Osteoclast-derived apoptotic bodies couple bone resorption and formation in bone remodeling

Bone remodeling is precisely coordinated by bone resorption and formation.Apoptotic osteoclasts generate large amounts of apoptotic bodies(ABs)marking the end of the bone resorption phase,whereas the functions of osteoclast-derived ABs remain largely unknown.Here,we identified the molecular profile of ABs derived from osteoclasts at distinct differentiation stages and investigated their corresponding functions.ABs were isolated from apoptotic bone marrow macrophages,preosteoclasts,and mature osteoclasts induced by staurosporine.Proteomic signature analysis with liquid chromatography-tandem mass spectrometry suggested marked protein cargo differences among the different ABs.Further bioinformatic analysis showed that the proteomic signatures of the ABs were highly similar to those of their parental cells.Functionally,pOC-ABs induced endothelial progenitor cell differentiation and increased CD31hiEmcnhi endothelial cell formation in a murine bone defect model via their PDGF-BB cargo.mOC-ABs induced osteogenic differentiation of mesenchymal stem cells and facilitated osteogenesis via RANKL reverse signaling.In summary,we mapped the detailed proteomic landscapes of ABs derived from osteoclasts and showed that their potential biological roles are important in coupling bone formation with resorption during bone remodeling.

The role of lipid metabolism in osteoporosis:Clinical implication and cellular mechanism

In recent years,researchers have become focused on the relationship between lipids and bone metabolism balance.Moreover,many diseases related to lipid metabolism dis-orders,such as nonalcoholic fatty liver disease,atherosclerosis,obesity,and menopause,are associated with osteoporotic phenotypes.It has been clinically observed in humans that these lipid metabolism disorders promote changes in osteoporosis-related indicators bone mineral density and bone mass.Furthermore,similar osteoporotic phenotype changes were observed in high-fat and high-cholesterol-induced animal models.Abnormal lipid metabolism(such as increased oxidized lipids and elevated plasma cholesterol)affects bone microenvironment ho-meostasis via cross-organ communication,promoting differentiation of mesenchymal stem cells to adipocytes,and inhibiting commitment towards osteoblasts.Moreover,disturbances in lipid metabolism affect the bone metabolism balance by promoting the secretion of cyto-kines such as receptor activator of nuclear factor-kappa B ligand by osteoblasts and stimulating the differentiation of osteoclasts.Conclusively,this review addresses the possible link be-tween lipid metabolism disorders and osteoporosis and elucidates the potential modulatory mechanisms and signaling pathways by which lipid metabolism affects bone metabolism bal-ance.We also summarize the possible approaches and prospects of intervening lipid meta-bolismforosteoporosistreatment.

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.

The role of dendritic cells derived osteoclasts in bone destruction diseases

The bone is previously considered as a dominant organ involved in the processes of locomotion.However,in the past two decades,a large number of studies have suggested that the skeletal system closely coordinated with the immune system so as to result in the emerging area of'osteoimmunology'.In the evolution of many kinds of bone destruction-related dis-eases,osteoclasts could differentiate from dendritic cells,which contributed to increased expression of osteoclast-related membrane receptors and relatively higher activity of bone destruction,inducing sewere bone destruction under inflammatory conditions.Numerous fac-tors could influence the interaction between osteoclasts and dendritic cells,contributing to the pathogenesis of several bone diseases in the context of inflammation,including both im-munocytes and a large number of cytokines.In addition,the products of osteoclasts released from bone destruction area serve as important signals for the differentiation and activation of immature dendritic cells.Therefore,the border between the dendritic cell-rela ted immune response and osteoclast-related bone destruction has gradually unravelled.Dendritic cells and osteoclasts cooperate with each other to mediate bone destruction and bone remodelling under inflammatory conditions.In this review,we will pay attention to the interactions be-tween dendritic cells and osteoclasts in physiological and pathological conditions to further understand the skeletal system and identifty potential new therapeutic targets for the future by summarizing their significant roles and molecular mechanisms in bone destruction.

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.

Mn-containing bioceramics inhibit osteoclastogenesis and promote osteoporotic bone regeneration via scavenging ROS

Osteoporosis is caused by an osteoclast activation mechanism.People suffering from osteoporosis are prone to bone defects.Increasing evidence indicates that scavenging reactive oxygen species(ROS)can inhibit receptor activator of nuclear factorκB ligand(RANKL)-induced osteoclastogenesis and suppress ovariectomy-induced osteoporosis.It is critical to develop biomaterials with antioxidant properties to modulate osteoclast activity for treating osteoporotic bone defects.Previous studies have shown that manganese(Mn)can improve bone regeneration,and Mn supplementation may treat osteoporosis.However,the effect of Mn on osteoclasts and the role of Mn in osteoporotic bone defects remain unclear.In present research,a model bioceramic,Mn-containedβ-tricalcium phosphate(Mn-TCP)was prepared by introducing Mn intoβ-TCP.The introduction of Mn intoβ-TCP significantly improved the scavenging of oxygen radicals and nitrogen radicals,demonstrating that Mn-TCP bioceramics might have antioxidant properties.The in vitro and in vivo findings revealed that Mn^(2+)ions released from Mn-TCP bioceramics could distinctly inhibit the formation and function of osteoclasts,promote the differentiation of osteoblasts,and accelerate bone regeneration under osteoporotic conditions in vivo.Mechanistically,Mn-TCP bioceramics inhibited osteoclastogenesis and promoted the regeneration of osteoporotic bone defects by scavenging ROS via Nrf2 activation.These results suggest that Mn-containing bioceramics with osteoconductivity,ROS scavenging and bone resorption inhibition abilities may be an ideal biomaterial for the treatment of osteoporotic bone defect.

Bone-targeted pH-responsive cerium nanoparticles for anabolic therapy in osteoporosis

Antiresorptive drugs are widely used for treatment of osteoporosis and cancer bone metastasis,which function mainly through an overall inhibition of osteoclast.However,not all osteoclasts are“bone eaters”;preosteoclasts(pOCs)play anabolic roles in bone formation and angiogenesis through coupling with osteoblasts and secreting platelet derived growth factor-BB(PDGF-BB).In this study,a bone-targeted pH-responsive nanomaterial was designed for selectively eliminating mature osteoclasts(mOCs)without affecting pOCs.Biocompatible cerium nano-system(CNS)was guided to the acidic extracellular microenvironment created by mOCs and gained oxidative enzymatic activity.Oxidative CNS decreased the viability of mOCs through accumulating intracellular reactive oxygen species and enhancing calcium oscillation.Non-acid secreting anabolic pOCs were thus preserved and kept producing PDGF-BB,which lead to mesenchymal stem cell osteogenesis and endothelial progenitor cell angiogenesis via PI3K-Akt activated focal adhesion kinase.In treating osteoporotic ovariectomized mice,CNS showed better protective effects compare with the current first line antiresorptive drug due to the better anabolic effects marked by higher level of bone formation and vascularization.We provided a novel anabolic therapeutic strategy in treating bone disorders with excessive bone resorption.

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.

Antagonizing exosomal miR-18a-5p derived from prostate cancer cells ameliorates metastasis-induced osteoblastic lesions by targeting Hist1h2bc and activating Wnt/β-catenin pathway

More than 50%of prostate cancer(PCa)patients have bone metastasis with osteo-blastic lesions.MiR-18a-5p is associated with the development and metastasis of PCa,but it remains unclear whether it is involved in osteoblastic lesions.We first found that miR-18a-5p was highly expressed in the bone microenvironment of patients with PCa bone metastases.To address how miR-18a-5p affects PCa osteoblastic lesions,antagonizing miR-18a-5p in PCa cells or pre-osteoblasts inhibited osteoblast differentiation in vitro.Moreover,injection of PCa cells with miR-18a-5p inhibition improved bone biomechanical properties and bone mineral mass in vivo.Furthermore,miR-18a-5p was transferred to osteoblasts by exosomes derived from PCa cells and targeted the Hist1h2bc gene,resulting in Ctnnb1 up-regulation in the Wnt/β-catenin signaling pathway.Translationally,antagomir-18a-5p significantly improved bone biomechanical properties and alleviated sclerotic lesions from osteoblastic me-tastases in BALB/c nude mice.These data suggest that inhibition of exosome-delivered miR-18a-5p ameliorates PCa-induced osteoblastic lesions.

Multi-functional osteoclasts in matrix-based tissue engineering bone

The repair of bone defects,especially for the large segment of bone defects,has always been an urgent problem in orthopedic clinic and attracted researchers'attention.Nowadays,the application of tissue engineering bone in the repair of bone defects has become the research hotspot.With the rapid development of tissue engineering,the novel and functional scaffold materials for bone repair have emerged.In this review,we have summarized the multi-functional roles of osteoclasts in bone remodeling.The development of matrix-based tissue engineering bone has laid a theoretical foundation for further investigation about the novel bone regeneration materials which could perform high bioactivity.From the point of view on preserving pre-osteoclasts and targeting mature osteoclasts,this review introduced the novel matrix-based tissue engineering bone based on osteoclasts in the field of bone tissue engineering,which provides a potential direction for the development of novel scaffold materials for the treatment of bone defects.

Mechanotransduction in subchondral bone microenvironment and targeted interventions for osteoarthritis

Osteoarthritis(OA)is a progressive degenerative joint sickness related with mechanics,obesity,ageing,etc.,mainly characterized by cartilage degeneration,subchondral bone damage and synovium inflammation.Coordinated mechanical absorption and conduction of the joint play significant roles in the prevalence and development of OA.Subchondral bone is generally considered a load-burdening tissue where mechanosensitive cells are resident,including osteocytes,osteoblast lineage cells,and osteoclast lineage cells(especially less concerned in mechanical studies).Mechano-signaling imbalances affect complicated cellular events and disorders of subchondral bone homeostasis.This paper will focus on the significance of mechanical force as the pathogenesis,involvement of various mechanical force patterns in mechanosensitive cells,and mechanobiology research of loading devices in vitro and in vivo,which are further discussed.Additionally,various mechanosensing structures(e.g.,transient receptor potential channels,gap junctions,primary cilia,podosome-associated complexes,extracellular vesicles)and mechanotransduction signaling pathways(e.g.,Ca^(2+) signaling,Wnt/β-catenin,RhoA GTPase,focal adhesion kinase,cotranscriptional activators YAP/TAZ)in mechanosensitive bone cells.Finally,we highlight potential targets for improving mechanoprotection in the treatment of OA.These advances furnish an integration of mechanical regulation of subchondral bone homeostasis,as well as OA therapeutic approaches by modulating mechanical homeostasis.