CHMP5 controls bone turnover rates by dampening NF-κB activity in osteoclasts.
CHMP5 controls bone turnover rates by dampening NF-κB activity in osteoclasts.
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DOI：
10.1084/jem.20150407
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发表时间：
2015-07-27
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影响因子：
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通讯作者：
Shim JH
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作者：
Greenblatt MB;Park KH;Oh H;Kim JM;Shin DY;Lee JM;Lee JW;Singh A;Lee KY;Hu D;Xiao C;Charles JF;Penninger JM;Lotinun S;Baron R;Ghosh S;Shim JH
Greenblatt等表明，在破骨细胞中缺失CHMP 5导致骨吸收增加，伴随着旺盛的成骨细胞活性，类似于人骨佩吉特病的早期发作形式。生理骨重塑要求成骨细胞的骨形成与破骨细胞的骨吸收紧密结合。然而，人们对这种耦合是如何调节的了解相对较少。在这里，我们证明了通过带电多泡体蛋白5（CHMP 5）的新活性调节破骨细胞中的NF-κB信号是全身骨转换率的关键决定因素。破骨细胞中CHMP 5的条件性缺失导致破骨细胞的骨吸收增加，伴随着成骨细胞的骨形成旺盛，类似于人佩吉特骨疾病（PDB）的早发性、多骨性形式。这些表型可通过Rank单倍不足以及抗吸收治疗（包括阿仑膦酸钠、唑仑膦酸钠和OPG-Fc）逆转。因此，CHMP 5缺陷型破骨细胞显示RANKL诱导的NF-κB活化和破骨细胞分化增加。生化分析表明，CHMP 5与PD B遗传风险因子含缬沙汀蛋白（VCP/p97）合作，稳定NF-κBα（IκBα）抑制剂，通过去泛素化酶USP 15下调IκBα的泛素化。因此，CHMP 5调节破骨细胞中RANK下游的NF-κB信号传导，以抑制破骨细胞分化、成骨细胞偶联和骨转换率，并且CHMP 5活性的破坏导致PDB样骨骼疾病。
Greenblatt et al. show that deletion of CHMP5 in osteoclasts leads to increased bone resorption coupled with exuberant osteoblast activity, resembling an early onset form of human Paget’s Disease of Bone Physiological bone remodeling requires that bone formation by osteoblasts be tightly coupled to bone resorption by osteoclasts. However, relatively little is understood about how this coupling is regulated. Here, we demonstrate that modulation of NF-κB signaling in osteoclasts via a novel activity of charged multivesicular body protein 5 (CHMP5) is a key determinant of systemic rates of bone turnover. A conditional deletion of CHMP5 in osteoclasts leads to increased bone resorption by osteoclasts coupled with exuberant bone formation by osteoblasts, resembling an early onset, polyostotic form of human Paget’s disease of bone (PDB). These phenotypes are reversed by haploinsufficiency for Rank, as well as by antiresorptive treatments, including alendronate, zolendronate, and OPG-Fc. Accordingly, CHMP5-deficient osteoclasts display increased RANKL-induced NF-κB activation and osteoclast differentiation. Biochemical analysis demonstrated that CHMP5 cooperates with the PDB genetic risk factor valosin-containing protein (VCP/p97) to stabilize the inhibitor of NF-κBα (IκBα), down-regulating ubiquitination of IκBα via the deubiquitinating enzyme USP15. Thus, CHMP5 tunes NF-κB signaling downstream of RANK in osteoclasts to dampen osteoclast differentiation, osteoblast coupling and bone turnover rates, and disruption of CHMP5 activity results in a PDB-like skeletal disorder.