Biochimica et Biophysica Acta (BBA) - General Subjects
ReviewSelenoproteins and selenium status in bone physiology and pathology
Introduction
The physiological functions of the essential micronutrient selenium (Se) are mediated principally through a class of selenocysteine (Sec)-containing proteins referred to as selenoproteins. The 25 selenoproteins found in humans are glutathione peroxidases (GPx1, 2, 3, 4, 6), thioredoxin reductases (TrxR1, 2, 3), iodothyronine deiodinases (Dio1, 2, 3), selenophosphate synthetase 2, 15 kDa selenoprotein, and selenoprotein H, I, K, M, N, O, P, R, S, T, V, and W [1], [2], [3], [4], of which many act as a redox gatekeeper and play an important role in maintaining cellular antioxidant homeostasis [1], [2], [3], [4].
The core part of the selenoprotein biosynthesis machinery is the co-translational incorporation of Sec, the 21st amino acid, into the growing polypeptide. Two distinct features are included in this multi-stage process (Fig. 1A): 1) UGA generally acts as the termination codon in protein translation; unusually, Sec insertion is dictated by an in-frame UGA provided that it is followed by a Sec insertion sequence (SECIS) element; 2) upon the binding of SECIS-binding protein 2 (SBP2) to the SECIS element, Sec-tRNA[Ser]Sec is recruited to provide Sec; uniquely, Sec synthesis from Se metabolites is confined on Sec-tRNA[Ser]Sec because Sec is a highly reactive amino acid with an exceptionally low pKa value of 5.2, so that there is no free pool of Sec [3], [5], [6]. Although these demanding steps are inefficient and energy-intensive, the evolutionary pressure for the preservation of selenoproteins and their conservation among species are attributed to the fact that Sec within enzymes has extraordinarily high nucleophilicity and confers resistance to oxidant-induced inactivation compared with cysteine (Cys), thus allowing selenoenzymes to turn over diverse substrates much better and to have 10- to 100-fold higher activities than Sec-to-Cys nonselenoprotein mutants [7], [8], [9], [10], [11], [12].
Among the various selenoproteins found in humans, the biological functions of the GPx and TrxR families have been well elucidated. GPx reduces hydrogen peroxide or other hydroperoxides to water or alcohols using glutathione (GSH) as a reductant. GPx knockout mice are sensitive to hydroperoxide challenges, which suggests that this class of selenoenzymes functions as antioxidants [13], [14], [15], [16]. Thioredoxin (Trx) participates in a broad range of cellular functions, including the reduction of peroxides, activation of redox-sensitive transcription factors via reduction of their conserved Cys residues that are required for DNA-binding, and apoptosis inhibition through binding apoptosis signal-regulating kinase 1 [17]. The functions of Trx rely on its reduced form, whereas TrxR is a specific enzyme responsible for catalyzing the reduction of the active site disulfide of Trx using nicotinamide-adenine dinucleotide phosphate (NADPH). Therefore, TrxR is implicated in regulating numerous biological functions [18], [19], [20], [21], [22].
Inadequate Se intake that compromises selenoprotein biosynthesis has long been known to be detrimental to health, including bone well-being [23], [24], [25], [26]. On the other hand, a growing body of evidence shows that Se at supranutritional levels, which exceed the requirement for selenoprotein biosynthesis, is able to modify some pathological alterations via various mechanisms, such as suppressing NFκB activation and inflammatory reactions [27], [28], [29], [30], [31], [32], [33], [34], activating p53 and DNA repair [35], [36], [37], [38], inducing chemoprotective enzymes [39], [40], [41], and inhibiting proliferation or promoting apoptosis [42], [43], [44]. The potential pharmacological effects of Se at supranutritional levels are principally mediated by low-molecular weight Se metabolites including selenodiglutathione and methylselenol, which have a highly reactive nature since the Se moiety in these selenocompounds has strong nucleophilicity [45], [46], [47], [48].
Healthy skeletal remodeling is maintained by an elegant equilibrium between the activities of mesenchymal stem cell-derived osteoblasts and hematopoesis-derived osteoclasts on the bone surface. Osteoblasts that deposit extracellular organic matrix in an orderly fashion are responsible for new bone formation, whereas multinucleated giant osteoclasts facilitate old bone degradation through secreting acid and lytic enzymes [49]. The molecular triad of receptor activator of NFκB ligand (RANKL) expressed by osteoblast lineage cells, osteoprotegerin (OPG) produced by osteoblastic/stromal cells, and receptor activator of NFκB (RANK) on osteoclasts functions as a pivotal signal link for osteoblast and osteoclast coupling [50], [51], [52], [53]. RANKL stimulates osteoclastic differentiation by binding RANK. OPG, acting as a decoy receptor for RANKL, blocks RANKL/RANK interactions and inhibits the terminal stages of osteoclastic differentiation. Once the coupling is significantly disturbed without timely repair, various types of bone diseases, such as osteopetrosis, osteoarthritis, osteoporosis, or osteolysis, tend to occur [53]. Oxidative stress with an increased level of reactive oxygen species (ROS) being present in the bone system is deleterious to normal bone physiology because excessive amounts of ROS suppress osteoblastic differentiation and promote osteoclastic differentiation along with NFκB activation independently [54], [55]. Moreover, excessive amounts of ROS orchestrate a crosstalk between cells of the osteoblastic and osteoclastic lineages in favor of osteoclastogenesis; namely, ROS stimulates RANKL expression in osteoblasts [56] and acts as a crucial intracellular signal mediator for RANKL-stimulated osteoclastic differentiation [57], [58]. Approaches that scavenge ROS in excess of physiological requirements or suppress NFκB activation have been validated to be highly efficient in inhibiting osteoclastogenesis [57], [58]. The goal of this article is to contextualize the information regarding selenoproteins in osteoblasts and osteoclasts as well as Se status in bone homeostasis and disorders, to provide an overview of the current state of knowledge of Se in bone physiology and pathology.
Section snippets
Selenoproteins in osteoblasts and osteoclasts
Most of the known selenoprotein genes and some important factors required for selenoprotein biosynthesis have been found in either osteoblasts or osteoclasts [59], [60], [61]. In standard cell cultures, known to be Se-deficient conditions [62], Se supplementation in human fetal osteoblast (hFOB) cells restored GPx and TrxR activities [63]. Likewise, Se supplementation in primary bone marrow stromal cells (BMSCs) that are able to differentiate into mesenchymal cells such as osteoblasts also
Selenoprotein knockout or biosynthesis impairment
Selenoprotein P (SePP) is a unique Sec-rich protein wherein the larger N-terminal domain has one Sec residue in the redox motif and unusually, the smaller C-terminal domain contains nine Sec residues [106]. Over 60% of the whole plasma Se level is contributed by SePP in Se-replete rats [107]. Plasma SePP is mainly secreted from the liver [108]. Hepatic biosynthesis of SePP has a salient influence on whole-body Se levels [109], [110]. The principal roles of SePP are Se transport and storage,
Skeletal development
Cao et al. reported that Se deprivation in first-generation mice that only had approximately 10% of normal hepatic Se levels and GPx activities augmented osteoclastic activity and bone resorption, as indicated by significantly reduced trabecular number and the ratio of BV to TV, as well as significantly increased trabecular separation, serum intact parathyroid hormone, and tartrate-resistant acid phosphatase (TRAP) [132]. Moreno-Reyes et al. showed that continuous Se deprivation up to
Se at supranutritional dose levels suppresses NFκB activity
Rheumatoid arthritis is a chronic autoimmune disease that affects synovial tissue in multiple joints. Compelling evidence shows that the activation of NFκB in the synovium is a hallmark of rheumatoid arthritis, and blockade of NFκB activation is an effective strategy of preventing against irreversible damage to the adjacent cartilage and bone [163], [164], [165], [166], [167], [168], [169]. Excessive amounts of ROS promote NFκB activation in the cytoplasm, whereas maintaining Cys residues
Vicious cycle
Bone metastasis occurs frequently in advanced breast cancer patients [182]. Metastatic breast cancer cells can induce an osteoblastic inflammatory response. The resultant pro-inflammatory cytokines then spur osteoclastic differentiation, leading to bone matrix degradation and concomitant growth factor leakage into the bone microenvironment. The released growth factors, such as transforming growth factor β, vascular endothelial growth factor, and insulin-like growth factors, in turn promote the
Conclusion
Removing the Trsp gene that encodes Sec-tRNA[Ser]Sec, which is required for Sec incorporation into selenoproteins, from skeletal progenitor cells impairs skeletal development. Mutations of SBP2, which are essential for Sec insertion into selenoproteins, cause growth retardation and delayed bone maturation in children probably through thyroid axis derangement due to impaired Dio enzymatic activities. Knockout of SePP, which is responsible for Se transport and local Se storage, evokes bone loss.
Conflict of interest
All authors state that they have no conflicts of interest.
Acknowledgements
This work was supported by the National Natural Science Foundation of China (31170648), Performance Appraisal Fund of Anhui Provincial Science and Technology Department (1306c083018), and Foundation of AHAU Subject Construction.
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