于绝经后骨质疏松症(OP)的长期治疗至关重要。 我们对患有严重 OP 的绝经后妇女进行了一项为期 6 个月的前瞻性观察研究,研究对象是单独接受罗莫索单抗治疗(对初次接受治疗的患者)或与正在进行的长期地诺单抗联合治疗(>2 年)或继续单独接受地诺单抗治疗(>2 年)的患者。我们在基线期、第 3 个月和第 6 个月采集了骨转换标志物、骨调节剂和磷酸钙代谢的血清样本,并在基线期和 6 个月后评估了骨矿物质密度。 52名患有OP的绝经后妇女参与了研究。其中 19 人单独接受了罗莫索单抗治疗,11 人在接受罗莫索单抗治疗的同时继续接受地诺单抗治疗,22 人继续单独接受地诺单抗治疗。在 6 个月的随访中,单用罗莫索单抗组所有部位的 BMD 均有明显增加(股骨颈 +8.1%、全髋 +6.8%、腰椎 +7.9%)。相比之下,联合用药组(+7.2%)和地诺单抗组(+1.5%)只有腰椎的 BMD 有明显增加。在第 3 个月时,罗莫索单抗组的 P1nP 显著增加(罗莫索单抗单药组增加 70.4%,联合用药组增加 99.1%)。罗莫索单抗两组的硬骨蛋白水平均急剧上升,而Dkk1则没有变化。 在持续使用地诺单抗的基础上加用 Romosozumab,可增加 P1nP 和腰椎 BMD,但不能增加股骨颈 BMD。对于使用地诺单抗的患者来说,与单独使用地诺单抗相比,使用 Romosozumab 作为额外治疗似乎对骨形成标志物和脊柱 BMD 有帮助。要证实我们的研究结果,还需要进一步的随机对照试验(可能针对骨折结果)。
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引用次数: 0
Structural differences contributing to sex-specific associations between FN BMD and whole-bone strength for adult White women and men. 导致成年白人女性和男性 FN BMD 与全骨强度之间性别特异性关联的结构差异。
IF 3.4 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-01-30 eCollection Date: 2024-04-01 DOI: 10.1093/jbmrpl/ziae013
Karl J Jepsen, Erin M R Bigelow, Robert W Goulet, Bonnie T Nolan, Michael A Casden, Kathryn Kennedy, Samantha Hertz, Chandan Kadur, Gregory A Clines, Aleda M Leis, Carrie A Karvonen-Gutierrez, Todd L Bredbenner

Hip areal BMD (aBMD) is widely used to identify individuals with increased fracture risk. Low aBMD indicates low strength, but this association differs by sex with men showing greater strength for a given aBMD than women. To better understand the structural basis giving rise to this sex-specific discrepancy, cadaveric proximal femurs from White female and male donors were imaged using nano-CT and loaded in a sideways fall configuration to assess strength. FN pseudoDXA images were generated to identify associations among structure, aBMD, and strength that differ by sex. Strength correlated significantly with pseudoDXA aBMD for females (R2 = 0.468, P < .001) and males (R2 = 0.393, P < .001), but the elevations (y-intercepts) of the linear regressions differed between sexes (P < .001). Male proximal femurs were 1045 N stronger than females for a given pseudoDXA aBMD. However, strength correlated with pseudoDXA BMC for females (R2 = 0.433, P < .001) and males (R2 = 0.443, P < .001) but without significant slope (P = .431) or elevation (P = .058) differences. Dividing pseudoDXA BMC by FN-width, total cross-sectional area, or FN-volume led to significantly different associations between strength and the size-adjusted BMC measures for women and men. Three structural differences were identified that differentially affected aBMD and strength for women and men: First, men had more bone mass per unit volume than women; second, different cross-sectional shapes resulted in larger proportions of bone mass orthogonal to the DXA image for men than women; and third, men and women had different proportions of cortical and trabecular bone relative to BMC. Thus, the proximal femurs of women were not smaller versions of men but were constructed in fundamentally different manners. Dividing BMC by a bone size measure was responsible for the sex-specific associations between hip aBMD and strength. Thus, a new approach for adjusting measures of bone mass for bone size and stature is warranted.

髋关节平均骨密度(aBMD)被广泛用于识别骨折风险增加的个体。低 aBMD 意味着低强度,但这种关联因性别而异,在给定 aBMD 的情况下,男性比女性显示出更大的强度。为了更好地了解造成这种性别差异的结构基础,我们使用纳米 CT 对来自白人女性和男性捐献者的尸体股骨近端进行了成像,并以侧向坠落配置加载以评估强度。生成了 FN pseudoDXA 图像,以确定结构、aBMD 和强度之间因性别而异的关联。女性的力量与伪 DXA aBMD 有明显的相关性(R2 = 0.468,P R2 = 0.393,P y-截距),线性回归的性别差异(P R2 = 0.433,P R2 = 0.443,P P = .431)或海拔差异(P = .058)。将假 DXA BMC 除以 FN 宽度、总横截面积或 FN 容积会导致女性和男性的力量与尺寸调整后的 BMC 测量值之间存在显著不同的关联。研究发现,有三种结构差异会对女性和男性的 aBMD 和力量产生不同影响:首先,男性单位体积的骨量比女性多;其次,横截面形状的不同导致男性骨量与 DXA 图像正交的比例比女性大;第三,相对于 BMC,男性和女性的皮质骨和小梁骨比例不同。因此,女性的股骨近端并不是男性的缩小版,而是以根本不同的方式构建的。将 BMC 除以骨量是髋部 aBMD 和力量之间存在性别特异性关联的原因。因此,需要一种新的方法来根据骨大小和身材调整骨量的测量。
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引用次数: 0
Loss of 24-hydroxylated catabolism increases calcitriol and fibroblast growth factor-23 and alters calcium and phosphate metabolism in fetal mice 24- 羟基分解代谢的缺失会增加降钙三醇和成纤维细胞生长因子-23,并改变胎鼠的钙和磷代谢
IF 3.8 Q1 Medicine Pub Date : 2024-01-29 DOI: 10.1093/jbmrpl/ziae012
David Bennin, Sarah A Hartery, B. J. Kirby, Alexandre S Maekawa, René St-Arnaud, Christopher S Kovacs
Calcitriol circulates at low levels in normal human and rodent fetuses, in part due to increased 24-hydroxylation of calcitriol and 25-hydroxyvitamin D by 24-hydroxylase (CYP24A1). Inactivating mutations of CYP24A1 cause high postnatal levels of calcitriol and the human condition of infantile hypercalcemia type 1, but whether the fetus is disturbed by loss of CYP24A1 is unknown. We hypothesized that loss of Cyp24a1 in fetal mice will cause high calcitriol, hypercalcemia, and increased placental calcium transport. Cyp24a1+/- mice were mated to create pregnancies with WT, Cyp24a1+/- and Cyp24a1 null fetuses. The null fetuses were hypercalcemic, modestly hypophosphatemic (compared to Cyp24a1+/- fetuses only), with 3.5-fold increased calcitriol, 4-fold increased FGF23, and unchanged PTH. qPCR confirmed absence of Cyp24a1 and 2-fold increases in S100g, Ncx1 and Casr in null placentas but not fetal kidneys; these changes predicted an increase in placental calcium transport. However, placental 45Ca and 32P transport were unchanged in null fetuses. Fetal ash weight and mineral content, placental weight, crown-rump length, and skeletal morphology did not differ among the genotypes. Serum P1NP and bone expression of Sost and Blgap were reduced while Calcr was increased in nulls. In conclusion, loss of Cyp24a1 in fetal mice causes hypercalcemia, modest hypophosphatemia, increased FGF23, but no alteration in skeletal development. Reduced incorporation of calcium into bone may contribute to the hypercalcemia without causing a detectable decrease in skeletal mineral content. The results predict that human fetuses bearing homozygous or compound heterozygous inactivating mutations of CYP24A1 will also be hypercalcemic in utero but with normal skeletal development.
正常人类和啮齿类动物胎儿体内的降钙三醇循环水平较低,部分原因是 24- 羟化酶(CYP24A1)对降钙三醇和 25- 羟维生素 D 的 24- 羟化作用增加。CYP24A1 的失活突变会导致出生后降钙素三醇水平过高和人类的 1 型婴儿高钙血症,但 CYP24A1 的缺失是否会对胎儿造成干扰尚不清楚。我们假设,胎鼠体内 Cyp24a1 的缺失会导致高钙三醇、高钙血症和胎盘钙转运增加。Cyp24a1+/-小鼠与WT、Cyp24a1+/-和Cyp24a1无效胎儿交配妊娠。qPCR证实了Cyp24a1的缺失,以及S100g、Ncx1和Casr在无效胎盘中增加了2倍,但在胎儿肾脏中没有增加;这些变化预示着胎盘钙转运的增加。然而,胎盘 45Ca 和 32P 转运在无效胎儿中没有变化。不同基因型的胎儿灰分重量和矿物质含量、胎盘重量、冠臀长度和骨骼形态没有差异。无效胎儿的血清 P1NP 和骨骼中 Sost 和 Blgap 的表达量减少,而 Calcr 的表达量增加。总之,胎儿小鼠中 Cyp24a1 的缺失会导致高钙血症、轻度低磷血症、FGF23 增加,但不会改变骨骼发育。钙在骨骼中的结合减少可能是导致高钙血症的原因之一,但不会导致骨骼矿物质含量明显降低。研究结果预测,CYP24A1同源或复合杂合失活突变的人类胎儿也会在子宫内出现高钙血症,但骨骼发育正常。
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引用次数: 0
Response rates for lumbar spine, total hip, and femoral neck bone mineral density in men treated with abaloparatide: results from the ATOM study. 阿巴帕肽治疗男性腰椎、全髋和股骨颈骨矿物质密度的应答率:ATOM 研究的结果。
IF 3.8 Q1 Medicine Pub Date : 2024-01-27 eCollection Date: 2024-02-01 DOI: 10.1093/jbmrpl/ziae009
Ruban Dhaliwal, David Kendler, Kenneth Saag, Steven W Ing, Andrea Singer, Robert A Adler, Leny Pearman, Yamei Wang, Bruce Mitlak

Osteoporosis in men is an underappreciated public health issue, accounting for approximately 30% of the societal burden of osteoporosis. Although the prevalence of osteoporosis in men is lower, fracture-related morbidity and mortality rates exceed those of women. Abaloparatide is a synthetic, 34-amino acid peptide with homology to human parathyroid hormone-related protein (PTHrP), which favors bone formation by selective activation of PTH receptor type 1. In the Abaloparatide for the Treatment of Men With Osteoporosis (ATOM; NCT03512262) trial, 228 men with primary or hypogonadism-associated osteoporosis were randomized to receive subcutaneous injections of abaloparatide 80 μg or placebo. Abaloparatide significantly improved LS, TH, and FN BMD when compared with placebo. In this prespecified analysis, the proportion of men with a percent change from baseline of >0%, >3%, and > 6% in BMD at the LS, TH, and FN at 3, 6, and 12 mo and/or a shift in T-score category (based on LS and TH T-scores) at 12 mo was compared between the abaloparatide and placebo groups in ATOM. There were significantly more men with a BMD gain of >3% at all 3 anatomical sites in the abaloparatide than placebo group at month 6 (18/122 [14.8%] vs 1/70 [1.4%], P = .002) and at month 12 (38/119 [31.9%] vs 1/66 [1.5%], P < .0001). At month 3, more men treated with abaloparatide than placebo had a > 3% BMD increase at the LS (82/134 [61.2%] vs 21/68 [30.9%], P < .0001). A greater proportion of men treated with abaloparatide had an improvement in T-score category from osteoporosis to low BMD or normal when compared with placebo. In conclusion, use of abaloparatide compared with placebo for 12 mo resulted in significant and rapid improvements in BMD in men with osteoporosis from the ATOM study.

男性骨质疏松症是一个未得到充分重视的公共健康问题,约占骨质疏松症社会负担的 30%。虽然男性骨质疏松症的发病率较低,但与骨折相关的发病率和死亡率却超过了女性。阿巴帕肽是一种合成的 34 氨基酸肽,与人类甲状旁腺激素相关蛋白(PTHrP)具有同源性,可通过选择性激活 PTH 受体 1 型来促进骨形成。在阿巴拉帕肽治疗男性骨质疏松症(ATOM;NCT03512262)试验中,228名患有原发性或性腺功能低下相关性骨质疏松症的男性被随机分配接受阿巴拉帕肽80微克或安慰剂的皮下注射。与安慰剂相比,阿巴拉帕肽能明显改善LS、TH和FN BMD。在这项预设分析中,比较了 ATOM 中阿巴帕肽组与安慰剂组之间在 3、6 和 12 个月时 LS、TH 和 FN BMD 与基线相比变化百分比大于 0%、大于 3% 和大于 6% 的男性比例,以及/或在 12 个月时 T 评分类别发生变化(基于 LS 和 TH T 评分)的男性比例。在第 6 个月时(18/122 [14.8%] vs 1/70 [1.4%],P = .002)和第 12 个月时(38/119 [31.9%] vs 1/66 [1.5%],P 3%),阿巴帕肽组在所有 3 个解剖部位的 BMD 增幅均大于安慰剂组的男性人数(82/134 [61.2%] vs 21/68 [30.9%],P = .002)。
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引用次数: 0
Glycoproteomic profile of human tissue-nonspecific alkaline phosphatase expressed in osteoblasts 成骨细胞中表达的人类组织-非特异性碱性磷酸酶的糖蛋白组图谱
IF 3.8 Q1 Medicine Pub Date : 2024-01-22 DOI: 10.1093/jbmrpl/ziae006
Diana Atanasova, Ekaterina Mirgorodskaya, Lavanya Moparthi, Stefan Koch, Mathias Haarhaus, S. Narisawa, José Luis Millán, Eva Landberg, Per Magnusson
Tissue-nonspecific alkaline phosphatase (TNALP) is a glycoprotein expressed by osteoblasts that promotes bone mineralization. TNALP catalyzes the hydrolysis of the mineralization inhibitor inorganic pyrophosphate (PPi) and ATP to provide inorganic phosphate (Pi), thus controlling the PPi/Pi ratio to enable the growth of hydroxyapatite crystals. N-linked glycosylation of TNALP is essential for protein stability and enzymatic activity and is responsible for the presence of different bone isoforms of TNALP associated with functional and clinical differences. The site-specific glycosylation profiles of TNALP are, however, elusive. TNALP has five potential N-glycosylation sites located at the asparagine (N) residues 140, 230, 271, 303 and 430. The objective of this study was to reveal the presence and structure of site-specific glycosylation in TNALP expressed in osteoblasts. Calvarial osteoblasts derived from Alpl+/− expressing SV40 Large T antigen were transfected with soluble epitope-tagged human TNALP. Purified TNALP was analyzed with a lectin microarray, matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF MS) and liquid chromatography with tandem mass spectrometry (LC/MS–MS). The results showed that all sites (n = 5) were fully occupied predominantly with complex-type N-glycans. High abundance of galactosylated biantennary N-glycans with various degrees of sialylation was observed on all sites, as well as glycans with no terminal galactose and sialic acid. Furthermore, all sites had core fucosylation except site N271. Modelling of TNALP, with the protein structure prediction software ColabFold, showed possible steric hindrance by the adjacent side chain of W270, which could explain the absence of core fucosylation at N271. These novel findings provide evidence for N-linked glycosylation on all five sites of TNALP, as well as core fucosylation on four out of five sites. We anticipate that this new knowledge can aid in the development of functional and clinical assays specific for the TNALP bone isoforms.
组织非特异性碱性磷酸酶(TNALP)是成骨细胞表达的一种糖蛋白,可促进骨矿化。TNALP 催化水解矿化抑制剂无机焦磷酸(PPi)和 ATP,提供无机磷酸盐(Pi),从而控制 PPi/Pi 的比例,使羟基磷灰石晶体生长。TNALP 的 N-连接糖基化对蛋白质的稳定性和酶活性至关重要,也是导致 TNALP 存在不同骨异构体并造成功能和临床差异的原因。然而,TNALP 的特异性位点糖基化特征却难以捉摸。TNALP 有五个潜在的 N-糖基化位点,分别位于天冬酰胺(N)残基 140、230、271、303 和 430。本研究的目的是揭示在成骨细胞中表达的 TNALP 中存在的特异性位点糖基化及其结构。用可溶性表位标记的人 TNALP 转染表达 SV40 大 T 抗原的 Alpl+/- 的钙化成骨细胞。用凝集素芯片、基质辅助激光解吸/电离飞行时间质谱(MALDI-TOF MS)和液相色谱串联质谱(LC/MS-MS)对纯化的 TNALP 进行了分析。结果表明,所有位点(n = 5)都被复合型 N-聚糖完全占据。在所有位点上都观察到了高丰度的半乳糖化双年基 N-聚糖(具有不同程度的硅烷基化),以及不含末端半乳糖和硅烷基酸的聚糖。此外,除 N271 位点外,所有位点都有核心岩藻糖基化。利用蛋白质结构预测软件 ColabFold 对 TNALP 进行的建模显示,W270 的邻近侧链可能存在立体阻碍,这可以解释 N271 位点没有核心岩藻糖基化的原因。这些新发现为 TNALP 所有五个位点上的 N-连接糖基化以及五个位点中四个位点上的核心岩藻糖基化提供了证据。我们预计这些新知识将有助于开发针对 TNALP 骨异构体的功能和临床检测方法。
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引用次数: 0
Wnt Pathway Inhibition with the Porcupine Inhibitor LGK974 Decreases Trabecular Bone but not Fibrosis in a Murine Model with Fibrotic Bone 用箭毒抑制剂 LGK974 抑制 Wnt 通路可降低纤维化骨小鼠模型中的骨小梁数量,但不会降低其纤维化程度
IF 3.8 Q1 Medicine Pub Date : 2024-01-21 DOI: 10.1093/jbmrpl/ziae011
H. Lung, K. Wentworth, T. Moody, Ariane Zamarioli, Apsara Ram, Gauri Ganesh, Misun Kang, Sunita Ho, Edward C. Hsiao
G protein-coupled receptors (GPCRs) mediate a wide spectrum of physiological functions, including the development, remodeling, and repair of the skeleton. Fibrous dysplasia (FD) of the bone is characterized by fibrotic, expansile bone lesions caused by activating mutations in GNAS. There are no effective therapies for FD. We previously showed that ColI(2.3)+/Rs1+ mice, in which Gs-GPCR signaling was hyper-activated in osteoblastic cell lineages using an engineered receptor strategy, developed a fibrotic bone phenotype with trabecularization that could be reversed by normalizing Gs-GPCR signaling, suggesting that targeting the Gs-GPCR or components of the downstream signaling pathway could serve as a promising therapeutic strategy for FD. The Wnt signaling pathway has been implicated in the pathogenesis of FD-like bone, but the specific Wnts and which cells produce them remain largely unknown. Single cell RNA sequencing on long-bone stromal cells of 9-week-old male ColI(2.3)+/Rs1+ mice and littermate controls showed that fibroblastic stromal cells in ColI(2.3)+/Rs1+ mice were expanded. Multiple Wnt ligands were up- or down-regulated in different cellular populations, including in non-osteoblastic cells. Treatment with the porcupine inhibitor LGK974, which blocks Wnt signaling broadly, induced partial resorption of the trabecular bone in the femurs of ColI(2.3)+/Rs1+ mice, but no significant changes in the craniofacial skeleton. Bone fibrosis remained evident after treatment. Notably, LGK974 caused significant bone loss in control mice. These results provide new insights into the role of Wnt and Gs-signaling in fibrosis and bone formation in a mouse model of Gs-GPCR pathway overactivation.
G 蛋白偶联受体(GPCR)可介导多种生理功能,包括骨骼的发育、重塑和修复。骨纤维性发育不良(FD)的特征是由 GNAS 激活突变引起的纤维性、扩张性骨病变。目前还没有治疗 FD 的有效疗法。我们以前的研究表明,ColI(2.3)+/Rs1+小鼠使用工程受体策略在成骨细胞系中过度激活了Gs-GPCR信号,形成了纤维化骨表型,并伴有骨小梁化,这种表型可通过使Gs-GPCR信号正常化而逆转。Wnt信号通路被认为与FD样骨的发病机制有关,但具体的Wnts以及哪些细胞会产生Wnts在很大程度上仍是未知数。对9周大雄性ColI(2.3)+/Rs1+小鼠和同窝对照小鼠的长骨基质细胞进行的单细胞RNA测序显示,ColI(2.3)+/Rs1+小鼠的成纤维基质细胞扩增。多种 Wnt 配体在不同的细胞群(包括非成骨细胞)中上调或下调。豪猪抑制剂 LGK974 能广泛阻断 Wnt 信号传导,它能诱导 ColI(2.3)+/Rs1+ 小鼠股骨小梁骨的部分吸收,但颅面骨骼没有明显变化。治疗后,骨纤维化仍然明显。值得注意的是,LGK974会导致对照组小鼠出现明显的骨质流失。这些结果为我们提供了一个新的视角,让我们了解在Gs-GPCR通路过度激活的小鼠模型中,Wnt和Gs信号在骨纤维化和骨形成中的作用。
{"title":"Wnt Pathway Inhibition with the Porcupine Inhibitor LGK974 Decreases Trabecular Bone but not Fibrosis in a Murine Model with Fibrotic Bone","authors":"H. Lung, K. Wentworth, T. Moody, Ariane Zamarioli, Apsara Ram, Gauri Ganesh, Misun Kang, Sunita Ho, Edward C. Hsiao","doi":"10.1093/jbmrpl/ziae011","DOIUrl":"https://doi.org/10.1093/jbmrpl/ziae011","url":null,"abstract":"\u0000 G protein-coupled receptors (GPCRs) mediate a wide spectrum of physiological functions, including the development, remodeling, and repair of the skeleton. Fibrous dysplasia (FD) of the bone is characterized by fibrotic, expansile bone lesions caused by activating mutations in GNAS. There are no effective therapies for FD. We previously showed that ColI(2.3)+/Rs1+ mice, in which Gs-GPCR signaling was hyper-activated in osteoblastic cell lineages using an engineered receptor strategy, developed a fibrotic bone phenotype with trabecularization that could be reversed by normalizing Gs-GPCR signaling, suggesting that targeting the Gs-GPCR or components of the downstream signaling pathway could serve as a promising therapeutic strategy for FD.\u0000 The Wnt signaling pathway has been implicated in the pathogenesis of FD-like bone, but the specific Wnts and which cells produce them remain largely unknown. Single cell RNA sequencing on long-bone stromal cells of 9-week-old male ColI(2.3)+/Rs1+ mice and littermate controls showed that fibroblastic stromal cells in ColI(2.3)+/Rs1+ mice were expanded. Multiple Wnt ligands were up- or down-regulated in different cellular populations, including in non-osteoblastic cells. Treatment with the porcupine inhibitor LGK974, which blocks Wnt signaling broadly, induced partial resorption of the trabecular bone in the femurs of ColI(2.3)+/Rs1+ mice, but no significant changes in the craniofacial skeleton. Bone fibrosis remained evident after treatment. Notably, LGK974 caused significant bone loss in control mice. These results provide new insights into the role of Wnt and Gs-signaling in fibrosis and bone formation in a mouse model of Gs-GPCR pathway overactivation.","PeriodicalId":14611,"journal":{"name":"JBMR Plus","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139609764","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Association of secondhand smoke with fracture risk in community-dwelling non-smoking adults in Korea 韩国社区居住的非吸烟成年人中二手烟与骨折风险的关系
IF 3.8 Q1 Medicine Pub Date : 2024-01-21 DOI: 10.1093/jbmrpl/ziae010
Junyeong Ahn, H. Park, Sung Joon Cho, Seungjin Baek, Yumie Rhee, N. Hong
Although the detrimental effects of active smoking on bone health have been widely recognized, the impact of secondhand smoke exposure on fracture risk in non-smokers remains less understood. A total of 4843 non-smokers aged 40–69 years, who participated in the Korean Genome and Epidemiology Study from 2001 to 2018, were analyzed. The participants were categorized into two groups based on their exposure status to secondhand smoke: currently exposed and unexposed. The exposure group was subsequently divided into two subgroups based on the median weekly exposure time (high versus low groups). The incidence of new fractures was determined using self-reported questionnaires. The identified fractures were categorized according to the fracture site: overall, vertebral, hip, non-vertebral, and non-vertebral non-hip fractures. The mean age of the participants was 52.4 years (84.1% women). Exposure to secondhand smoke was associated with an increased risk of fracture (adjusted hazard ratio [aHR]: 1.27, P = 0.028) after adjusting for multiple covariates including age, sex, body mass index, household income, bone density of mid-shaft tibia, c-reactive protein, alcohol consumption, and history of fracture. Secondhand smoke remained as a significant risk factor for fracture, independent of the major osteoporotic fracture probabilities estimated using a fracture risk assessment tool (aHR: 1.24, P = 0.038). The high exposure group had higher risk of fracture than that of the unexposed group (aHR: 1.33, P = 0.025) whereas the fracture risk did not differ significantly between low exposure and unexposed groups (aHR: 1.18, P = 0.253), suggesting a potential dose–response relationship. Secondhand smoke showed robust association with increased risk of non-vertebral (aHR: 1.37, P = 0.008) or non-vertebral non-hip fractures (aHR: 1.36, P = 0.013), while its association with vertebral fracture was attenuated (aHR: 1.03, P = 0.908). Secondhand smoke was associated with an elevated risk of fracture in non-smokers, independent of clinical risk factors.
尽管主动吸烟对骨骼健康的有害影响已被广泛认可,但二手烟暴露对非吸烟者骨折风险的影响仍不甚了解。研究人员分析了 4843 名 40-69 岁的非吸烟者,他们参加了 2001 年至 2018 年的韩国基因组与流行病学研究。根据参与者的二手烟暴露状况,将他们分为两组:目前暴露组和未暴露组。暴露组随后根据每周暴露时间的中位数分为两个亚组(高组和低组)。新骨折的发生率是通过自我报告的问卷调查确定的。已确定的骨折根据骨折部位进行分类:整体骨折、椎体骨折、髋部骨折、非椎体骨折和非椎体非髋部骨折。参与者的平均年龄为 52.4 岁(84.1% 为女性)。在对年龄、性别、体重指数、家庭收入、胫骨中轴骨密度、c 反应蛋白、饮酒量和骨折史等多个协变量进行调整后,暴露于二手烟与骨折风险增加有关(调整后危险比 [aHR]:1.27,P = 0.028)。二手烟仍然是导致骨折的重要风险因素,与使用骨折风险评估工具估算的主要骨质疏松性骨折概率无关(aHR:1.24,P = 0.038)。高暴露组的骨折风险高于未暴露组(aHR:1.33,P = 0.025),而低暴露组和未暴露组的骨折风险差异不大(aHR:1.18,P = 0.253),这表明可能存在剂量反应关系。二手烟与非椎体骨折(aHR:1.37,P = 0.008)或非椎体非髋部骨折(aHR:1.36,P = 0.013)风险增加密切相关,而二手烟与椎体骨折的关系减弱(aHR:1.03,P = 0.908)。二手烟与非吸烟者骨折风险升高有关,与临床风险因素无关。
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引用次数: 0
Post-fracture survival in a population-based study of adults aged ≥ 66 years: a call to action at hospital discharge 对年龄≥ 66 岁的成年人进行的基于人口的骨折后存活率研究:呼吁在出院时采取行动
IF 3.8 Q1 Medicine Pub Date : 2024-01-20 DOI: 10.1093/jbmrpl/ziae002
Geneviève Vincent, J. Adachi, Emil Schemitsch, J. Tarride, Nathan Ho, Rajvi J Wani, Jacques P. Brown
Post-fracture survival rates provide prognostic information but are rarely reported along with other mortality outcomes in adults aged ≥50 years. The timing of survival change following a fracture also needs to be further elucidated. This population-based, matched-cohort, retrospective database study examined 98 474 patients (73% women) aged ≥66 years with an index fracture occurring at an osteoporotic site (hip, clinical vertebral, proximal non-hip non-vertebral [pNHNV], and distal non-hip non-vertebral [dNHNV]) from 2011 to 2015, who were matched (1:1) to non-fracture individuals based on sex, age, and comorbidities. All-cause 1- and 5-year overall survival and relative survival ratios (RSRs) were assessed and time trends in survival changes were characterized starting immediately after a fracture. In both sexes, overall survival was markedly decreased over 6 years of follow-up after hip, vertebral, and pNHNV fractures, and as expected, worse survival rates were observed in older patients and males. The lowest 5-year RSRs were observed after hip fractures in males (66–85 years, 51.9%–63.9%; ≥86 years, 34.5%), followed by vertebral fractures in males (66–85 years, 53.2%–69.4%; ≥86 years, 35.5%), and hip fractures in females (66–85 years, 69.8%–79.0%; ≥86 years, 52.8%). Although RSRs did not decrease as markedly after dNHNV fractures in younger patients, relatively low 5-year RSRs were observed in females (75.9%) and males (69.5%) aged ≥86 years. The greatest reduction in survival occurred within the initial month after hip, vertebral, and pNHNV fractures, indicating a high relative impact of short-term factors, with survival-reduction effects persisting over time. Therefore, the most critical period for implementing interventions aimed at improving post-fracture prognosis appears to be immediately after a fracture; however, considering the immediate need for introducing such interventions, primary fracture prevention is also crucial to prevent the occurrence of the initial fracture in high-risk patients.
骨折后存活率提供了预后信息,但很少与其他死亡率结果一起报告年龄≥50 岁的成年人的骨折后存活率。骨折后存活率变化的时间也需要进一步阐明。这项基于人群、配对队列的回顾性数据库研究调查了 2011 年至 2015 年期间 98 474 名年龄≥66 岁的患者(73% 为女性),他们的骨折发生在骨质疏松部位(髋部、临床椎体、近端非髋部非椎体 [pNHNV] 和远端非髋部非椎体 [dNHNV]),并根据性别、年龄和合并症与非骨折患者进行了配对(1:1)。评估了全因1年和5年总生存率和相对生存率(RSR),并描述了骨折后立即开始的生存率变化的时间趋势。在髋部骨折、椎体骨折和 pNHNV 骨折后的 6 年随访期间,男女患者的总存活率都明显下降,正如预期的那样,老年患者和男性患者的存活率更低。男性髋部骨折后的 5 年 RSR 最低(66-85 岁,51.9%-63.9%;≥86 岁,34.5%),其次是男性椎体骨折(66-85 岁,53.2%-69.4%;≥86 岁,35.5%)和女性髋部骨折(66-85 岁,69.8%-79.0%;≥86 岁,52.8%)。虽然年轻患者发生 dNHNV 骨折后 RSRs 的下降并不明显,但在年龄≥86 岁的女性(75.9%)和男性(69.5%)中观察到的 5 年 RSRs 相对较低。髋部、椎体和 pNHNV 骨折发生后的最初一个月内,存活率降低幅度最大,这表明短期因素的相对影响较大,存活率降低的影响会随着时间的推移而持续。因此,实施旨在改善骨折后预后的干预措施的最关键时期似乎是骨折后的第一时间;然而,考虑到引入此类干预措施的迫切需要,骨折的初级预防对于防止高危患者发生初次骨折也至关重要。
{"title":"Post-fracture survival in a population-based study of adults aged ≥ 66 years: a call to action at hospital discharge","authors":"Geneviève Vincent, J. Adachi, Emil Schemitsch, J. Tarride, Nathan Ho, Rajvi J Wani, Jacques P. Brown","doi":"10.1093/jbmrpl/ziae002","DOIUrl":"https://doi.org/10.1093/jbmrpl/ziae002","url":null,"abstract":"\u0000 Post-fracture survival rates provide prognostic information but are rarely reported along with other mortality outcomes in adults aged ≥50 years. The timing of survival change following a fracture also needs to be further elucidated. This population-based, matched-cohort, retrospective database study examined 98 474 patients (73% women) aged ≥66 years with an index fracture occurring at an osteoporotic site (hip, clinical vertebral, proximal non-hip non-vertebral [pNHNV], and distal non-hip non-vertebral [dNHNV]) from 2011 to 2015, who were matched (1:1) to non-fracture individuals based on sex, age, and comorbidities. All-cause 1- and 5-year overall survival and relative survival ratios (RSRs) were assessed and time trends in survival changes were characterized starting immediately after a fracture. In both sexes, overall survival was markedly decreased over 6 years of follow-up after hip, vertebral, and pNHNV fractures, and as expected, worse survival rates were observed in older patients and males. The lowest 5-year RSRs were observed after hip fractures in males (66–85 years, 51.9%–63.9%; ≥86 years, 34.5%), followed by vertebral fractures in males (66–85 years, 53.2%–69.4%; ≥86 years, 35.5%), and hip fractures in females (66–85 years, 69.8%–79.0%; ≥86 years, 52.8%). Although RSRs did not decrease as markedly after dNHNV fractures in younger patients, relatively low 5-year RSRs were observed in females (75.9%) and males (69.5%) aged ≥86 years. The greatest reduction in survival occurred within the initial month after hip, vertebral, and pNHNV fractures, indicating a high relative impact of short-term factors, with survival-reduction effects persisting over time. Therefore, the most critical period for implementing interventions aimed at improving post-fracture prognosis appears to be immediately after a fracture; however, considering the immediate need for introducing such interventions, primary fracture prevention is also crucial to prevent the occurrence of the initial fracture in high-risk patients.","PeriodicalId":14611,"journal":{"name":"JBMR Plus","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139610553","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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