Guanylyl Cyclase-B Dependent Bone Formation in Mice is Associated with Youth, Increased Osteoblasts, and Decreased Osteoclasts.
Guanylyl Cyclase-B Dependent Bone Formation in Mice is Associated with Youth, Increased Osteoblasts, and Decreased Osteoclasts.
复制标题
小鼠体内鸟苷酸环化酶 B 依赖性骨形成与青春期、成骨细胞增加和破骨细胞减少有关。
DOI：
10.1007/s00223-022-01014-7
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发表时间：
2022
影响因子：
4.2
通讯作者：
Potter,LincolnR
中科院分区：
文献类型：
--
作者：
Wagner,BrandonM;Robinson,JeridW;Prickett,TimothyCR;Espiner,EricA;Khosla,Sundeep;Gaddy,Dana;Suva,LarryJ;Potter,LincolnR
C型利钠肽（CNP）激活鸟苷酸环化酶-B（GC-B）催化软骨细胞和成骨细胞中cGMP的合成。cGMP升高刺激长骨生长，CNP或GC-B的失活突变减少cGMP，导致侏儒症。表达不能通过去磷酸化失活的GC-B突变体的GC-B7 E/7 Emice表现出增加的CNP依赖性GC-B活性，其增加骨长度以及骨量和强度。重要的是，GC-B如何增加骨量尚不清楚。在这里，我们每天一次注射12周龄的野生型小鼠，持续28天，注射或不注射BMN-111（Vosoritide），一种蛋白水解抗性CNP类似物。我们发现BMN-111处理的小鼠具有升高的骨钙素和胶原蛋白1C-末端肽（CTX）水平以及增加的成骨细胞和破骨细胞。在注射BMN-111的小鼠中，Rank配体和骨保护素的胫骨mRNA分别增加和减少，而sclerostin mRNA升高400倍，与破骨细胞活性增加和成骨细胞活性降低一致。骨矿物质沉积率和骨小梁质量没有升高，对BMN-111的反应。由于9周龄雄性GC-B7 E/7 Emice的骨量增加，但没有表现出增加的矿物质沉积率，我们检查了4周龄雄性GC-B7 E/7 Emice，发现这些动物的血清骨钙素增加，但没有CTX。重要的是，这些小鼠的胫骨成骨细胞增加了37%，破骨细胞减少了26%，矿物质沉积和骨形成率分别增加了36%和40%。我们的结论是，GC-B-依赖性骨形成耦合到一个早期的少年过程，需要增加成骨细胞和减少破骨细胞。
C-type natriuretic peptide (CNP) activation of guanylyl cyclase-B (GC-B) catalyzes the synthesis of cGMP in chondrocytes and osteoblasts. Elevated cGMP stimulates long bone growth, and inactivating mutations in CNP or GC-B reduce cGMP, which causes dwarfism. GC-B7E/7Emice that express a GC-B mutant that cannot be inactivated by dephosphorylation exhibit increased CNP-dependent GC-B activity, which increases bone length, as well as bone mass and strength. Importantly, how GC-B increases bone mass is not known. Here, we injected 12-week-old, wild type mice once daily for 28 days with or without BMN-111 (Vosoritide), a proteolytically resistant CNP analog. We found that BMN-111 treated mice had elevated levels of osteocalcin and collagen 1 C-terminal telopeptide (CTX) as well as increased osteoblasts and osteoclasts. In BMN-111 injected mice, tibial mRNAs for Rank ligand and osteoprotegrin were increased and decreased, respectively, whereas sclerostin mRNA was elevated 400-fold, consistent with increased osteoclast activity and decreased osteoblast activity. Mineral apposition rates and trabecular bone mass were not elevated in response to BMN-111. Because 9-week-old male GC-B7E/7Emice have increased bone mass but do not exhibit increased mineral apposition rates, we examined 4-week-old male GC-B7E/7Emice and found that these animals had increased serum osteocalcin, but not CTX. Importantly, tibias from these mice had 37% more osteoblasts, 26% fewer osteoclasts as well as 36% and 40% higher mineral apposition and bone formation rates, respectively. We conclude that GC-B-dependent bone formation is coupled to an early juvenile process that requires both increased osteoblasts and decreased osteoclasts.