Stem Cells International
Volume 2018, Article ID 3712083, 9 pages
https://doi.org/10.1155/2018/3712083
Review Article
Deubiquitinating Enzymes and Bone Remodeling
Yu-chen Guo
, Shi-wen Zhang, and Quan Yuan
State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
Correspondence should be addressed to Quan Yuan; yuanquan@scu.edu.cn
Received 29 March 2018; Accepted 29 May 2018; Published 8 July 2018
Academic Editor: Bo Yu
Copyright © 2018 Yu-chen Guo et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
1. IntroductionThe human skeleton undergoes continuous bone remodeling throughout a lifetime [1]. This process initiates with the destruction of mineralized bone, followed by the formation and mineralization of a new bone matrix [1, 2]. This critical process adapts bone architecture and strength to mechanical needs as well as growth. Meanwhile, it repairs microdamage of bone structure and maintains calcium homeostasis [1, 2]. Thus, bone remodeling is pretty important to general health.
To maintain bone homeostasis, bone remodeling is carried out by three main cell lineages: osteoclasts, multinucleated cells differentiate from macrophages and monocytes in the human hematopoietic lineage, resorb mineralized bone, and initiate the bone remodeling cycle [3]; osteoblasts, differentiate from mesenchymal stem cells (MSCs), deposit, and mineralize a new bone matrix [4]; osteocytes, which are the most common cells divided from osteoblasts, serve as a sensing and information transfer system [2]. These cells constitute the basic multicellular unit (BMU) that carries out the bone remodeling cycle. Based on current knowledge, bone remodeling mainly involves the following phases: formation of osteoclasts and resorption of bone, which initiates the cycle; completion of bone resorption followed by recruitment and differentiation of MSCs into osteoblasts; and bone formation mediated by osteoblasts [2]. Thus, the differentiation, function, and interaction of these BMU cells are critical to regulate bone remodeling and maintain bone homeostasis.
Osteoclasts that trigger the bone remodeling cycle are formed by the fusion of mononuclear progenitors in osteoclastogenesis [2]. They exist in a motile state during which they migrate from the bone marrow to the resorption site or a resorptive state performing their bone resorption function [5]. Osteoclasts are derived from the hematopoietic lineage and regulated by several factors [6]. Among these factors, M-SCF and RANKL produced by marrow stromal cells and osteoblasts are essential to promote osteoclastogenesis [2]. Osteoblasts play a key role in bone formation. They arise from MSCs and their differentiation is mainly regulated by transcription factor RUNX2 at the early time. They begin to express osteoblast phenotypic genes and synthesize the bone matrix at a later stage [7, 8]. Then osteoblasts are embedded into the bone matrix as osteocytes or die at the end of their destiny [9]. Several mechanisms including transcription factors, growth factors, hormones, and the extracellular matrix regulate these stages [7, 10].
In the last few years, significant findings have unveiled the mysterious role of the ubiquitin-dependent proteolysis system (UPS) in regulating differentiation and function of osteoclasts as well as osteoblasts [11–13].
2. Ubiquitin-Dependent Proteolysis System (UPS)
Ubiquitin is a highly conserved protein which is made up of 76 amino acids. It is linked to the lysine side chains of target proteins, which results in monoubiquitination or polyubiquitination of the protein. Polyubiquitylated proteins are degraded within a cylindrical multiprotein complex that is named proteasome [14, 15], while monoubiquitination has a variety of ends except proteasomal degradation [14, 15]. For example, the adapter protein TRAF6 contains the RING finger domain which could generate nondegradative K63-linked ubiquitin and contribute to form signaling complexes [16]. This is important to mediate RANK/TRAF6 signaling [17]. To successfully add ubiquitin to target protein, three enzymes involved in this process are essential. The E1 enzyme that recruits ubiquitin is named ubiquitin-activating enzyme. The E2 enzyme, called ubiquitin-conjugating enzyme, transfers the ubiquitin to protein. The E3 enzyme, also known as ubiquitin ligase, acts as a scaffold protein which interacts with the ubiquitin-conjugating enzyme and transfers ubiquitin to protein [18]. Consequently, the UPS affects multiple processes such as protein degradation, cell death, vesicular trafficking, signal transduction, DNA repair, and stress responses [11, 14, 15, 19–23].
The ubiquitin-dependent proteolysis system plays an important role in mediating bone remodeling. Initially, by inhibiting the proteasomal function through proteasome inhibitor I (PSI), study demonstrated that the
UPS is an important regulator of bone turnover and chondrogenesis [24]. And administration of proteasome inhibitor Bortezomib induced MSCs to undergo osteoblastic differentiation partially by modulation of RUNX2 in mice [25]. As a clinically available proteasome inhibitor used in myeloma, Bortezomib is also reported to promote osteoblastogenesis as well as inhibit bone resorption in clinical studies [26, 27]. Following studies demonstrated that these effects are mainly mediated by inhibiting the proteasomal degradation of important proteins, which regulate osteoblast function such as β-catenin [28] and Dkk1 [26]. Another protein stabilized by proteasome inhibitor is
Gli2, which promotes bone formation through upregulating bone morphogenetic protein-2 (BMP2) [29, 30].
To date, studies investigating ubiquitin ligase and bone remodeling have demonstrated that several E3 ubiquitin ligases take part in regulation of bone metabolism. For example, the first known ubiquitin ligase affecting bone formation is
Smuf1. Smurf1 has been proved to mediate RUNX2 degradation, resulting in downregulated osteoblast differentiation and bone formation [31–35]. Smurf1 also regulates the degradation of
Smad1 and downregulates
BMP-induced osteogenic differentiation of MSCs [35–37]. Moreover, Smuf1 mediates
JunB, MEKK2, and other molecule proteasomal degradation, which causes the inhibition of osteoblast differentiation [32, 38, 39]. Another important ubiquitin ligase which regulates osteoblastogenesis is
Cbl. It controls osteoblastogenesis by controlling the ubiquitination and degradation of receptor tyrosine kinases (
RTKs), including
IGFR,
FGFR, and PDGFR [40–43]. Cbl also interacts with
Pl3K to regulate bone formation [44–47]. Besides,
Itch and
Wwp1 are demonstrated to regulate osteogenesis by promoting
RUNX2 degradation [48, 49]. On the other hand, E3 ligases also influence osteoclastogenesis and bone resorption. The E3 ligase
LNX2 promotes osteoclastogenesis through M-SCF/RANKL signaling as well as the Notch pathway [13]. Another ubiquitin E3 ligase
RNF146 inhibits osteoclastogenesis and cytokine production via RANK signaling [50]. As there are over 600 E3 ligases expressed in the human genome, lots of E3 ligases are found to regulate bone remodeling by governing BMU cell differentiation and function.
3. Deubiquitinases (DUBs)
Like other posttranslational modifications, the process of ubiquitination is reversible by the function of deubiquitinases (DUBs) which remove monoubiquitin or polyubiquitin chains from such ubiquitin-modified proteins [51]. Ubiquitin itself is a long-lived protein [52, 53]; thus, it is necessary to remove ubiquitin from proteins for maintaining a sufficient pool of free ubiquitin in the cell to sustain a normal rate of proteolysis. As key hydrolytic emzymes, DUBs hydrolyze the peptide bond that links target protein and ubiquitin [54]. Deubiquitinases are modular proteins which contain catalytic domains, ubiquitin binding domains, and protein-protein interaction domains. Such modules make positive contribution to the recognition of and binding to various chain linkages [55]. To date, about 100 DUBs have been reported to be encoded by the human genome [56, 57] (Table 1). According to their catalytic domains, these DUBs can be classified into five families including 4 thiol protease DUBS (USP, UCH, OUT, and Josephin) and 1 ubiquitin specific metalloproteases (JAMM) [54].
Table 1: Members of deubiquitinases.
Family Members
USP
USPL1, CYLD, USP1, USP2, USP3, USP4, USP5, USP6, USP7, YSP8, USP9x, USP10, USP11, USP12, USP13, USP14, USP15, USP16, USP17L2, USP18, USP19, USP20, USP21, USP22, USP23, USP24, USP25, USP26, USP27, USP28, USP29, USP30, USP31, USP32, USP33, USP34, USP35, USP36, USP37, USP38, USP39, USP40, USP41, USP42, USP43, USP44, USP45, USP46, USP47, USP48, USP49, USP50, USP51, USP52, USP53, USP54
OTU
OTUB1, OTUB2, OTUD1, OTUD3, OTUD4, OTUD5, OTUD6A, OTUD6B, OTU1, HIN1L, A20, Cezanne, Cezanne2, TRABID, VCPIP1
UCH
UCH-L1, UCH-L3, UCH37/UCH-L5, BAP1
Josephin
ATXN3, ATXN3L, JOSD1, JOSD2
JAMM/MPN+
BRCC36, CSNS, POH1, AMSH, AMSH-LP, MPND, MYSM1, PRPF8
Deubiquitination has also been reported to be involved in many cellular functions, including DNA repair, protein degradation, cell cycle regulation, stem cell differentiation, and cell signaling [58–69]. Besides, a number of articles demonstrated that DUBs are essential for bone remodeling through regulating related BMU cell differentiation and function [69–78].
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