IGF-1 Receptor Expression on Circulating Osteoblast Progenitor Cells Predicts Tissue-Based Bone Formation Rate and Response to Teriparatide in Premenopausal Women With Idiopathic Osteoporosis.
IGF-1 Receptor Expression on Circulating Osteoblast Progenitor Cells Predicts Tissue-Based Bone Formation Rate and Response to Teriparatide in Premenopausal Women With Idiopathic Osteoporosis.
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DOI：
10.1002/jbmr.3109
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发表时间：
2017-06
期刊：
影响因子：
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通讯作者：
Shane E
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作者：
Cohen A;Kousteni S;Bisikirska B;Shah JG;Manavalan JS;Recker RR;Lappe J;Dempster DW;Zhou H;McMahon DJ;Bucovsky M;Kamanda-Kosseh M;Stubby J;Shane E
我们以前曾报道过绝经前妇女的特发性骨质疏松症（IOP）有深刻的微结构缺陷和异质性骨重建。那些骨形成率最低的人具有较高的基线血清IGF-1水平和对特立哌酮的较不稳健的反应。由于IGF-1刺激骨形成，并且对成骨细胞的三联作用至关重要，因此这些发现表明某些IOP女性存在IGF-1抵抗状态。为了进一步研究成骨细胞和IGF-1相关机制介导IOP中对特立帕肽的差异反应性的假设，我们研究了循环成骨细胞祖细胞（COP）及其IGF-1受体（IGF-1 R）表达。在患有IOP的绝经前女性中，在基线（n=25）和特立帕鲁肽治疗24个月（n=11）时获得外周血单核细胞（PBMC）。流式细胞术用于鉴定和定量COP（表达骨钙素和Runx 2的非造血谱系细胞），并定量IGF-1 R表达水平。基线时，COP的PBMC百分比（%COP）和COP细胞表面IGF-1 R表达与四环素标记的髂间皮活检中骨形成的几个组织形态计量学指标直接相关。在接受治疗的受试者中，%COP和IGF-1 R表达在teriparbal后迅速增加，在18个月时恢复至基线水平。虽然基线%COP和三个月后%COP的增加都不能预测对特立帕肽的BMD反应，但3个月时COP上IGF-1 R表达的百分比增加与对特立帕肽的BMD反应直接相关。此外，teriparbal后较低的IGF-1 R表达与较高的体脂相关，表明teriparbal抵抗，身体组成和GH/IGF-1轴之间的联系。总之，这些测定可能有助于非侵入性地表征骨重建，并可用于预测对特立哌齐和其他可能的骨形成刺激药物的早期反应。这些新的工具也可能在绝经前IOP中以及可能在其他人群中的特立哌酮耐药性的机制研究中具有实用性。
We have previously reported that premenopausal women with idiopathic osteoporosis (IOP) have profound microarchitectural deficiencies and heterogeneous bone remodeling. Those with the lowest bone formation rate have higher baseline serum IGF-1 levels and less robust response to teriparatide. Because IGF-1 stimulates bone formation and is critical for teriparatide action on osteoblasts, these findings suggest a state of IGF-1 resistance in some IOP women. To further investigate the hypothesis that osteoblast and IGF-1 related mechanisms mediate differential responsiveness to teriparatide in IOP, we studied circulating osteoblast progenitor (COP) cells and their IGF-1 receptor (IGF-1R) expression. In premenopausal women with IOP, peripheral blood mononuclear cells (PBMCs) were obtained at baseline (n=25) and over 24 months of teriparatide treatment (n=11). Flow cytometry was used to identify and quantify COPs (non-hematopoetic lineage cells expressing osteocalcin and Runx2) and to quantify IGF-1R expression levels. At baseline, both the percent of PBMCs that were COPs (%COP) and COP cell-surface IGF-1R expression correlated directly with several histomorphometric indices of bone formation in tetracycline-labeled transiliac biopsies. In treated subjects, both %COP and IGF-1R expression increased promptly after teriparatide, returning toward baseline by 18 months. While neither baseline %COP nor increase in %COP after three months predicted the BMD response to teriparatide, the percent increase in IGF-1R expression on COPs at 3 months correlated directly with the BMD response to teriparatide. Additionally, lower IGF-1R expression after teriparatide was associated with higher body fat, suggesting links between teriparatide resistance, body composition and the GH/IGF-1 axis. In conclusion, these assays may be useful to characterize bone remodeling noninvasively, and may serve to predict early response to teriparatide, and possibly other bone formation stimulating medications. These new tools may also have utility in the mechanistic investigation of teriparatide resistance in premenopausal IOP, and perhaps in other populations.