Ma et al recently reported in the World Journal of Diabetes that ferroptosis occurs in osteoblasts under high glucose conditions,reflecting diabetes pathology.This condition could be protected by the upregulation of t...Ma et al recently reported in the World Journal of Diabetes that ferroptosis occurs in osteoblasts under high glucose conditions,reflecting diabetes pathology.This condition could be protected by the upregulation of the gene encoding polycytosine RNA-binding protein 1(PCBP1).Additionally,Ma et al used a lentivirus infection system to express PCBP1.As the authors’method of administration can be improved in terms of stability and cost,we propose delivering PCBP1 to treat type 2 diabetic osteoporosis by encapsulating it in protein nanoparticles.First,PCBP1 is small and druggable.Second,intravenous injection can help deliver PCBP1 across the mucosa while avoiding acid and enzyme-catalyzed degradation.Furthermore,incorporating PCBP1 into nanoparticles prevents its interaction with water or oxygen and protects PCBP1’s structure and activity.Notably,the safety of the protein materials and the industrialization techniques for large-scale production of protein nanoparticles must be comprehensively investigated before clinical application.展开更多
Osteoporosis represents a prevalent and debilitating comorbidity in patients diagnosed with type 2 diabetes mellitus(T2DM),which is characterized by suppressed osteoblast function and disrupted bone microarchitecture....Osteoporosis represents a prevalent and debilitating comorbidity in patients diagnosed with type 2 diabetes mellitus(T2DM),which is characterized by suppressed osteoblast function and disrupted bone microarchitecture.In this study,we utilized male C57BL/6 J mice to investigate the role of SIRT3 in T2DM.Decreased SIRT3 expression and impaired mitochondrial quality control mechanism are observed in both in vitro and in vivo models of T2DM.Mechanistically,SIRT3 suppression results in hyperacetylation of FOXO3,hindering the activation of the PINK1/PRKN mediated mitophagy pathway and resulting in accumulation of dysfunctional mitochondria.Genetical overexpression or pharmacological activation of SIRT3 restores deacetylation status of FOXO3,thus facilitating mitophagy and ameliorating osteogenic impairment in T2DM.Collectively,our findings highlight the fundamental regulatory function of SIRT3 in mitochondrial quality control,crucial for maintaining bone homeostasis in T2DM.These insights not only enhance our understanding of the molecular mechanisms underlying diabetic osteoporosis but also identify SIRT3 as a promising therapeutic target for diabetic osteoporosis.展开更多
The delicate balance between bone formation by osteoblasts and bone resorption by osteoclasts maintains bone homeostasis.Nuclear receptors(NRs)are now understood to be crucial in bone physiology and pathology.However,...The delicate balance between bone formation by osteoblasts and bone resorption by osteoclasts maintains bone homeostasis.Nuclear receptors(NRs)are now understood to be crucial in bone physiology and pathology.However,the function of the Farnesoid X receptor(FXR),a member of the NR family,in regulating bone homeostasis remains incompletely understood.In this study,in vitro and in vivo models revealed delayed bone development and an osteoporosis phenotype in mice lacking FXR in bone marrow mesenchymal stem cells(BMSCs)and osteoblasts due to impaired osteoblast differentiation.Mechanistically,FXR could stabilize RUNX2 by inhibiting Thoc6-mediated ubiquitination,thereby promoting osteogenic activity in BMSCs.Moreover,activated FXR could directly bind to the Thoc6 promoter,suppressing its expression.The interaction between RUNX2 and Thoc6 was mediated by the Runt domain of RUNX2 and the WD repeat of Thoc6.Additionally,Obeticholic acid(OCA),an orally available FXR agonist,could ameliorate bone loss in an ovariectomy(OVX)-induced osteoporotic mouse model.Taken together,our findings suggest that FXR plays pivotal roles in osteoblast differentiation by regulating RUNX2 stability and that targeting FXR may be a promising therapeutic approach for osteoporosis.展开更多
The death of osteoblasts induced by glucocorticoid(GC)-mediated oxidative stress plays a crucial role in the development of steroid-induced osteonecrosis of the femoral head(SIONFH).Improving bone formation driven by ...The death of osteoblasts induced by glucocorticoid(GC)-mediated oxidative stress plays a crucial role in the development of steroid-induced osteonecrosis of the femoral head(SIONFH).Improving bone formation driven by osteoblasts has shown promising outcomes in the prognosis of SIONFH.Isovitexin has demonstrated antioxidant properties,but its therapeutic effects on GC-induced oxidative stress and SIONFH remain unexplored.In this study,we analyzed clinical samples obtained from SIONFH patients using proteomic and bioinformatic approaches.展开更多
This study investigated the regulatory potential of salidroside(SAL),a primary active compound in Rhodiola rosea L.,on osteoclast differentiation by modulating the hypoxia-inducible factor 1-alpha(HIF-1α)pathway in o...This study investigated the regulatory potential of salidroside(SAL),a primary active compound in Rhodiola rosea L.,on osteoclast differentiation by modulating the hypoxia-inducible factor 1-alpha(HIF-1α)pathway in osteoblasts.Luciferase reporter assay and chromatin immunoprecipitation(Ch IP)assay were employed to validate whether the receptor activator of nuclear factor-κB ligand(RANKL)is the downstream target gene of HIF-1αin osteoblasts.The study also utilized lipopolysaccharide(LPS)-induced mouse osteolysis to examine the impact of SAL on osteolysis in vivo.Furthermore,conditioned medium(CM)from SAL-pretreated osteoblasts was used to investigate the paracrine effects on osteoclastogenesis through the HIF-1αpathway.Hypoxic condition-induced overexpression of HIF-1αupregulated RANKL levels by binding to the RANKL promoter and enhancing transcription in osteoblastic cells.In vivo,SAL significantly alleviated bone tissue hypoxia and decreased the expression of HIF-1αby downregulating the expression of RANKL,vascular endothelial growth factor(VEGF),interleukin 6(IL-6),and angiopoietin-like 4(ANGPTL4).In the paracrine experiment,conditioned media from SAL-pretreated osteoblasts inhibited differentiation through the HIF-1α/RANKL,VEGF,IL-6,and ANGPTL4 pathways.RANKL emerges as the downstream target gene regulated by HIF-1αin osteoblasts.SAL significantly alleviates bone tissue hypoxia and bone loss in LPS-induced osteolysis through the HIF-1α/RANKL,VEGF,IL-6,and ANGPTL4 pathways.SAL inhibits osteoclast differentiation by regulating osteoblast paracrine secretion.展开更多
Neural EGFL-like 2(NELL2)is a secreted protein known for its regulatory functions in the nervous and reproductive systems,yet its role in bone biology remains unexplored.In this study,we observed that NELL2 was dimini...Neural EGFL-like 2(NELL2)is a secreted protein known for its regulatory functions in the nervous and reproductive systems,yet its role in bone biology remains unexplored.In this study,we observed that NELL2 was diminished in the bone of aged and ovariectomized(OVX)mice,as well as in the serum of osteopenia and osteoporosis patients.In vitro loss-of-function and gain-offunction studies revealed that NELL2 facilitated osteoblast differentiation and impeded adipocyte differentiation from stromal progenitor cells.In vivo studies further demonstrated that the deletion of NELL2 in preosteoblasts resulted in decreased cancellous bone mass in mice.Mechanistically,NELL2 interacted with the FNI-type domain located at the C-terminus of Fibronectin 1(Fn1).Moreover,we found that NELL2 activated the focal adhesion kinase(FAK)/AKT signaling pathway through Fn1/integrinβ1(ITGB1),leading to the promotion of osteogenesis and the inhibition of adipogenesis.Notably,administration of NELL2-AAV was found to ameliorate bone loss in OVX mice.These findings underscore the significant role of NELL2 in osteoblast differentiation and bone homeostasis,suggesting its potential as a therapeutic target for managing osteoporosis.展开更多
Chinese dwarf cherry(Cerasus humilis)is a fruit unique to China,which is considered to have osteoprotective effects.However,no systematic experimental characterization was available.In this study,the osteoprotective a...Chinese dwarf cherry(Cerasus humilis)is a fruit unique to China,which is considered to have osteoprotective effects.However,no systematic experimental characterization was available.In this study,the osteoprotective activity and mechanism of Chinese dwarf cherry polyphenol extract(OPE)was studied.In vitro,OPE stimulated the alkaline phosphatase activity in the early differentiation stage,increased the osteocalcin level in the middle differentiation stage,and induced the formation of more bonemineralized nodules in the late osteogenic stage.In vivo,OPE improved cancellous bone structure and maximum load of the femur in ovariectomized(OVX)rats.The balance between bone formation and resorption was regulated.Oxidative stress levels in the peripheral blood,liver and femur were reduced.OPE alleviated the disturbance in energy metabolism,muscle development,and muscle regulation-related signaling pathways caused by OVX and activated the calcium/adenosine monophosphate-activated protein kinase signaling pathway.Therefore,OPE is a potential dietary supplement for the prevention and treatment of osteoporosis.展开更多
Diabetic osteoporosis(DOP)is a common complication in diabetes,driven by hyperglycemia-induced metabolic disturbances,chronic inflammation,and oxi-dative stress.This review describes the critical role of iron metaboli...Diabetic osteoporosis(DOP)is a common complication in diabetes,driven by hyperglycemia-induced metabolic disturbances,chronic inflammation,and oxi-dative stress.This review describes the critical role of iron metabolism dysregu-lation in DOP pathogenesis,focusing on ferroptosis,a novel iron-dependent cell death pathway characterized by lipid peroxidation and reactive oxygen species(ROS)overproduction.Diabetic conditions exacerbate iron overload,impairing osteoblast function and enhancing osteoclast activity,while triggering ferroptosis in bone cells.Ferroptosis not only accelerates osteoblast apoptosis but also amplifies osteoclast-mediated bone resorption,synergistically promoting bone loss.Furthermore,chronic inflammation and oxidative stress disrupt the balance between bone formation and resorption,with elevated pro-inflammatory cyto-kines(e.g.,tumor necrosis factor-α,interleukin-6)and ROS exacerbating cellular dysfunction.Therapeutic strategies targeting iron metabolism(e.g.,deferoxamine)and ferroptosis inhibition(e.g.,nuclear factor erythroid 2-related factor 2/heme oxygenase-1 pathway activation,antioxidants like melatonin)demonstrate potential to mitigate DOP progression.Future research should prioritize personalized interventions,clinical trials of iron chelators and antioxidants,and mechanistic studies to refine therapeutic approaches.This review provides a comprehensive framework for understanding DOP pathogenesis and highlights innovative strategies to improve bone health in diabetic patients.展开更多
Hypertrophic chondrocytes(HCs)could transform into osteoblastic lineage cells while the pathophysiological implications of HC transformation remain largely unknown.Here,we generated a mouse line utilizing Col10a1-Cre ...Hypertrophic chondrocytes(HCs)could transform into osteoblastic lineage cells while the pathophysiological implications of HC transformation remain largely unknown.Here,we generated a mouse line utilizing Col10a1-Cre to induce DTA expression to genetically ablate HCs and their descendants.Col10a1-Cre;R26^(DTA/+)mice displayed dwarf phenotype,abnormal spongy bone,and significantly delayed drill-hole injuries healing,suggesting an indispensable role of HC lineage extension in bone growth and injury repair.Intriguingly,single-cell RNA sequencing analysis revealed the most significant loss of a cell cluster expressing multiple angiogenic factors(Pro-Angiogenic Descendants of HCs,PADs)among cells derived from Col10a1-Cre;R26^(DTA/+)and control femurs.In silico analysis of cell-cell communication supported Thrombospondin 4(THBS4)as a specific angiogenic factor mediating the crosstalk between PADs and vascular endothelial cells.Concordantly,analyses using immunostaining combined with tissue clearing revealed that PADs physically contacted with endothelial cells,whereas Col10a1-Cre;R26^(DTA/+)mice showed defective metaphyseal and cortical vessel formation and post-injury angiogenesis along with a significant loss of THBS4.Moreover,in vitro assays showed that supplying THBS4 was sufficient to promote proliferation and tube formation of endothelial cells and rescue defective angiogenesis of Col10a1-Cre;R26D TA/+metatarsal explants.Collectively,these findings demonstrate a critical role of PADs in bone growth and injury repair by secreting THBS4 to regulate angiogenesis.展开更多
Membrane-initiated estrogen receptorα(mERα)signaling has been shown to affect bone mass in murine models.However,it remains unknown which cell types mediate the mERα-dependent effects on bone.In this study,we gener...Membrane-initiated estrogen receptorα(mERα)signaling has been shown to affect bone mass in murine models.However,it remains unknown which cell types mediate the mERα-dependent effects on bone.In this study,we generated a novel mouse model with a conditional C451A mutation in Esr1,which enables selective knockout of the palmitoylation site essential for the membrane localization of ERα(C451A^(f/f)).First,we used Runx2-Cre mice to generate Runx2-C451A^(f/f)mice with conditional inactivation of mERαsignaling in Runx2-expressing osteoblast lineage cells.No significant changes were observed in body weight,weights of estrogen-responsive organs,or serum concentrations of estradiol between female Runx2-C451A^(f/f)and homozygous C451A^(f/f)littermate controls.High-resolution microcomputed tomography analysis showed a consistent decrease in cortical bone mass in the tibia,femur,and vertebra L5 of Runx2-C451A^(f/f)mice and three-point bending analysis of humerus revealed an impaired mechanical bone strength in Runx2-C451A^(f/f)female mice compared to controls.Additionally,primary osteoblast cultures from mice lacking mERαsignaling showed impaired differentiation compared to controls.展开更多
<正>骨膜蛋白(periostin),又称为成骨细胞特异性因子-2(osteoblast specific factor-2,OSF-2),属于转化生长因子-β(transforming growth factor-β,TGF-β)诱导的蛋白超家族,主要促进整合素依赖的细胞黏附和运动~[1,2]。骨膜蛋...<正>骨膜蛋白(periostin),又称为成骨细胞特异性因子-2(osteoblast specific factor-2,OSF-2),属于转化生长因子-β(transforming growth factor-β,TGF-β)诱导的蛋白超家族,主要促进整合素依赖的细胞黏附和运动~[1,2]。骨膜蛋白可以在全身多种组织中表达,如牙周韧带、心脏瓣膜、肺、胃肠道、肾上腺、甲状腺、前列腺、乳腺等~[1];同时。展开更多
Some of the most common human cancers, including breast cancer, prostate cancer, and lung cancer, metastasize with avidity to bone. What is the basis for their preferential growth within the bone microenvironment? Bid...Some of the most common human cancers, including breast cancer, prostate cancer, and lung cancer, metastasize with avidity to bone. What is the basis for their preferential growth within the bone microenvironment? Bidirectional interactions between tumor cells and cells that make up bone result in a selective advantage for tumor growth and can lead to bone destruction or new bone matrix deposition. This review discusses our current understanding of the molecu- lar components and mechanisms that are responsible for those interactions.展开更多
Osteoporosis,a global age-related health problem in both male and female elderly,insidiously deteriorates the microstructure of bone,particularly at trabecular sites,such as vertebrae,ribs and hips,culminating in frag...Osteoporosis,a global age-related health problem in both male and female elderly,insidiously deteriorates the microstructure of bone,particularly at trabecular sites,such as vertebrae,ribs and hips,culminating in fragility fractures,pain and disability.Although osteoporosis is normally associated with senescence and estrogen deficiency,diabetes mellitus(DM),especially type 1 DM,also contributes to and/or aggravates bone loss in osteoporotic patients.This topic highlight article focuses on DM-induced osteoporosis and DM/ osteoporosis comorbidity,covering alterations in bone metabolism as well as factors regulating bone growth under diabetic conditions including,insulin,insulin-like growth factor-1 and angiogenesis.Cellular and molecular mechanisms of DM-related bone loss are also discussed.This information provides a foundation for the better understanding of diabetic complications and for development of early screening and prevention of osteoporosis in diabetic patients.展开更多
The skeleton is a dynamic organ that is constantly remodeled. Proteins secreted from bone cells, namely osteoblasts, osteocytes,and osteoclasts exert regulation on osteoblastogenesis, osteclastogenesis, and angiogenes...The skeleton is a dynamic organ that is constantly remodeled. Proteins secreted from bone cells, namely osteoblasts, osteocytes,and osteoclasts exert regulation on osteoblastogenesis, osteclastogenesis, and angiogenesis in a paracrine manner. Osteoblasts secrete a range of different molecules including RANKL/OPG, M-CSF, SEMA3A, WNT5A, and WNT16 that regulate osteoclastogenesis. Osteoblasts also produce VEGFA that stimulates osteoblastogenesis and angiogenesis. Osteocytes produce sclerostin（SOST） that inhibits osteoblast differentiation and promotes osteoclast differentiation. Osteoclasts secrete factors including BMP6, CTHRC1, EFNB2, S1P, WNT10B, SEMA4D, and CT-1 that act on osteoblasts and osteocytes, and thereby influencea A osteogenesis. Osteoclast precursors produce the angiogenic factor PDGF-BB to promote the formation of Type H vessels, which then stimulate osteoblastogenesis. Besides, the evidences over the past decades show that at least three hormones or ＂osteokines＂from bone cells have endocrine functions. FGF23 is produced by osteoblasts and osteocytes and can regulate phosphate metabolism. Osteocalcin（OCN） secreted by osteoblasts regulates systemic glucose and energy metabolism, reproduction, and cognition. Lipocalin-2（LCN2） is secreted by osteoblasts and can influence energy metabolism by suppressing appetite in the brain.We review the recent progresses in the paracrine and endocrine functions of the secretory proteins of osteoblasts, osteocytes, and osteoclasts, revealing connections of the skeleton with other tissues and providing added insights into the pathogenesis of degenerative diseases affecting multiple organs and the drug discovery process.展开更多
The present study aimed at investigating the effects of Puerarin(PR), a major isoflavonoid isolated from the Chinese medicinal herb Puerariae radix, on bone metabolism and the underlying mechanism of action. The in vi...The present study aimed at investigating the effects of Puerarin(PR), a major isoflavonoid isolated from the Chinese medicinal herb Puerariae radix, on bone metabolism and the underlying mechanism of action. The in vivo assay, female mice were ovariectomized(OVX), and the OVX mice were fed with a diet containing low, middle, and high doses of PR(2, 4, and 8 mg·d^(-1), respectively) or 17β-estradiol(E_2, 0.03 μg·d^(-1)) for 4 weeks. In OVX mice, the uterine weight declined, and intake of PR at any dose did not affect uterine weight, compared with the control. The total femoral bone mineral density(BMD) was significantly reduced by OVX, which was reversed by intake of the diet with PR at any dose, especially at the low dose. In the in vitro assay, RAW264.7 cells were used for studying the direct effect of PR on the formation of osteoclasts. PR reduced the formation of tartrate resistant acid phosphatase(TRAP)-positive multi-nucleated cells in the RAW 264.7 cells induced by receptor activator for nuclear factor-κB Ligand(RANKL). MC3T3-E1 cells were used for studying the effects of PR on the expression of osteoprotegerin(OPG) and RANKL m RNA expression in osteoblasts. The expression of OPG m RNA and RANKL m RNA was detected by RT-PCR on Days of 5, 7, 10, and 12 after PR exposure. PR time-dependently enhanced the expression of OPG m RNA and reduced the expression of RANKL m RNA in MC3T3-E1 cells. In conclusion, our results suggest that PR can effectively prevent bone loss in OVX mice without any hyperplastic effect on the uterus, and the antiosteoporosis activity of PR may be related to its effects on the formation of osteoclasts and the expression of RANKL OPG in osteoblasts.展开更多
AIM: Osteoblasts are key functional cells in the process of bone metabolic balance. Phytoestrogens have an important influence on the proliferation and differentiation of osteoblasts. Puerarin, a plant estrogen, has a...AIM: Osteoblasts are key functional cells in the process of bone metabolic balance. Phytoestrogens have an important influence on the proliferation and differentiation of osteoblasts. Puerarin, a plant estrogen, has a wide range concentration in vitro on the function of osteoblasts. The current study investigates the effect of the phytoestrogen puerarin on the proliferation, differentiation, and mineralization of osteoblasts in vitro. METHODS: The calvaria bone of eight-ten Wistar rats which were born within 24 h were obtained in aseptic condition. After enzyme digestion, isolation, purified osteoblasts of rats were cultured for further study. The cells of the first to third generation were divided into a control group and a puerarin-treated group with 10-3–10-10 mol·L-1 puerarin. The cells were exposed to the medium containing a low level of carbohydrates, 10%(V/V) FBS for 24 h. After 1 to 4 days of culture, the OD values on the proliferation of osteoblasts in each group were determined by microplate reader. The cells were cultured in the medium containing 50 μg·mL-1 vitamin C, 10-2 mol·L-1 sodium glycerophosphate, 10% FBS and the medium was changed every 3 to 4 days. After 2 to 8 days of culture, expression of alkaline phosphatase were tested and compared by microplate reader. The mineral nodes of osteoblasts were dyed using alizarin red or improved Von Kossa way after four weeks. RESULTS: Compared with those in the 10-5–10-9 mol·L-1 puerarin, the proliferation of osteoblasts, the expression of alkaline phosphatase, and the number of mineral nodes of osteoblasts were significantly decreased in the control group. The increase was the fastest in the third day, while on the fourth day it was decreased, and arrived at statistical significance compared with the alkaline phosphatase activities and control group. The 10-6 mol·L-1 group was the most distinct, and formed the most mineralized nodule. Compared with the 10-3 mol·L-1 puerarin group, those changes were markedly increased in the control group. CONCLUSIONS: Puerarin has proliferation, differentiation, and mineralization effects on osteoblasts in a dose-dependent manner, and has a double-way effect on the osteoblasts in vitro. A low-dose showed positive effects on the development of osteoblasts, and high-dose puerarin could inhibit the formation of bone.展开更多
Wnts are a large family of growth factors that mediate essential biological processes like embryogenesis, morpho- genesis and organogenesis. These proteins also play a role in oncogenesis, and they regulate apoptosis ...Wnts are a large family of growth factors that mediate essential biological processes like embryogenesis, morpho- genesis and organogenesis. These proteins also play a role in oncogenesis, and they regulate apoptosis in many tissues. Wnts bind to a membrane receptor complex comprised of a frizzled （FZD） G-protein-coupled receptor and a low-density lipoprotein （LDL） receptor-related protein （LRP）. The formation of this ligand-receptor complex initiates a number of signaling cascades that include the canonical/beta-catenin pathway as well as several noncanonical pathways. In recent years, canonical Wnt signaling has been reported to play a significant role in the control of bone formation. Clinical studies have found that mutations in LRP-5 are associated with reduced bone mineral density （BMD） and fractures. Investigations of knockout and transgenic mouse models of Wnt pathway components have shown that canonical Wnt signaling modulates most aspects ofosteoblast physiology including proliferation, differentiation, function and apoptosis. Transgenic mice expressing a gain of function mutant of LRP-5 in bone, or mice lacking the Wnt antagonist secreted frizzled-related protein-l, exhibit elevated BMD and suppressed osteoblast apoptosis. In addition, preclinical studies with pharmacologic compounds such as those that inhibit glycogen synthase kinase-3β support the importance of the canonical Wnt pathway in modulation of bone formation and osteoblast apoptosis.展开更多
INTRODUCTIONThe transforming growth factor-β （TGF-β） superfamily com- prises TGF-βs, Activin, bone morphogenetic proteins （BMPs） and other related proteins. TGF-β superfamily members act through a heteromeric ...INTRODUCTIONThe transforming growth factor-β （TGF-β） superfamily com- prises TGF-βs, Activin, bone morphogenetic proteins （BMPs） and other related proteins. TGF-β superfamily members act through a heteromeric receptor complex,, comprised of type I and type II receptors at the cell surface that transduce intracellular signals via Smad complex or mitogen-activated protein kinase （MAPK） cascade.展开更多
The importance of the vascular supply for bone is well-known to orthopaedists but is still rather overlooked within the wider field of skeletal research. Blood supplies oxygen, nutrients and regulatory factors to tiss...The importance of the vascular supply for bone is well-known to orthopaedists but is still rather overlooked within the wider field of skeletal research. Blood supplies oxygen, nutrients and regulatory factors to tissues, as well as removing metabolic waste products such as carbon dioxide and acid. Bone receives up to about 10% of cardiac output, and this blood supply permits a much higher degree of cellularity, remodelling and repair than is possible in cartilage, which is avascular. The blood supply to bone is delivered to the endosteal cavity by nutrient arteries, then flows through marrow sinusoids before exiting via numerous small vessels that ramify through the cortex. The marrow cavity affords a range of vascular niches that are thought to regulate the growth and differentiation of hematopoietic and stromal cells, in part via gradients of oxygen tension. The quality of vascular supply to bone tends to decline with age and may be compromised in common pathological settings, including diabetes, anaemias, chronic airway diseases and immobility, as well as by tumours. Reductions in vascular supply are associated with bone loss. This may be due in part to the direct effects of hypoxia, which blocks osteoblast function and bone formation but causes reciprocal increases in osteoclastogenesis and bone resorption. Common regulatory factors such as parathyroid hormone or nitrates, both of which are potent vasodilators, might exert their osteogenic effects on bone via the vasculature. These observations suggest that the bone vasculature will be a fruitful area for future research.展开更多
文摘Ma et al recently reported in the World Journal of Diabetes that ferroptosis occurs in osteoblasts under high glucose conditions,reflecting diabetes pathology.This condition could be protected by the upregulation of the gene encoding polycytosine RNA-binding protein 1(PCBP1).Additionally,Ma et al used a lentivirus infection system to express PCBP1.As the authors’method of administration can be improved in terms of stability and cost,we propose delivering PCBP1 to treat type 2 diabetic osteoporosis by encapsulating it in protein nanoparticles.First,PCBP1 is small and druggable.Second,intravenous injection can help deliver PCBP1 across the mucosa while avoiding acid and enzyme-catalyzed degradation.Furthermore,incorporating PCBP1 into nanoparticles prevents its interaction with water or oxygen and protects PCBP1’s structure and activity.Notably,the safety of the protein materials and the industrialization techniques for large-scale production of protein nanoparticles must be comprehensively investigated before clinical application.
基金supported by the National Key Research and Development Project (2021YFA1201404)National Natural Science Foundation of China Major Project (81991514)+6 种基金General Project (82272530, 82372459)Jiangsu Province Medical Innovation Center of Orthopedic Surgery (CXZX202214)Jiangsu Provincial Key Medical Center FoundationJiangsu Provincial Medical Outstanding Talent FoundationJiangsu Provincial Medical Youth Talent FoundationJiangsu Provincial Key Medical Talent Foundationthe Fundamental Research Funds for the Central Universities (14380493, 14380494)
文摘Osteoporosis represents a prevalent and debilitating comorbidity in patients diagnosed with type 2 diabetes mellitus(T2DM),which is characterized by suppressed osteoblast function and disrupted bone microarchitecture.In this study,we utilized male C57BL/6 J mice to investigate the role of SIRT3 in T2DM.Decreased SIRT3 expression and impaired mitochondrial quality control mechanism are observed in both in vitro and in vivo models of T2DM.Mechanistically,SIRT3 suppression results in hyperacetylation of FOXO3,hindering the activation of the PINK1/PRKN mediated mitophagy pathway and resulting in accumulation of dysfunctional mitochondria.Genetical overexpression or pharmacological activation of SIRT3 restores deacetylation status of FOXO3,thus facilitating mitophagy and ameliorating osteogenic impairment in T2DM.Collectively,our findings highlight the fundamental regulatory function of SIRT3 in mitochondrial quality control,crucial for maintaining bone homeostasis in T2DM.These insights not only enhance our understanding of the molecular mechanisms underlying diabetic osteoporosis but also identify SIRT3 as a promising therapeutic target for diabetic osteoporosis.
基金supported by National Natural Science Foundation of China(grant numbers 82072523 to Zhiyong Hou)Postdoctoral program of Clinical medicine of Hebei Medical University(grant numbers PD2023012 to Sujuan Xu)+2 种基金Excellent postdoctoral research funding project of Hebei Province(grant numbers B2023005011 to Sujuan Xu)The 16th special grant of China Postdoctoral Science Foundation(grant numbers 2023T160182 to Sujuan Xu)Natural Science Foundation of Hebei Province,China(grant numbers H2023206230 to Yingchao Yin,H2024206186 to Sujuan Xu).
文摘The delicate balance between bone formation by osteoblasts and bone resorption by osteoclasts maintains bone homeostasis.Nuclear receptors(NRs)are now understood to be crucial in bone physiology and pathology.However,the function of the Farnesoid X receptor(FXR),a member of the NR family,in regulating bone homeostasis remains incompletely understood.In this study,in vitro and in vivo models revealed delayed bone development and an osteoporosis phenotype in mice lacking FXR in bone marrow mesenchymal stem cells(BMSCs)and osteoblasts due to impaired osteoblast differentiation.Mechanistically,FXR could stabilize RUNX2 by inhibiting Thoc6-mediated ubiquitination,thereby promoting osteogenic activity in BMSCs.Moreover,activated FXR could directly bind to the Thoc6 promoter,suppressing its expression.The interaction between RUNX2 and Thoc6 was mediated by the Runt domain of RUNX2 and the WD repeat of Thoc6.Additionally,Obeticholic acid(OCA),an orally available FXR agonist,could ameliorate bone loss in an ovariectomy(OVX)-induced osteoporotic mouse model.Taken together,our findings suggest that FXR plays pivotal roles in osteoblast differentiation by regulating RUNX2 stability and that targeting FXR may be a promising therapeutic approach for osteoporosis.
基金supported by the National Natural Science Foundation of China(Grant Nos:82374475 and 82104883,China).
文摘The death of osteoblasts induced by glucocorticoid(GC)-mediated oxidative stress plays a crucial role in the development of steroid-induced osteonecrosis of the femoral head(SIONFH).Improving bone formation driven by osteoblasts has shown promising outcomes in the prognosis of SIONFH.Isovitexin has demonstrated antioxidant properties,but its therapeutic effects on GC-induced oxidative stress and SIONFH remain unexplored.In this study,we analyzed clinical samples obtained from SIONFH patients using proteomic and bioinformatic approaches.
基金supported by grants from the National Natural Science Foundation of China(Nos.81572852 and 82104671)the Great Program of the Science Foundation of Tianjin(No.18JCZDJC33200)+1 种基金Heilongjiang Province Fund(No.LH2020H102)Tianjin Key Medical Discipline(Specialty)Construction Project(No.TJYXZDXK-032A)。
文摘This study investigated the regulatory potential of salidroside(SAL),a primary active compound in Rhodiola rosea L.,on osteoclast differentiation by modulating the hypoxia-inducible factor 1-alpha(HIF-1α)pathway in osteoblasts.Luciferase reporter assay and chromatin immunoprecipitation(Ch IP)assay were employed to validate whether the receptor activator of nuclear factor-κB ligand(RANKL)is the downstream target gene of HIF-1αin osteoblasts.The study also utilized lipopolysaccharide(LPS)-induced mouse osteolysis to examine the impact of SAL on osteolysis in vivo.Furthermore,conditioned medium(CM)from SAL-pretreated osteoblasts was used to investigate the paracrine effects on osteoclastogenesis through the HIF-1αpathway.Hypoxic condition-induced overexpression of HIF-1αupregulated RANKL levels by binding to the RANKL promoter and enhancing transcription in osteoblastic cells.In vivo,SAL significantly alleviated bone tissue hypoxia and decreased the expression of HIF-1αby downregulating the expression of RANKL,vascular endothelial growth factor(VEGF),interleukin 6(IL-6),and angiopoietin-like 4(ANGPTL4).In the paracrine experiment,conditioned media from SAL-pretreated osteoblasts inhibited differentiation through the HIF-1α/RANKL,VEGF,IL-6,and ANGPTL4 pathways.RANKL emerges as the downstream target gene regulated by HIF-1αin osteoblasts.SAL significantly alleviates bone tissue hypoxia and bone loss in LPS-induced osteolysis through the HIF-1α/RANKL,VEGF,IL-6,and ANGPTL4 pathways.SAL inhibits osteoclast differentiation by regulating osteoblast paracrine secretion.
基金supported by grants from National Natural Science Foundation of China(82272444,81972031,81972033)China Postdoctoral Science Foundation(2022M722382)Tianjin Key Medical Discipline(Specialty)Construction Project(TJYXZDXK-032A)。
文摘Neural EGFL-like 2(NELL2)is a secreted protein known for its regulatory functions in the nervous and reproductive systems,yet its role in bone biology remains unexplored.In this study,we observed that NELL2 was diminished in the bone of aged and ovariectomized(OVX)mice,as well as in the serum of osteopenia and osteoporosis patients.In vitro loss-of-function and gain-offunction studies revealed that NELL2 facilitated osteoblast differentiation and impeded adipocyte differentiation from stromal progenitor cells.In vivo studies further demonstrated that the deletion of NELL2 in preosteoblasts resulted in decreased cancellous bone mass in mice.Mechanistically,NELL2 interacted with the FNI-type domain located at the C-terminus of Fibronectin 1(Fn1).Moreover,we found that NELL2 activated the focal adhesion kinase(FAK)/AKT signaling pathway through Fn1/integrinβ1(ITGB1),leading to the promotion of osteogenesis and the inhibition of adipogenesis.Notably,administration of NELL2-AAV was found to ameliorate bone loss in OVX mice.These findings underscore the significant role of NELL2 in osteoblast differentiation and bone homeostasis,suggesting its potential as a therapeutic target for managing osteoporosis.
基金supported by the National Natural Science Foundation of China(32470399)Beijing Natural Science Foundation(5212014)Key Research and Development Program in the Ningxia Hui Autonomous Region,China(2020BBF02027).
文摘Chinese dwarf cherry(Cerasus humilis)is a fruit unique to China,which is considered to have osteoprotective effects.However,no systematic experimental characterization was available.In this study,the osteoprotective activity and mechanism of Chinese dwarf cherry polyphenol extract(OPE)was studied.In vitro,OPE stimulated the alkaline phosphatase activity in the early differentiation stage,increased the osteocalcin level in the middle differentiation stage,and induced the formation of more bonemineralized nodules in the late osteogenic stage.In vivo,OPE improved cancellous bone structure and maximum load of the femur in ovariectomized(OVX)rats.The balance between bone formation and resorption was regulated.Oxidative stress levels in the peripheral blood,liver and femur were reduced.OPE alleviated the disturbance in energy metabolism,muscle development,and muscle regulation-related signaling pathways caused by OVX and activated the calcium/adenosine monophosphate-activated protein kinase signaling pathway.Therefore,OPE is a potential dietary supplement for the prevention and treatment of osteoporosis.
基金Supported by Henan Province Key Research and Development Program,No.231111311000Henan Provincial Science and Technology Research Project,No.232102310411+2 种基金Henan Province Medical Science and Technology Key Project,No.LHGJ20220566 and No.LHGJ20240365Henan Province Medical Education Research Project,No.WJLX2023079Zhengzhou Medical and Health Technology Innovation Guidance Program,No.2024YLZDJH022.
文摘Diabetic osteoporosis(DOP)is a common complication in diabetes,driven by hyperglycemia-induced metabolic disturbances,chronic inflammation,and oxi-dative stress.This review describes the critical role of iron metabolism dysregu-lation in DOP pathogenesis,focusing on ferroptosis,a novel iron-dependent cell death pathway characterized by lipid peroxidation and reactive oxygen species(ROS)overproduction.Diabetic conditions exacerbate iron overload,impairing osteoblast function and enhancing osteoclast activity,while triggering ferroptosis in bone cells.Ferroptosis not only accelerates osteoblast apoptosis but also amplifies osteoclast-mediated bone resorption,synergistically promoting bone loss.Furthermore,chronic inflammation and oxidative stress disrupt the balance between bone formation and resorption,with elevated pro-inflammatory cyto-kines(e.g.,tumor necrosis factor-α,interleukin-6)and ROS exacerbating cellular dysfunction.Therapeutic strategies targeting iron metabolism(e.g.,deferoxamine)and ferroptosis inhibition(e.g.,nuclear factor erythroid 2-related factor 2/heme oxygenase-1 pathway activation,antioxidants like melatonin)demonstrate potential to mitigate DOP progression.Future research should prioritize personalized interventions,clinical trials of iron chelators and antioxidants,and mechanistic studies to refine therapeutic approaches.This review provides a comprehensive framework for understanding DOP pathogenesis and highlights innovative strategies to improve bone health in diabetic patients.
基金financial support from the National Natural Science Foundation of China(grants 82394442,82422043,82272442)the Key Industrial Chain Program of Shaanxi,China(No.2022ZDLSF02-12)。
文摘Hypertrophic chondrocytes(HCs)could transform into osteoblastic lineage cells while the pathophysiological implications of HC transformation remain largely unknown.Here,we generated a mouse line utilizing Col10a1-Cre to induce DTA expression to genetically ablate HCs and their descendants.Col10a1-Cre;R26^(DTA/+)mice displayed dwarf phenotype,abnormal spongy bone,and significantly delayed drill-hole injuries healing,suggesting an indispensable role of HC lineage extension in bone growth and injury repair.Intriguingly,single-cell RNA sequencing analysis revealed the most significant loss of a cell cluster expressing multiple angiogenic factors(Pro-Angiogenic Descendants of HCs,PADs)among cells derived from Col10a1-Cre;R26^(DTA/+)and control femurs.In silico analysis of cell-cell communication supported Thrombospondin 4(THBS4)as a specific angiogenic factor mediating the crosstalk between PADs and vascular endothelial cells.Concordantly,analyses using immunostaining combined with tissue clearing revealed that PADs physically contacted with endothelial cells,whereas Col10a1-Cre;R26^(DTA/+)mice showed defective metaphyseal and cortical vessel formation and post-injury angiogenesis along with a significant loss of THBS4.Moreover,in vitro assays showed that supplying THBS4 was sufficient to promote proliferation and tube formation of endothelial cells and rescue defective angiogenesis of Col10a1-Cre;R26D TA/+metatarsal explants.Collectively,these findings demonstrate a critical role of PADs in bone growth and injury repair by secreting THBS4 to regulate angiogenesis.
基金supported by the Swedish Research Council(2017-01286,2020-01840)the Swedish state under the agreement between the Swedish government and the county councils(ALF-agreement)(ALFGBG721581)+2 种基金the Gustaf V 80-years fund(FAI-2018-0466)the IngaBritt and Arne Lundberg Foundation(LU2017-0076)the Novo Nordisk Foundation(26844).
文摘Membrane-initiated estrogen receptorα(mERα)signaling has been shown to affect bone mass in murine models.However,it remains unknown which cell types mediate the mERα-dependent effects on bone.In this study,we generated a novel mouse model with a conditional C451A mutation in Esr1,which enables selective knockout of the palmitoylation site essential for the membrane localization of ERα(C451A^(f/f)).First,we used Runx2-Cre mice to generate Runx2-C451A^(f/f)mice with conditional inactivation of mERαsignaling in Runx2-expressing osteoblast lineage cells.No significant changes were observed in body weight,weights of estrogen-responsive organs,or serum concentrations of estradiol between female Runx2-C451A^(f/f)and homozygous C451A^(f/f)littermate controls.High-resolution microcomputed tomography analysis showed a consistent decrease in cortical bone mass in the tibia,femur,and vertebra L5 of Runx2-C451A^(f/f)mice and three-point bending analysis of humerus revealed an impaired mechanical bone strength in Runx2-C451A^(f/f)female mice compared to controls.Additionally,primary osteoblast cultures from mice lacking mERαsignaling showed impaired differentiation compared to controls.
文摘<正>骨膜蛋白(periostin),又称为成骨细胞特异性因子-2(osteoblast specific factor-2,OSF-2),属于转化生长因子-β(transforming growth factor-β,TGF-β)诱导的蛋白超家族,主要促进整合素依赖的细胞黏附和运动~[1,2]。骨膜蛋白可以在全身多种组织中表达,如牙周韧带、心脏瓣膜、肺、胃肠道、肾上腺、甲状腺、前列腺、乳腺等~[1];同时。
文摘Some of the most common human cancers, including breast cancer, prostate cancer, and lung cancer, metastasize with avidity to bone. What is the basis for their preferential growth within the bone microenvironment? Bidirectional interactions between tumor cells and cells that make up bone result in a selective advantage for tumor growth and can lead to bone destruction or new bone matrix deposition. This review discusses our current understanding of the molecu- lar components and mechanisms that are responsible for those interactions.
文摘Osteoporosis,a global age-related health problem in both male and female elderly,insidiously deteriorates the microstructure of bone,particularly at trabecular sites,such as vertebrae,ribs and hips,culminating in fragility fractures,pain and disability.Although osteoporosis is normally associated with senescence and estrogen deficiency,diabetes mellitus(DM),especially type 1 DM,also contributes to and/or aggravates bone loss in osteoporotic patients.This topic highlight article focuses on DM-induced osteoporosis and DM/ osteoporosis comorbidity,covering alterations in bone metabolism as well as factors regulating bone growth under diabetic conditions including,insulin,insulin-like growth factor-1 and angiogenesis.Cellular and molecular mechanisms of DM-related bone loss are also discussed.This information provides a foundation for the better understanding of diabetic complications and for development of early screening and prevention of osteoporosis in diabetic patients.
基金supported in part by grants from 973 Program from the Chinese Ministry of Science and Technology (MOST) (2014CB964704 and 2015CB964503)the Strategic Priority Research Program of the Chinese Academy of Sciences (Grant No. XDB19000000)the National Natural Science Foundation of China (NSFC) (31371463, 81672119, and 81725010)
文摘The skeleton is a dynamic organ that is constantly remodeled. Proteins secreted from bone cells, namely osteoblasts, osteocytes,and osteoclasts exert regulation on osteoblastogenesis, osteclastogenesis, and angiogenesis in a paracrine manner. Osteoblasts secrete a range of different molecules including RANKL/OPG, M-CSF, SEMA3A, WNT5A, and WNT16 that regulate osteoclastogenesis. Osteoblasts also produce VEGFA that stimulates osteoblastogenesis and angiogenesis. Osteocytes produce sclerostin（SOST） that inhibits osteoblast differentiation and promotes osteoclast differentiation. Osteoclasts secrete factors including BMP6, CTHRC1, EFNB2, S1P, WNT10B, SEMA4D, and CT-1 that act on osteoblasts and osteocytes, and thereby influencea A osteogenesis. Osteoclast precursors produce the angiogenic factor PDGF-BB to promote the formation of Type H vessels, which then stimulate osteoblastogenesis. Besides, the evidences over the past decades show that at least three hormones or ＂osteokines＂from bone cells have endocrine functions. FGF23 is produced by osteoblasts and osteocytes and can regulate phosphate metabolism. Osteocalcin（OCN） secreted by osteoblasts regulates systemic glucose and energy metabolism, reproduction, and cognition. Lipocalin-2（LCN2） is secreted by osteoblasts and can influence energy metabolism by suppressing appetite in the brain.We review the recent progresses in the paracrine and endocrine functions of the secretory proteins of osteoblasts, osteocytes, and osteoclasts, revealing connections of the skeleton with other tissues and providing added insights into the pathogenesis of degenerative diseases affecting multiple organs and the drug discovery process.
基金supported by a grant from the National Natural Science Foundation of China(No.30873290)
文摘The present study aimed at investigating the effects of Puerarin(PR), a major isoflavonoid isolated from the Chinese medicinal herb Puerariae radix, on bone metabolism and the underlying mechanism of action. The in vivo assay, female mice were ovariectomized(OVX), and the OVX mice were fed with a diet containing low, middle, and high doses of PR(2, 4, and 8 mg·d^(-1), respectively) or 17β-estradiol(E_2, 0.03 μg·d^(-1)) for 4 weeks. In OVX mice, the uterine weight declined, and intake of PR at any dose did not affect uterine weight, compared with the control. The total femoral bone mineral density(BMD) was significantly reduced by OVX, which was reversed by intake of the diet with PR at any dose, especially at the low dose. In the in vitro assay, RAW264.7 cells were used for studying the direct effect of PR on the formation of osteoclasts. PR reduced the formation of tartrate resistant acid phosphatase(TRAP)-positive multi-nucleated cells in the RAW 264.7 cells induced by receptor activator for nuclear factor-κB Ligand(RANKL). MC3T3-E1 cells were used for studying the effects of PR on the expression of osteoprotegerin(OPG) and RANKL m RNA expression in osteoblasts. The expression of OPG m RNA and RANKL m RNA was detected by RT-PCR on Days of 5, 7, 10, and 12 after PR exposure. PR time-dependently enhanced the expression of OPG m RNA and reduced the expression of RANKL m RNA in MC3T3-E1 cells. In conclusion, our results suggest that PR can effectively prevent bone loss in OVX mice without any hyperplastic effect on the uterus, and the antiosteoporosis activity of PR may be related to its effects on the formation of osteoclasts and the expression of RANKL OPG in osteoblasts.
基金supported by the Program for New Century Excellent Talents in University(No.NCET-13-0954)the Changjiang Scholars and Innovative Research Team in University(No.IRT1174),the National Natural Science Foundation of China(Nos.J1210063,81001622,81073029)+3 种基金the project"As a Major New Drug to Create a Major National Science and Technology Special"(Nos.2011ZX09401-308-034,2014ZX09304-307-02)the China Postdoctoral Science Foundation(No.2012M521831),the Key Program for the International S&T Cooperation Projects of Shaanxi Province(No.2013KW31-01)the Natural Science Foundation of Shaanxi Provincial Education Department(No.2013JK0811)the Administration of Traditional Chinese Medicine of Shaanxi(No.13-ZY006)
文摘AIM: Osteoblasts are key functional cells in the process of bone metabolic balance. Phytoestrogens have an important influence on the proliferation and differentiation of osteoblasts. Puerarin, a plant estrogen, has a wide range concentration in vitro on the function of osteoblasts. The current study investigates the effect of the phytoestrogen puerarin on the proliferation, differentiation, and mineralization of osteoblasts in vitro. METHODS: The calvaria bone of eight-ten Wistar rats which were born within 24 h were obtained in aseptic condition. After enzyme digestion, isolation, purified osteoblasts of rats were cultured for further study. The cells of the first to third generation were divided into a control group and a puerarin-treated group with 10-3–10-10 mol·L-1 puerarin. The cells were exposed to the medium containing a low level of carbohydrates, 10%(V/V) FBS for 24 h. After 1 to 4 days of culture, the OD values on the proliferation of osteoblasts in each group were determined by microplate reader. The cells were cultured in the medium containing 50 μg·mL-1 vitamin C, 10-2 mol·L-1 sodium glycerophosphate, 10% FBS and the medium was changed every 3 to 4 days. After 2 to 8 days of culture, expression of alkaline phosphatase were tested and compared by microplate reader. The mineral nodes of osteoblasts were dyed using alizarin red or improved Von Kossa way after four weeks. RESULTS: Compared with those in the 10-5–10-9 mol·L-1 puerarin, the proliferation of osteoblasts, the expression of alkaline phosphatase, and the number of mineral nodes of osteoblasts were significantly decreased in the control group. The increase was the fastest in the third day, while on the fourth day it was decreased, and arrived at statistical significance compared with the alkaline phosphatase activities and control group. The 10-6 mol·L-1 group was the most distinct, and formed the most mineralized nodule. Compared with the 10-3 mol·L-1 puerarin group, those changes were markedly increased in the control group. CONCLUSIONS: Puerarin has proliferation, differentiation, and mineralization effects on osteoblasts in a dose-dependent manner, and has a double-way effect on the osteoblasts in vitro. A low-dose showed positive effects on the development of osteoblasts, and high-dose puerarin could inhibit the formation of bone.
文摘Wnts are a large family of growth factors that mediate essential biological processes like embryogenesis, morpho- genesis and organogenesis. These proteins also play a role in oncogenesis, and they regulate apoptosis in many tissues. Wnts bind to a membrane receptor complex comprised of a frizzled （FZD） G-protein-coupled receptor and a low-density lipoprotein （LDL） receptor-related protein （LRP）. The formation of this ligand-receptor complex initiates a number of signaling cascades that include the canonical/beta-catenin pathway as well as several noncanonical pathways. In recent years, canonical Wnt signaling has been reported to play a significant role in the control of bone formation. Clinical studies have found that mutations in LRP-5 are associated with reduced bone mineral density （BMD） and fractures. Investigations of knockout and transgenic mouse models of Wnt pathway components have shown that canonical Wnt signaling modulates most aspects ofosteoblast physiology including proliferation, differentiation, function and apoptosis. Transgenic mice expressing a gain of function mutant of LRP-5 in bone, or mice lacking the Wnt antagonist secreted frizzled-related protein-l, exhibit elevated BMD and suppressed osteoblast apoptosis. In addition, preclinical studies with pharmacologic compounds such as those that inhibit glycogen synthase kinase-3β support the importance of the canonical Wnt pathway in modulation of bone formation and osteoblast apoptosis.
基金supported by grants by NIH grant AR-044741(Y-PL) and R01DE023813 (Y-PL)
文摘INTRODUCTIONThe transforming growth factor-β （TGF-β） superfamily com- prises TGF-βs, Activin, bone morphogenetic proteins （BMPs） and other related proteins. TGF-β superfamily members act through a heteromeric receptor complex,, comprised of type I and type II receptors at the cell surface that transduce intracellular signals via Smad complex or mitogen-activated protein kinase （MAPK） cascade.
文摘The importance of the vascular supply for bone is well-known to orthopaedists but is still rather overlooked within the wider field of skeletal research. Blood supplies oxygen, nutrients and regulatory factors to tissues, as well as removing metabolic waste products such as carbon dioxide and acid. Bone receives up to about 10% of cardiac output, and this blood supply permits a much higher degree of cellularity, remodelling and repair than is possible in cartilage, which is avascular. The blood supply to bone is delivered to the endosteal cavity by nutrient arteries, then flows through marrow sinusoids before exiting via numerous small vessels that ramify through the cortex. The marrow cavity affords a range of vascular niches that are thought to regulate the growth and differentiation of hematopoietic and stromal cells, in part via gradients of oxygen tension. The quality of vascular supply to bone tends to decline with age and may be compromised in common pathological settings, including diabetes, anaemias, chronic airway diseases and immobility, as well as by tumours. Reductions in vascular supply are associated with bone loss. This may be due in part to the direct effects of hypoxia, which blocks osteoblast function and bone formation but causes reciprocal increases in osteoclastogenesis and bone resorption. Common regulatory factors such as parathyroid hormone or nitrates, both of which are potent vasodilators, might exert their osteogenic effects on bone via the vasculature. These observations suggest that the bone vasculature will be a fruitful area for future research.
