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ATP‐citrate lyase (ACLY), generating most of the nucleocytosolic acetyl coenzyme A (acetyl‐CoA) for histone acetylation, links cell metabolism to epigenetic regulation. Recent investigations demonstrated that ACLY activated by metabolic reprogramming played an essential role in both M1 and M2 macrophage activation via histone acetylation. Previous studies also revealed that histone methylation and acetylation were critical for transcriptional regulation of osteoclast‐specific genes. Considering that osteoclast differentiation also undergoes metabolic reprogramming and the activity of ACLY is always Akt‐dependent, we inferred that receptor activator of NF‐κB (RANK) activation might enhance the activity of ACLY through downstream pathways and ACLY might play a role in osteoclast formation. In the current study, we found that ACLY was gradually activated during RANK ligand (RANKL)‐induced osteoclast differentiation from bone marrow‐derived macrophages (BMMs). Both ACLY knock‐down and small molecular ACLY inhibitor BMS‐303141 significantly decreased nucleocytosolic acetyl‐CoA in BMMs and osteoclasts and suppressed osteoclast formation in vitro. BMS‐303141 also suppressed osteoclast formation in vivo and prevents ovariectomy (OVX)‐induced bone loss. Further investigations showed that RANKL triggered ACLY translocation into nucleus, consistent with increasing histone H3 acetylation, which was correlated to ACLY. The H3 lysine residues influenced by ACLY were in accordance with GCN5 targets. Using GCN5 knock‐down and overexpression, we showed that ACLY and GCN5 functioned in the same pathway for histone H3 acetylation. Analysis of pathways downstream of RANK activation revealed that ACLY was Akt‐dependent and predominately affected Akt pathway. With the help of RNA‐sequencing, we discovered Rac1 as a downstream regulator of ACLY, which was involved in shACLY‐mediated suppression of osteoclast differentiation, cytoskeleton organization, and signal transduction and was transcriptionally regulated by ACLY via histone H3 acetylation. To summarize, our results proved that inhibition of ATP‐citrate lyase led to suppression of osteoclast differentiation and function via regulation of histone acetylation. Rac1 could be a downstream regulator of ACLY. © 2021 American Society for Bone and Mineral Research (ASBMR). [ABSTRACT FROM AUTHOR]

Intervertebral disc degeneration (IVDD) is characterized by fibrosis of nucleus pulposus (NP) cells and accelerated surrounding extracellular matrix catabolism. Bioactive hydrogels have shown significant potential in regulating cellular functions and tissue homeostasis. In this work, a dynamic hydrogel (HA-NCSN/Cu) is designed via the reductive chelation of hyaluronic acid grafted with thiourea (HA-NCSN) and Cu 2+ . The reductivity of the grafted thiourea groups of HA-NCSN can quickly reduce part of the chelated Cu 2+ to Cu + . Therefore, during the gelation process, the color of hydrogel become dark immediately, which endowed hydrogel with remarkable photothermal effect. The abundant thiourea groups inside hydrogel can effectively scavenge reactive oxygen species to mitigate the inflammatory stress of NP cells. RNA sequencing analysis further reveals that glutathione signaling pathway is significantly altered. Meanwhile, mild photothermal therapy could activate the TGF-β/Smad pathway in NP cells, promoting the expression and secretion of Aggrecan and Collagen II. Ultimately, the combined modulation of inflammation alleviation and matrix regeneration achieves the restoration of the structure and function of the damaged intervertebral disc, which is also strongly demonstrated by the in vivo animal experiments. All of these results demonstrate the great potential of the dynamic HA-NCSN/Cu hydrogel in IVDD treatment., (© 2024 Wiley‐VCH GmbH.)

Fatty amide hydrolase (FAAH) is a key degradation enzyme of the endocannabinoid system, mainly responsible for the hydrolysis of arachidonic acid ethanolamine (AEA). Previous investigations have shown that FAAH is involved in a series of biological processes, such as inflammation, immune regulation, and transmembrane signal transduction of neurons. Endogenous cannabinoids and cannabinoid receptors have been reported to participate in the regulation of bone homeostasis by regulating the differentiation of osteoblasts and osteoclasts. We hypothesized that FAAH may play an important role in osteoclastogenesis based on the above evidence. The present study found that the FAAH expression was increased at both mRNA and protein levels during RANKL-induced osteoclastogenesis. Pharmacological and genetic inhibition of FAAH in bone marrow-derived macrophages (BMMs) inhibited osteoclastogenesis, F-actin ring formation, bone resorption, and osteoclast-specific gene expression in vitro. Moreover, intragastric administration of the FAAH inhibitor PF-04457845(PF) ameliorated ovariectomy (OVX)-induced bone loss in mice. Further investigation revealed that nuclear factor κB (NF-κB) and mitogen-activated protein kinase (MAPK) pathways were inhibited by PF treatment and FAAH knockdown. RNAseq indicated that the IL17 pathway was blocked by PF, and administration of recombinant murine IL17 protein could partially restore osteoclastogenesis and activate NF-κB and MAPK pathways. To sum up, our findings demonstrate that targeting FAAH could be a promising candidate strategy for treating osteoclast-related diseases, especially osteoporosis., (© 2022 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)