Male mice with elevated C-type natriuretic peptide-dependent guanylyl cyclase-B activity have increased osteoblasts, bone mass and bone strength,Bone

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Male mice with elevated C-type natriuretic peptide-dependent guanylyl cyclase-B activity have increased osteoblasts, bone mass and bone strength
Bone ( IF 3.5 ) Pub Date : 2020-06-01 , DOI: 10.1016/j.bone.2020.115320
Jerid W Robinson ₁ , Nicholas C Blixt ₂ , Andrew Norton ₃ , Kim C Mansky ₃ , Zhou Ye ₄ , Conrado Aparicio ₄ , Brandon M Wagner ₅ , Andrew M Benton ₆ , Gordon L Warren ₆ , Sundeep Khosla ₇ , Dana Gaddy ₈ , Larry J Suva ₉ , Lincoln R Potter ₁₀

Affiliation

Departments of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN, USA.
Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, MN, USA.
Developmental and Surgical Sciences, University of Minnesota, Minneapolis, MN, USA.
Restorative Sciences, University of Minnesota, Minneapolis, MN, USA.
Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN, USA.
Department of Physical Therapy, Georgia State University, Atlanta, GA, USA.
Robert and Arlene Kogod Center on Aging and Division of Endocrinology, Mayo Clinic College of Medicine, Rochester, MN, USA.
Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, TX, USA.
Department of Physiology and Pharmacology, Texas A&M University, College Station, TX, USA.
Departments of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN, USA; Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN, USA.

C-type natriuretic peptide (CNP) activation of guanylyl cyclase (GC)-B, also known as NPR2, stimulates cGMP synthesis and bone elongation. CNP activation requires the phosphorylation of multiple GC-B residues and dephosphorylation inactivates the receptor. GC-B7E/7E knockin mice, expressing a glutamate-substituted, "pseudophosphorylated," form of GC-B, exhibit increased CNP-dependent GC activity. Since mutations that constitutively activate GC-B in the absence of CNP result in low bone mineral density in humans, we determined the skeletal phenotype of 9-week old male GC-B7E/7E mice. Unexpectedly, GC-B7E/7E mice have significantly greater tibial and L5 vertebral trabecular bone volume fraction, tibial trabecular number, and tibial bone mineral density. Cortical cross-sectional area, cortical thickness, periosteal diameter and cortical cross-sectional moment of inertia were also significantly increased in GC-B7E/7E tibiae. Three-point bending measurements demonstrated that the mutant tibias and femurs had greater ultimate load, stiffness, energy to ultimate load, and energy to failure. No differences in microhardness indicated similar bone quality at the tissue level between the mutant and wildtype bones. Procollagen 1 N-terminal propeptide and osteocalcin were elevated in serum, and osteoblast number per bone perimeter and osteoid width per bone perimeter were elevated in tibias from the mutant mice. In contrast to mutations that constitutively activate GC-B, we report that mutations that enhance GC-B activity only in the presence of its natural ligand, increase bone mass, bone strength, and the number of active osteoblasts at the bone surface.

中文翻译：

C型利钠肽依赖性鸟苷酸环化酶-B活性升高的雄性小鼠成骨细胞、骨量和骨强度增加

C 型利钠肽 (CNP) 激活鸟苷酸环化酶 (GC)-B（也称为 NPR2），刺激 cGMP 合成和骨伸长。 CNP 激活需要多个 GC-B 残基的磷酸化，去磷酸化会使受体失活。 GC-B7E/7E 敲入小鼠表达谷氨酸取代的“假磷酸化”形式的 GC-B，表现出 CNP 依赖性 GC 活性增加。由于在缺乏 CNP 的情况下组成性激活 GC-B 的突变会导致人类骨矿物质密度降低，因此我们确定了 9 周龄雄性 GC-B7E/7E 小鼠的骨骼表型。出乎意料的是，GC-B7E/7E 小鼠的胫骨和 L5 椎骨小梁骨体积分数、胫骨小梁数量和胫骨骨矿物质密度显着更高。 GC-B7E/7E 胫骨的皮质横截面积、皮质厚度、骨膜直径和皮质横截惯性矩也显着增加。三点弯曲测量表明，突变体胫骨和股骨具有更大的极限载荷、刚度、极限载荷能量和失效能量。显微硬度没有差异表明突变型骨和野生型骨在组织水平上具有相似的骨质量。突变小鼠的胫骨中，血清中前胶原 1 N 端前肽和骨钙素升高，每骨周长的成骨细胞数量和每骨周长的类骨质宽度升高。与组成性激活 GC-B 的突变相反，我们报告仅在其天然配体存在的情况下增强 GC-B 活性的突变，增加骨量、骨强度和骨表面活性成骨细胞的数量。

更新日期：2020-06-01

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