In the recent two decades,it has been well elucidated that receptor activator of nuclear factor-κB ligand(RANKL;also known as TNFSF11)binding to its receptor RANK(also known as TNFRSF11A)drives osteoclast development as the crucial signaling pathway.1-3However,accumulating evidence also implies that osteoblastic RANKL regulates osteoblastogenesis.4-6The studies“RANKL signaling in bone marrow mesenchymal stem cells negatively regulates osteoblastic bone formation”by Chen et al.in the current issue of Bone Research,and“Coupling of bone resorption and formation by RANKL reverse signalling”by Yuki Ikeuchi et al.in Nature(2018;561:195-200)reveal that RANKLRANK signaling regulates osteoblastogenesis in addition to its role in osteoclastogenesis.

“枫桥经验”发源于20世纪60年代绍兴枫桥的“社教运动”，主要内容是发动和依靠群众，坚持矛盾不上交，就地解决，实现捕人少，治安好。50年来，“枫桥经验”不断寻求自身突破与理念升华，成为有效化解社会矛盾的好经验、社会治安综合治理的好典型、新时期社会管理创新的好样板。“枫桥经验”作为一种独特的地方治理模式探索，在一定意义上，已成为一种活的、具有本土性质的法治实践。从法治的视角看，“枫桥经验”与时俱进的发展，呈现出四种转变：

Chen et al.demonstrate that RANK is expressed in bone marrow mesenchymal stem cells(BMSCs)and is decreased during osteogenic differentiation.RANK silencing significantly promotes,while overexpression suppresses,the osteoblast differentiation of BMSCs in vitro.Mice with a conditional knock-out of RANK in MSCs(Prx1-Cre:RANK fl ox/ fl ox)show a significant increase of osteoblast differentiation and bone formation.Interestingly,in an ovariectomized mouse model,RANK conditional knock-out mice exhibit resistance to ovariectomy-induced bone loss relative to the shamoperated mice.This study reveals that RANKL forward signaling in BMSCs functions as a negative regulator in osteoblast differentiation and bone formation(Fig.1).

RANKL belongs to the tumor necrosis factor family and its bidirectional signaling has been indicated.6,7The most recent study by Yuki Ikeuchi et al.provided evidence for RANKL reverse signaling in the coupling of bone resorption and formation.8RANK in small extracellular vesicles,secreted from the maturing osteoclasts,binds osteoblastic RANKL and promotes osteoblast differentiation by triggering RANKL reverse signaling,which activates runt-related transcription factor 2(Fig.1).In vivo,the authors also establish a mouse model(RANKLP29A)to inhibit RANKLreverse signaling butnotforward signaling.Bone formation is disrupted in RANKLP29Amice compared with wildtype mice after recombinant RANKL is administered.At last,the authors show that targeting RANKL reverse signaling prevents decreased bone formation by compensating for the shortage of coupling signals.The results suggest that RANKL reverse signaling is involved in the bone formation as a potential pharmacological target.

Fig.1 Mechanism of RANKL signaling in osteoblast differentiation.RANKL signaling drives osteoclastogenesis.In BMSCs,RANKL binding to RANK activates RANKL forward signaling,which inhibits osteoblast differentiation.Maturing osteoclasts secrete vesicular RANK which activates RANKL reverse signaling in osteoblasts and promotes osteoblast differentiation.During osteoblastogenesis,the RANK expression is reduced and RANKL forward signaling on osteoblast differentiation is relieved.

These two studies convincingly demonstrate the functions of RANKL-RANK forward and reverse signaling in the regulation of osteoblast differentiation and bone formation.Chen et al.show that RANKL binds to RANK and inhibits osteoblastogenesis,while Yuki et al.demonstrate that vesicular RANK from maturing osteoclasts promotes osteoblastogenesis for the bone formation through RANKL reverse signaling.Specifically,RANKL forward signaling activates NF-κB for degradation of β-catenin.In RANKL reverse signaling,a proline-rich motif in the RANKL cytoplasmic tail interacts with Src homology 3 domains and activates PI3K.

煤基质在吸附气体时会发生膨胀，在气体解吸后发生收缩，吸附不同气体的膨胀张量也不相同。煤基质膨胀和收缩不仅对煤层裂缝产生严重的影响，还对煤岩表面积、孔隙度、渗透率和吸附量等产生影响。研究表明煤岩膨胀程度与解吸气的体积成正比，而煤岩胀缩对渗透率的影响则依赖于煤层的力学性质。研究假设煤基质的胀缩应力主要作用在割理两壁之上，主要影响煤层割理孔隙的变化，进一步会对煤层渗透性进行影响。为了得到煤层渗透率变化的特征，PALMER等[20]提出了一系列孔隙度随气体吸附量和压力变化的关系式。引用煤层孔隙度变化与气体吸附和压力变化之间的关系式得到不同气体含量下的孔隙度。

In summary,these two reports provide evidence that RANKLRANK forward and reverse signaling regulates osteoblast differentiation and bone formation.The forward signaling inhibits osteogenic differentiation and the reverse signaling promotes osteoblast differentiation for bone formation(Fig.1).Not only do the findings discover the novel regulatory roles of RANKL-RANK signaling in osteoblastogenesis but also they provide a potential pharmacological target in an anabolic therapy.

ADDITIONAL INFORMATION

Competing interests:The authors declare no competing interests.

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