Parental Origin of Gsα Inactivation Differentially Affects Bone Remodeling in a Mouse Model of Albright Hereditary Osteodystrophy.
Parental Origin of Gsα Inactivation Differentially Affects Bone Remodeling in a Mouse Model of Albright Hereditary Osteodystrophy.
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DOI：
10.1002/jbm4.10570
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发表时间：
2022-01
期刊：
影响因子：
3.8
通讯作者：
Germain-Lee EL
中科院分区：
文献类型：
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作者：
McMullan P;Maye P;Yang Q;Rowe DW;Germain-Lee EL
Albright遗传性骨营养不良症（AHO）是由GNAS杂合失活引起的，GNAS是一个复杂的基因座，编码异三聚体G蛋白（Gsα）的α刺激亚基（Gsα），除了NESP55和XLαs，由于第一外显子的选择。who骨骼表现包括指趾短、掌骨短、成人身材受损和皮下骨化。世卫组织母亲遗传GNAS突变的患者会发展为1A型假性甲状旁腺功能低下（PHP1A），并对多种激素产生耐药性，这些激素通过G蛋白偶联受体（gpcr）介导其作用，需要gs - α（如甲状旁腺激素[PTH]、促甲状腺激素[TSH]、生长激素释放激素[GHRH]、降钙素）和严重肥胖。父系遗传的GNAS突变引起假性甲状旁腺功能低下（PPHP），患者具有世卫组织的骨骼特征，但不会出现激素抵抗或明显的肥胖。这些PHP1A和PPHP之间的差异是由组织特异性的父本Gsα表达减少引起的。先前的小鼠报告显示，由于成骨细胞数量和功能受损，Gsα的丧失会导致骨质减少，并表明世卫组织患者可能表现出骨密度降低的证据。然而，我们之前的研究表明，PHP1A患者的骨密度测量值正常升高，与体重指数或血清甲状旁腺激素无关。由于PHP1A和PPHP之间存在这些差异，我们利用实验室的ho小鼠模型来研究基于突变的亲代遗传，Gsα杂合失活是否会对骨重塑产生不同的影响。我们确定了具有父系遗传（GnasE1+/ - p）和母系遗传（GnasE1+/ - m）突变的小鼠骨重塑的基本区别，这些发现主要在雌性小鼠中观察到。具体而言，GnasE1+/−p小鼠由于骨形成受损和骨吸收增强而表现出骨参数降低。然而，由于成骨细胞活性和正常骨吸收的增加，GnasE1+/−m小鼠显示出增强的骨参数。GnasE1+/ - p和GnasE1+/ - m小鼠骨重塑的体内差异可能与GnasE1+/ - m破骨细胞内降钙素抗性驱动的骨微环境变化有关。有必要进一步研究Gsα如何影响成骨细胞-破骨细胞偶联。©2021作者。JBMR Plus由Wiley期刊有限责任公司代表美国骨骼和矿物研究协会出版。
Albright hereditary osteodystrophy (AHO) is caused by heterozygous inactivation of GNAS, a complex locus that encodes the alpha‐stimulatory subunit of heterotrimeric G proteins (Gsα) in addition to NESP55 and XLαs due to alternative first exons. AHO skeletal manifestations include brachydactyly, brachymetacarpia, compromised adult stature, and subcutaneous ossifications. AHO patients with maternally‐inherited GNAS mutations develop pseudohypoparathyroidism type 1A (PHP1A) with resistance to multiple hormones that mediate their actions through G protein‐coupled receptors (GPCRs) requiring Gsα (eg, parathyroid hormone [PTH], thyroid‐stimulating hormone [TSH], growth hormone–releasing hormone [GHRH], calcitonin) and severe obesity. Paternally‐inherited GNAS mutations cause pseudopseudohypoparathyroidism (PPHP), in which patients have AHO skeletal features but do not develop hormonal resistance or marked obesity. These differences between PHP1A and PPHP are caused by tissue‐specific reduction of paternal Gsα expression. Previous reports in mice have shown loss of Gsα causes osteopenia due to impaired osteoblast number and function and suggest that AHO patients could display evidence of reduced bone mineral density (BMD). However, we previously demonstrated PHP1A patients display normal‐increased BMD measurements without any correlation to body mass index or serum PTH. Due to these observed differences between PHP1A and PPHP, we utilized our laboratory's AHO mouse model to address whether Gsα heterozygous inactivation differentially affects bone remodeling based on the parental inheritance of the mutation. We identified fundamental distinctions in bone remodeling between mice with paternally‐inherited (GnasE1+/−p) versus maternally‐inherited (GnasE1+/−m) mutations, and these findings were observed predominantly in female mice. Specifically, GnasE1+/−p mice exhibited reduced bone parameters due to impaired bone formation and enhanced bone resorption. GnasE1+/−m mice, however, displayed enhanced bone parameters due to both increased osteoblast activity and normal bone resorption. These in vivo distinctions in bone remodeling between GnasE1+/−p and GnasE1+/−m mice could potentially be related to changes in the bone microenvironment driven by calcitonin‐resistance within GnasE1+/−m osteoclasts. Further studies are warranted to assess how Gsα influences osteoblast–osteoclast coupling. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.