Chondrogenesis mediates progression of ankylosing spondylitis through heterotopic ossification

Ankylosing spondylitis(AS)is chronic inflammatory arthritis with a progressive fusion of axial joints.Anti-inflammatory treatments such as anti-TNF-αantibody therapy suppress inflammation but do not effectively halt the progression of spine fusion in AS patients.Here we report that the autoimmune inflammation of AS generates a microenvironment that promotes chondrogenesis in spine ligaments as the process of spine fusion.Chondrocyte differentiation was observed in the ligaments of patients with earlystage AS,and cartilage formation was followed by calcification.Moreover,a large number of giant osteoclasts were found in the inflammatory environment of ligaments and on bony surfaces of calcified cartilage.Resorption activity by these giant osteoclasts generated marrow with high levels of active TGF-β,which induced new bone formation in the ligaments.Notably,no Osterix+osteoprogenitors were found in osteoclast resorption areas,indicating uncoupled bone resorption and formation.Even at the late and maturation stages,the uncoupled osteoclast resorption in bony interspinous ligament activates TGF-βto induce the progression of ossification in AS patients.Osteoclast resorption of calcified cartilage-initiated ossification in the progression of AS is a similar pathologic process of acquired heterotopic ossification(HO).Our finding of cartilage formation in the ligaments of AS patients revealed that the pathogenesis of spinal fusion is a process of HO and explained why anti-inflammatory treatments do not slow ankylosing once there is new bone formation in spinal soft tissues.Thus,inhibition of HO formation,such as osteoclast activity,cartilage formation,or TGF-βactivity could be a potential therapy for AS.

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.

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.

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.

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.

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.