Abstract
SummaryEmerging evidence indicates that the dysregulation of protein ubiquitination plays a crucial role in aging‐associated diseases. Smad‐dependent canonical BMP signaling pathway is indispensable for osteoblastic bone formation, which could be disrupted by the ubiquitination and subsequent proteasomal degradation of Smad1/5, the key molecules for BMP signaling transduction. However, whether the dysregulation of Smad1/5 ubiquitination and disrupted BMP signaling pathway is responsible for the age‐related bone formation reduction is still underexplored. Pleckstrin homology domain‐containing family O member 1 (PLEKHO1) is a previously identified ubiquitination‐related molecule that could specifically target the linker region between the WW domains of Smurf1 to promote the ubiquitination of Smad1/5. Here, we found an age‐related increase in the expression of PLEKHO1 in bone specimens from either fractured patients or aging rodents, which was associated with the age‐related reduction in Smad‐dependent BMP signaling and bone formation. By genetic approach, we demonstrated that loss of Plekho1 in osteoblasts could promote the Smad‐dependent BMP signaling and alleviated the age‐related bone formation reduction. In addition, osteoblast‐specific Smad1 overexpression had beneficial effect on bone formation during aging, which could be counteracted after overexpressing Plekho1 within osteoblasts. By pharmacological approach, we showed that osteoblast‐targeted Plekho1 siRNA treatment could enhance Smad‐dependent BMP signaling and promote bone formation in aging rodents. Taken together, it suggests that the increased PLEKHO1 could suppress Smad‐dependent BMP signaling to inhibit bone formation during aging, indicating the translational potential of targeting PLEKHO1 in osteoblast as a novel bone anabolic strategy for reversing established osteoporosis during aging.
Highlights
Aging-induced reduction in osteoblastic bone formation results in decreased bone mass and deteriorated bone architecture, leading to increased fracture risk in elderly patients (Boskey & Coleman, 2010)
We demonstrated that loss of Plekho1 in osteoblasts could promote the Smad-dependent bone morphogenetic protein (BMP) signaling and alleviated the age-related bone formation reduction
We showed that osteoblast-targeted Plekho1 siRNA treatment could enhance Smad-dependent BMP signaling and promote bone formation in aging rodents
Summary
Aging-induced reduction in osteoblastic bone formation results in decreased bone mass and deteriorated bone architecture, leading to increased fracture risk in elderly patients (Boskey & Coleman, 2010). Albeit emerging studies have established that the ubiquitin/proteasome system is indispensable for osteoblastic bone formation (Zhao et al, 2004; Yamashita et al, 2005; Kim et al, 2011; Qiang et al, 2012; Severe et al, 2013; Zhang & Xing, 2013; Choi et al, 2015; Tsubakihara et al, 2015), the extent to which it contributes to the aging-induced bone formation reduction is underexplored. The ubiquitination and subsequent proteasomal degradation of Smad1/5 represent one of the crucial regulatory processes for controlling the BMP signaling cascade, which is mediated by the HECT family of E3 ubiquitin ligases, for example, Smad ubiquitin regulatory factor (Smurf) including Smurf and Smurf (Zhang et al, 2001; Yamashita et al, 2005; Xing et al, 2010).
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