Modulation of SIRT6 activity acts as an emerging therapeutic implication for pathological disorders in the skeletal system

The skeletal system is a dynamically balanced system, which undergoes continuous bone resorption and formation to maintain bone matrix homeostasis. As an important ADP-ribosylase and NAD+-dependent deacylase, SIRT6 (SIR2-like protein 6) is widely expressed on various kinds of bone cells, such as chondrocytes, osteoblasts, osteoclasts. The aberration of SIRT6 impairs gene expression (e.g., NF-κB and Wnt target genes) and cellular functions (e.g., DNA repair, glucose and lipid metabolism, telomeric maintenance), which disturbs the dynamic balance and ultimately leads to several bone-related diseases. In this review, we summarize the critical roles of SIRT6 in the onset and progression of bone-related diseases including osteoporosis, osteoarthritis, rheumatoid arthritis, and intervertebral disc degeneration, as well as the relevant signaling pathways. In addition, we discuss the advances in the development of SIRT6 activators and elucidate their pharmacological profiles, which may provide novel treatment strategies for these skeletal diseases.

Phosphorylation inhibition of protein-tyrosine phosphatase 1B tyrosine-152 induces bone regeneration coupled with angiogenesis for bone tissue engineering

A close relationship has been reported to exist between cadherin-mediated cell-cell adhesion and integrin-mediated cell mobility,and protein tyrosine phosphatase 1B(PTP1B)may be involved in maintaining this homeostasis.The stable residence of mesenchymal stem cells(MSCs)and endothelial cells(ECs)in their niches is closely related to the regulation of PTP1B.However,the exact role of the departure of MSCs and ECs from their niches during bone regeneration is largely unknown.Here,we show that the phosphorylation state of PTP1B tyrosine-152(Y152)plays a central role in initiating the departure of these cells from their niches and their subsequent recruitment to bone defects.Based on our previous design of a PTP1B Y152 region-mimicking peptide(152RM)that significantly inhibits the phosphorylation of PTP1B Y152,further investigations revealed that 152RM enhanced cell migration partly via integrinαvβ3 and promoted MSCs osteogenic differentiation partly by inhibiting ATF3.Moreover,152RM induced type H vessels formation by activating Notch signaling.Demineralized bone matrix(DBM)scaffolds were fabricated with mesoporous silica nanoparticles(MSNs),and 152RM was then loaded onto them by electrostatic adsorption.The DBM-MSN/152RM scaffolds were demonstrated to induce bone formation and type H vessels expansion in vivo.In conclusion,our data reveal that 152RM contributes to bone formation by coupling osteogenesis with angiogenesis,which may offer a potential therapeutic strategy for bone defects.

Long non-coding RNA HCAR promotes endochondral bone repair by upregulating VEGF and MMP13 in hypertrophic chondrocyte through sponging miR-15b-5p

Endochondral bone formation is an important route for bone repair.Although emerging evidence has revealed the functions of long non-coding RNAs(lncRNAs)in bone and cartilage development,the effect of lncRNAs in endochondral bone repair is still largely unknown.Here,we identified a lncRNA,named Hypertrophic Chondrocyte Angiogenesis-related lncRNA(HCAR),and proved it to promote the endochondral bone repair by upregulating the expression of matrix metallopeptidase 13(Mmp13)and vascular endothelial growth factorα(Vegfa)in hypertrophic chondrocytes.Lnc-HCAR knockdown in hypertrophic chondrocytes restrained the cartilage matrix remodeling and decrease the CD31hiEmcnhi vessels number in a bone repair model.Mechanistically,we proved that lnc-HCAR was mainly enriched in the cytoplasm using fluorescence in situ hybridization(FISH)assay,and it acted as a molecular sponge for miR-15b-5p.Further,in hypertrophic chondrocytes,lnc-HCAR competitively bound to miR-15b-5p to increase Vegfa and Mmp13 expression.Our results proved that lncRNA is deeply involved in endochondral bone repair,which will provide a new theoretical basis for future strategies for promoting fracture healing.