WP4788 - Autosomal recessive osteopetrosis pathways - Homo sapiens

Taken from Osteopetrosis: genetics, treatment and new insights into osteoclast function by Cristina Sobacchi, Ansgar Schulz, Fraser P. Coxon, Anna Villa and Miep H. Helfrich [https://www.ncbi.nlm.nih.gov/pubmed/23877423].

The osteopetroses are genetic diseases characterized by increased bone mass and density due to a failure in bone resorption. Two major forms can be distinguished on the basis of their mode of inheritance: autosomal dominant osteopetrosis (ADO, formerly known as Albers-Schönberg disease), is usually considered an adult-onset, more benign form (and has been comprehensively reviewed elsewhere); whereas autosomal recessive osteopetrosis (ARO), also termed malignant infantile osteopetrosis, presents soon after birth, is often severe and leads to death if left untreated.

Mechanisms underlying osteoclast-‑rich ARO:
Ruffled border formation and bone resorption by osteoclasts are dependent on secretory lysosome trafficking. Genes implicated in osteoclast-‑rich autosomal recessive osteopetrosis encode proteins that localize to secretory lysosomes in osteoclasts. TCIRG1 encodes the a3 subunit of the V0 complex, part of the V‑ATPase proton pump that acidifies endosomes and lysosomes; CLCN7 encodes ClC‑7, the Cl– antiporter responsible for increasing lumenal Cl– concentration; OSTM1 encodes the β‑subunit of CIC‑7; PLEKHM1 encodes a cytosolic protein that binds to the active (GTP-‑bound) form of Rab7, which is associated with late endosomes and lysosomes; and SNX10 encodes sorting nexin 10, which localizes to endosomes via a phosphoinositide-‑binding PX domain. This domain also interacts with the V1 complex D subunit of V‑ATPase, raising the possibility that SNX10 is involved in trafficking of V‑ATPase. ARO-‑causing mutations in all five genes disrupt trafficking of secretory lysosomes, thereby impairing ruffled-‑border formation and bone resorption. Osteoclast formation and adhesion to bone through the sealing zone are unaffected.

Mechanisms underlying osteoclast-‑poor ARO:
Osteoclastogenesis is dependent on the RANK signalling pathway. In normal osteoclasts, binding of RANKL recruits TRAF6, which releases NFκB from its phosphorylated inhibitor IκB. NFκB translocates to the nucleus and regulates transcription of key osteoclast genes. Osteopetrosis-‑causing mutations in TNFRSF11A (which encodes RANK) either reduce protein expression at the plasma membrane or impair RANKL binding, which leads to the loss of NFκB signalling and prevents differentiation and fusion of osteoclast precursors. Similarly, osteoclast differentiation defects are seen if osteopetrosis-‑causing mutations in TNFSF11 (which encodes RANKL) are present. Mutations identified so far lead to reduced RANKL trimerization or impaired RANK binding. Osteoclast formation studies in vitro reveal these two distinct osteoclast-‑poor forms of ARO: those in which osteoclastogenesis cannot be induced by synthetic RANKL (TNFRSF11A-‑related ARO) and those in which osteoclastogenesis can be induced by synthetic RANKL, resulting in osteoclasts that function normally (TNFSF11-‑related ARO).

Linked with a dotted arrow to the GeneProduct nodes are diseases caused by mutation in the respective gene.

本文献引用自Cristina Sobacchi、Ansgar Schulz、Fraser P. Coxon、Anna Villa与Miep H. Helfrich合著的《骨硬化症：遗传学、治疗及破骨细胞功能新进展》（原文链接：https://www.ncbi.nlm.nih.gov/pubmed/23877423）。

骨硬化症是一类因骨吸收功能障碍导致骨量与骨密度升高的遗传性疾病。根据遗传模式可分为两大主要类型：常染色体显性遗传性骨硬化症（autosomal dominant osteopetrosis, ADO，既往又称Albers-Schönberg病）通常为成年起病的良性亚型（相关内容已有全面综述）；而常染色体隐性遗传性骨硬化症（autosomal recessive osteopetrosis, ARO）又称为恶性婴儿型骨硬化症，多在出生后不久发病，病情通常较为严重，若未接受治疗可导致患者死亡。

伴破骨细胞增多的ARO发病机制：
破骨细胞的皱褶缘形成与骨吸收功能依赖于分泌性溶酶体的转运过程。与伴破骨细胞增多的常染色体隐性遗传性骨硬化症相关的基因，均编码定位于破骨细胞分泌性溶酶体的蛋白。其中，TCIRG1编码V型ATP酶（V‑ATPase）V0复合物的a3亚基，该复合物是负责酸化内体与溶酶体的质子泵组成部分；CLCN7编码ClC-7，即负责升高管腔氯离子浓度的氯逆向转运蛋白；OSTM1编码ClC-7的β亚基；PLEKHM1编码一种胞质蛋白，可结合与晚期内体及溶酶体相关的Rab7蛋白的活性（GTP结合）形式；SNX10编码分选连接蛋白10（sorting nexin 10），其通过磷酸肌醇结合PX结构域定位于内体，该结构域还可与V型ATP酶的V1复合物D亚基相互作用，提示SNX10可能参与V型ATP酶的转运过程。上述5个基因中导致ARO的突变均会破坏分泌性溶酶体的转运过程，进而损害皱褶缘形成与骨吸收功能，但破骨细胞的形成以及通过封闭带与骨基质的黏附过程不受影响。

伴破骨细胞减少的ARO发病机制：
破骨细胞生成依赖于RANK信号通路。在正常破骨细胞中，RANKL（核因子κB受体活化因子配体）结合后会招募TRAF6（肿瘤坏死因子受体相关因子6），使NFκB（核因子κB）从其磷酸化抑制蛋白IκB中释放。NFκB转位进入细胞核并调控关键破骨细胞基因的转录。TNFRSF11A（编码RANK，即核因子κB受体活化因子）上导致骨硬化症的突变，要么会降低该蛋白在细胞膜表面的表达量，要么会损害其与RANKL的结合能力，进而导致NFκB信号通路丧失，阻断破骨细胞前体细胞的分化与融合过程。同样，若TNFSF11（编码RANKL）存在导致骨硬化症的突变，也会出现破骨细胞分化缺陷。目前已发现的此类突变会降低RANKL的三聚化水平或损害其与RANK的结合能力。体外破骨细胞生成实验证实，伴破骨细胞减少的ARO存在两种截然不同的亚型：一类无法通过合成RANKL诱导破骨细胞生成（与TNFRSF11A相关的ARO），另一类则可通过合成RANKL诱导破骨细胞生成，且生成的破骨细胞功能正常（与TNFSF11相关的ARO）。

各基因突变引发的疾病通过虚线箭头与对应的基因产物（GeneProduct）节点相连。