Sclerostin (SOST) is produced by osteocytes and is known as a negative regulator of bone homeostasis. Parathyroid hormone (PTH) regulates calcium, phosphate as well as vitamin D metabolism, and is a strong inhibitor of SOST synthesis in vitro and in vivo. PTH has two methionine amino acids (positions 8 and 18) which can be oxidized. PTH oxidized at Met18 (Met18(ox)-PTH) continues to be bioactive, whereas PTH oxidized at Met8 (Met8(ox)-PTH) or PTH oxidized at Met8 and Met18 (Met8, Met18(di-ox)-PTH) has minor bioactivity. How non-oxidized PTH (n-oxPTH) and oxidized forms of PTH act on sclerostin synthesis is unknown. The effects of n-oxPTH and oxidized forms of PTH on SOST gene expression were evaluated in UMR106 osteoblast-like cells. Moreover, we analyzed the relationship of SOST with n-oxPTH and all forms of oxPTH in 516 stable kidney transplant recipients using an assay system that can distinguish in clinical samples between n-oxPTH and the sum of all oxidized PTH forms (Met8(ox)-PTH, Met18(ox)-PTH, and Met8, Met18(di-ox)-PTH). We found that both n-oxPTH and Met18(ox)-PTH at doses of 1, 3, 20, and 30 nmol/L significantly inhibit SOST gene expression in vitro, whereas Met8(ox)-PTH and Met8, Met18(di-ox)-PTH only have a weak inhibitory effect on SOST gene expression. In the clinical cohort, multivariate linear regression showed that only n-oxPTH, but not intact PTH (iPTH) nor oxPTH, is independently associated with circulating SOST after adjusting for known confounding factors. In conclusion, only bioactive PTH forms such as n-oxPTH and Met18(ox)-PTH, inhibit SOST synthesis.

The most common cause for prosthetic revision surgery is wear particle-induced periprosthetic osteolysis, which leads to aseptic loosening of the prosthesis. Both SOST gene and its synthetic protein, sclerostin, are hallmarks of osteocytes. According to our previous findings, blocking SOST induces bone formation and protects against bone loss and deformation caused by titanium (Ti) particles by activating the Wnt/β-catenin cascade. Although SOST has been shown to influence osteoblasts, its ability to control wear-particle-induced osteolysis via targeting osteoclasts remains unclear. Mice were subjected to development of a cranial osteolysis model. Micro CT, HE staining, and TRAP staining were performed to evaluate bone loss in the mouse model. Bone marrow-derived monocyte-macrophages (BMMs) made from the C57BL/6 mice were exposed to the medium of MLO-Y4 (co-cultured with Ti particles) to transform them into osteoclasts. Bioinformatics methods were used to predict and validate the interaction among SOST, Wnt/β-catenin, RANKL/OPG, TNF-α, and IL-6. Local bone density and bone volume improved after SOST inhibition, both the number of lysis pores and the rate of skull erosion decreased. Histological research showed that β-catenin and OPG expression were markedly increased after SOST inhibition, whereas TRAP and RANKL levels were markedly decreased. In-vitro, Ti particle treatment elevated the expression of sclerostin, suppressed the expression of β-catenin, and increased the RANKL/OPG ratio in the MLO-Y4 cell line. TNF-α and IL-6 also elevated after treatment with Ti particles. The expression levels of NFATc1, CTSK, and TRAP in osteoclasts were significantly increased, and the number of positive cells for TRAP staining was increased. Additionally, the volume of bone resorption increased at the same time. In contrast, when SOST expression was inhibited in the MLO-Y4 cell line, these effects produced by Ti particles were reversed. All the results strongly show that SOST inhibition triggered the osteocyte Wnt/β-catenin signaling cascade and prevented wear particle-induced osteoclastogenesis, which might reduce periprosthetic osteolysis. KEY MESSAGES: SOST is a molecular regulator in maintaining bone homeostasis. SOST plays in regulating bone homeostasis through the Wnt/β-catenin signaling pathway. SOST gene suppression stimulates osteocyte Wnt/β-catenin signaling to prevent bone resorption and attenuates particle-induced osteolysis.

Osteoporosis, one of the serious health diseases, involves bone mass loss, bone density diminishing, and degeneration of bone microstructure, which is accompanied by a tendency toward bone fragility and a predisposition to fracture. More than 200 million people worldwide suffer from osteoporosis, and the cost of treating osteoporotic fractures is expected to reach at least $25 billion by 2025. The generation and development of osteoporosis are regulated by genetic factors and regulatory factors such as TGF-β, BMP, and FGF through multiple pathways, including the Wnt signaling pathway, the Notch signaling pathway, and the MAPK signaling pathway. Among them, the Wnt signaling pathway is one of the most important pathways. It is not only involved in bone development and metabolism but also in the differentiation and proliferation of chondrocytes, mesenchymal stem cells, osteoclasts, and osteoblasts. Dkk-1 and SOST are Wnt inhibitory proteins that can inhibit the activation of the canonical Wnt signaling pathway and block the proliferation and differentiation of osteoblasts. Therefore, they may serve as potential targets for the treatment of osteoporosis. In this review, we analyzed the mechanisms of Wnt proteins, β-catenin, and signaling molecules in the process of signal transduction and summarized the relationship between the Wnt signaling pathway and bone-related cells. We hope to attract attention to the role of the Wnt signaling pathway in osteoporosis and offer new perspectives and approaches to making a diagnosis and giving treatment for osteoporosis.

UNASSIGNED: To explore the role of sclerosteosis (SOST) gene expression in the occurrence and development of multiple myeloma (MM) complicated with sarcopenia.
UNASSIGNED: Analysis of the SOST expression in skeletal muscle tissue of patients with MM using high-throughput sequencing combined with transcriptomics; observation of morphological changes of the mouse C2C12 myoblasts co-cultured with SP2/0 myeloma cells in Transwell; observation of the SOST expression in the C2C12 myoblasts using the immunofluorescence labeling method; and assessment of the changes in exercise capacity of mice with MM using ethology; and the measurement of the SOST expression in muscles of mice using immunohistochemistry.
UNASSIGNED: The transcription level of the SOST gene in the muscle tissue was significantly higher in patients with MM and sarcopenia than in patients with MM without sarcopenia and elderly patients with sarcopenia; the area of C2C12 mouse myoblasts co-cultured with SP2/0 myeloma cells was 167,904 ± 8653.7 pix; this was significantly lower than the area of 402,994 ± 13,575.0 pix in the control group (CG); the fluorescence intensity of SOST in the cells of the experimental group (EG) was 159,389 ± 10,534 AU; this was significantly higher than the intensity of 26,338 ± 6059 AU in the CG; the differences in results of the coat-hanger test, the tail suspension test, the weight-bearing forced swimming test, and the grip strength test between the tumor-bearing mice in the EG and the CG were statistically significant; and the quantitative result of SOST expression in the muscle tissue of the EG mice was 11,515 ± 1573 pix; this was significantly higher than the result of 3399 ± 798.8 pix in the CG.
UNASSIGNED: The SOST gene expression was significantly higher in muscle of mice in EG than in CG; and increased SOST gene expression might be a pathogenesis of MM complicated with sarcopenia.

Breast cancer metastasis to the bone can be exacerbated by osteoporosis, is associated with poor long-term survival, and has limited therapeutic options. Sclerostin (SOST) is an endogenous inhibitor of bone formation, and an attractive target for treatment of osteoporosis. However, it is unclear whether SOST can be used as a therapeutic target for bone metastases of breast cancer, and whether small molecule compounds that target SOST in breast cancer cells can inhibit breast cancer bone metastasis.
SOST expression in 442 breast cancer tissues was characterized by immunohistochemistry and statistically analyzed for the association with breast cancer bone metastases. Bone metastatic breast cancer SCP2 cells were induced for SOST silencing or overexpression and their bone metastatic behaviors were tested in vitro and in vivo. To identify potential therapeutics, we screened inhibitors of the interaction of SOST with STAT3 from a small chemical molecule library and tested the inhibitory effects of one inhibitor on breast cancer growth and bone metastasis in vitro and in vivo.
We found that up-regulated SOST expression was associated with breast cancer bone metastases and worse survival of breast cancer patients. SOST silencing significantly reduced the bone metastatic capacity of SCP2 cells. SOST interacted with STAT3 to enhance the TGF-β/KRAS signaling, increasing both tumor growth and bone metastasis. Treatment with one lead candidate, S6, significantly inhibited the growth of breast-cancer organoids and bone metastasis in mice.
Our findings highlight a new class of potential therapeutics for treatment of bone metastasis in breast cancer.

Sclerostin is the protein product of the SOST gene and is known for its inhibitory effects on bone formation. The monoclonal antibody against sclerostin has been approved as a novel treatment method for osteoporosis. Oral health is one of the essential aspects of general human health. Hereditary bone dysplasia syndrome caused by sclerostin deficiency is often accompanied by some dental malformations, inspiring the therapeutic exploration of sclerostin in the oral and dental fields. Recent studies have found that sclerostin is expressed in several functional cell types in oral tissues, and the expression level of sclerostin is altered in pathological conditions. Sclerostin not only exerts similar negative outcomes on the formation of alveolar bone and bone-like tissues, including dentin and cementum, but also participates in the development of oral inflammatory diseases such as periodontitis, pulpitis, and peri-implantitis. This review aims to highlight related research progress of sclerostin in oral cavity, propose necessary further research in this field, and discuss its potential as a therapeutic target for dental indications and regenerative dentistry.

In the current study, we synthesized nanocellulose (NCF)-collagen (Col)-nano hydroxyapatite (NHA) organic-inorganic hybrid aerogels loaded with stromal cell derived factor-1 (SDF-1) and sclerostin monoclonal antibody (SOST McAb) and investigated their ability to repair steroid-induced osteonecrosis. Rabbit bone marrow mesenchymal stem cells (BMSCs) and human vascular endothelial cells (HUVECs) were used for the in vitro study. A rabbit steroid-induced osteonecrosis model was used for the in vivo study. The best elastic modulus reached 12.95 ± 4.77 MPa with a mean compressive property of 0.4067 ± 0.084 MPa for the scaffold containing 100% mass fraction. The average pore diameter of the aerogel was 75 ± 18 µm with a porosity of more than 90% (96.4 ± 1.6%). The aerogel-loaded SDF-1 and SOST were released at 40-50% from the material within the initial 3 h and maintained a stable release for more than 21 days. The in vitro study showed osteogenesis and vascularization capabilities of the scaffold. The in vivo study showed that rabbits received implantation of the scaffold with SOST McAb and SDF-1 showed the best osteogenesis of the osteonecrosis zone in the femoral head. Imaging examination revealed that most of the necrotic area of the femoral head was repaired. These results suggest that this hybrid aerogel scaffold could be used for future steroid-induced osteonecrosis repair.

Retinoblastoma (RB) is the most common intraocular malignancy in children. It has been previously reported that p38 MAPK is related to the pathogenesis of RB. Here we aim at investigating how p38 MAPK affected RB progression through mediating USP22/SIRT1/SOST axis. In this study, Thirty-two cases of RB and normal retinal tissues were collected. The expression of p38 MAPK, phosphorylation of p38 MAPK (P-p38 MAPK), USP22, SIRT1 and SOST in clinical tissues and cells was measured using RT-qPCR, IHC assay or western blot analysis. Cell proliferation was detected by CCK-8. Apoptosis rate of cells was examined by flow cytometry. Cell migration was evaluated using scratch test. Cell invasion ability was examined by Transwell assay. Co-immunoprecipitation (CO-IP) was utilized to measure the deubiquitination of USP22 on SIRT1. In vivo, mice were respectively injected with plasmids and the tumor growth as well as the tumor weight were detected. Results showed that p38 MAPK, P-p38 MAPK and SOST were poorly expressed in RB tissues and cells whereas USP22 and SIRT1 were overly expressed. P-p38 MAPK inhibited the expression of USP22, and overexpression of USP22 eliminated the inhibitory roles of P-p38 MAPK on tumor growth, as well as cell proliferation, migration and invasion. USP22 stabilized and promoted the expression of SIRT1 through its deubiquitination function. Silencing the expression of SIRT1 contributed to boosted expression of SOST, thus suppressing the growth of tumor cells. Collectively, the phosphorylation of p38 MAPK regulates the SIRT1/SOST axis to protect against RB via silencing USP22. The findings present some cues for a further approach to RB.

Ankylosis spondylitis (AS) is a disease mainly characterized by sacroiliac joint and spinal attachment point inflammation. Long non-coding RNA (lncRNA) plays a key role in the progression of many diseases. However, few studies have been conducted on the function of lncRNA maternally expressed gene 3 (MEG3) in AS. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to measure the relative levels of MEG3, microRNA let-7i, sclerostin (SOST), and inflammatory cytokines. Dual-luciferase reporter assay, RNA immunoprecipitation (RIP) assay and biotin-labeled RNA pull-down assay were used to confirm the interaction between MEG3 and let-7i or let-7i and SOST. In addition, western blot (WB) analysis was performed to detect the protein levels of osteogenesis markers and SOST. The expression levels of MEG3 and SOST were decreased and let-7i was increased in AS patients. MEG3 could interact with let-7i in AS fibroblasts, and let-7i overexpression reversed the suppressive effect of MEG3 upregulation on the inflammation and bone formation of AS. Additionally, let-7i could target SOST, and SOST silencing reversed the inhibitory effect of let-7i inhibitor or MEG3 overexpression on the inflammation and bone formation of AS. Furthermore, SOST expression was positively regulated by MEG3, while was negatively regulated by let-7i. Our results revealed that lncRNA MEG3 promoted SOST expression to restrain the progression of AS by sponging let-7i, which provided a treatment target for AS.

Previously we have demonstrated that sclerostin inhibits stress-induced odontogenic differentiation of odontoblasts and accelerates senescence of dental pulp cells (DPCs) Odontoblasts and DPCs are main functioning cells for inflammation resistance and tissue regeneration in dentine-pulp complex. Sclerostin is relevant for systemic inflammation and chronic periodontitis processes, but its effects on dental pulp inflammation remains unclear. In this study, we found that sclerostin expression of odontoblasts was elevated in lipopolysaccharide-induced inflammatory environment, and exogenous sclerostin increased the production of pro-inflammatory cytokines in inflamed odontoblasts. Furthermore, sclerostin activated the NF-κB signaling pathway in inflamed odontoblasts and the NF-κB inhibitor reversed the exaggerative effects of sclerostin on the pro-inflammatory cytokines production. Additionally, sclerostin promoted adhesion and migration of inflamed DPCs, while inhibiting odontoblastic differentiation of inflamed DPCs. Sclerostin also might enhance pulpal angiogenesis. Taken together, it can therefore be inferred that sclerostin is upregulated in inflamed odontoblasts under pulpal inflammatory condition to enhance inflammatory responses in dentine-pulp complex and impair reparative dentinogenesis. This indicates that sclerostin inhibition might be a therapeutic target for anti-inflammation and pro-regeneration during dental pulp inflammation.