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| 1 | Simultaneous incorporation of PTH(1-34) and nano-hydroxyapatite into Chitosan/Alginate Hydrogels for efficient bone regeneration显示文摘Tissue regeneration based on the utilization of artificial soft materials is considered a promising treatment for bone-related diseases.Here,we report cranial bone regeneration promoted by hydrogels that contain parathyroid hormone(PTH)peptide PTH(1-34)and nano-hydroxyapatite(nHAP).A combination of the positively charged natural polymer chitosan(CS)and negatively charged sodium alginate led to the formation of hydrogels with porous structures,as shown by scanning electron microscopy.Rheological characterizations revealed that the mechanical properties of the hydrogels were almost maintained upon the addition of nHAP and PTH(1-34).In vitro experiments showed that the hydrogel containing nHAP and PTH(1-34)exhibited strong biocompatibility and facilitated osteogenic differentiation of rat bone marrow mesenchymal stem cells(rBMSCs)via the Notch signaling pathway,as shown by the upregulated expression of osteogenic-related proteins.We found that increasing the content of PTH(1-34)in the hydrogels resulted in enhanced osteogenic differentiation of BMSCs.Implantation of the complex hydrogel into a rat cranial defect model led to efficient bone regeneration compared to the rats treated with the hydrogel alone or with nHAP,indicating the simultaneous therapeutic effect of nHAP and PTH during the treatment process.Both the in vitro and in vivo results demonstrated that simultaneously incorporating nHAP and PTH into hydrogels shows promise for bone regeneration,suggesting a new strategy for tissue engineering and regeneration in the future. | Zhiyuan Zou Le Wang Zhifei Zhou Qing Sun Delong Liu Yan Chen Hao Hu Yu Cai Sixiong Lin Zhengran Yu Bizhi Tan Wei Guo Zemin Ling Xuenong Zou | 2021 | Bioactive Materials2021，6，6： | 7 |
| 2 | LIM domain proteins Pinch1/2 regulate chondrogenesis and bone mass in mice显示文摘The LIM domain-containing proteins Pinch1/2 regulate integrin activation and cell–extracellular matrix interaction and adhesion.Here,we report that deleting Pinch1 in limb mesenchymal stem cells(MSCs)and Pinch2 globally(double knockout;dKO)in mice causes severe chondrodysplasia,while single mutant mice do not display marked defects.Pinch deletion decreases chondrocyte proliferation,accelerates cell differentiation and disrupts column formation.Pinch loss drastically reduces Smad2/3 protein expression in proliferative zone(PZ)chondrocytes and increases Runx2 and Col10a1 expression in both PZ and hypertrophic zone(HZ)chondrocytes.Pinch loss increases sclerostin and Rankl expression in HZ chondrocytes,reduces bone formation,and increases bone resorption,leading to low bone mass.In vitro studies revealed that Pinch1 and Smad2/3 colocalize in the nuclei of chondrocytes.Through its C-terminal region,Pinch1 interacts with Smad2/3 proteins.Pinch loss increases Smad2/3 ubiquitination and degradation in primary bone marrow stromal cells(BMSCs).Pinch loss reduces TGF-β-induced Smad2/3 phosphorylation and nuclear localization in primary BMSCs.Interestingly,compared to those from single mutant mice,BMSCs from dKO mice express dramatically lower protein levels ofβ-catenin and Yap1/Taz and display reduced osteogenic but increased adipogenic differentiation capacity.Finally,ablating Pinch1 in chondrocytes and Pinch2 globally causes severe osteopenia with subtle limb shortening.Collectively,our findings demonstrate critical roles for Pinch1/2 and a functional redundancy of both factors in the control of chondrogenesis and bone mass through distinct mechanisms. | Yiming Lei Xuekun Fu Pengyu Li Sixiong Lin Qinnan Yan Yumei Lai Xin Liu Yishu Wang Xiaochun Bai Chuanju Liu Di Chen Xuenong Zou Xu Cao Huiling Cao Guozhi Xiao | 2020 | Bone Research2020，8，4： | 2 |
| 3 | Kindlin-2 regulates skeletal homeostasis by modulating PTH1R in mice显示文摘In vertebrates,the type 1 parathyroid hormone receptor(PTH1R)is a critical regulator of skeletal development and homeostasis;however,how it is modulated is incompletely understood.Here we report that deleting Kindlin-2 in osteoblastic cells using the mouse 10-kb Dmp1-Cre largely neutralizes the intermittent PTH-stimulated increasing of bone volume fraction and bone mineral density by impairing both osteoblast and osteoclast formation in murine adult bone.Single-cell profiling reveals that Kindlin-2 loss increases the proportion of osteoblasts,but not mesenchymal stem cells,chondrocytes and fibroblasts,in non-hematopoietic bone marrow cells,with concomitant depletion of osteoblasts on the bone surfaces,especially those stimulated by PTH.Furthermore,haploinsufficiency of Kindlin-2 and Pth1r genes,but not that of either gene,in mice significantly decreases basal and,to a larger extent,PTH-stimulated bone mass,supporting the notion that both factors function in the same genetic pathway.Mechanistically,Kindlin-2 interacts with the C-terminal cytoplasmic domain of PTH1R via aa 474–475 and Gsα.Kindlin-2 loss suppresses PTH induction of cAMP production and CREB phosphorylation in cultured osteoblasts and in bone.Interestingly,PTH promotes Kindlin-2 expression in vitro and in vivo,thus creating a positive feedback regulatory loop.Finally,estrogen deficiency induced by ovariectomy drastically decreases expression of Kindlin-2 protein in osteocytes embedded in the bone matrix and Kindlin-2 loss essentially abolishes the PTH anabolic activity in bone in ovariectomized mice.Thus,we demonstrate that Kindlin-2 functions as an intrinsic component of the PTH1R signaling pathway in osteoblastic cells to regulate bone mass accrual and homeostasis. | Xuekun Fu Bo Zhou Qinnan Yan Chu Tao Lei Qin Xiaohao Wu Sixiong Lin Sheng Chen Yumei Lai Xuenong Zou Zengwu Shao Meiqing Wang Di Chen Wenfei Jin Youqiang Song Huiling Cao Ge Zhang Guozhi Xiao | 2020 | Signal Transduction and Targeted Therapy2020，5，1： | 0 |
| 4 | Bone marrow adipoq+ cell population controls bone mass via sclerostin in mice显示文摘Dear editor,The comorbidity of obesity and osteoporosis illustrates the communication and coordination of adipose and bone tissues.Leptin and adiponectin derived from adipocytes regulate osteoblast formation and function to impact bone mass through direct and indirect mechanisms.1 It is known that bone marrow adipocytes(BMA)can control bone mass by modulating the bone morphogenetic protein(BMP)and other signaling pathways.BMAs can secret soluble factors,which impact osteoblasts,osteoclasts,and osteocytes.2 Sclerostin is a potent inhibitor of bone acquisition that antagonizes Wnt/β-catenin signaling. | Huanqing Gao Yiming Zhong Sixiong Lin Qinnan Yan Xuenong Zou Guozhi Xiao | 2023 | Signal Transduction and Targeted Therapy2023，8，8： | 0 |
| 5 | Kindlin-2 regulates skeletal homeostasis by modulating PTH1R in mice显示文摘In vertebrates,the type 1 parathyroid hormone receptor(PTH1R)is a critical regulator of skeletal development and homeostasis;however,how it is modulated is incompletely understood.Here we report that deleting Kindlin-2 in osteoblastic cells using the mouse 10-kb Dmp1-Cre largely neutralizes the intermittent PTH-stimulated increasing of bone volume fraction and bone mineral density by impairing both osteoblast and osteoclast formation in murine adult bone.Single-cell profiling reveals that Kindlin-2 loss increases the proportion of osteoblasts,but not mesenchymal stem cells,chondrocytes and fibroblasts,in non-hematopoietic bone marrow cells,with concomitant depletion of osteoblasts on the bone surfaces,especially those stimulated by PTH.Furthermore,haploinsufficiency of Kindlin-2 and Pth1r genes,but not that of either gene,in mice significantly decreases basal and,to a larger extent,PTH-stimulated bone mass,supporting the notion that both factors function in the same genetic pathway.Mechanistically,Kindlin-2 interacts with the C-terminal cytoplasmic domain of PTH1R via aa 474–475 and Gsα.Kindlin-2 loss suppresses PTH induction of cAMP production and CREB phosphorylation in cultured osteoblasts and in bone.Interestingly,PTH promotes Kindlin-2 expression in vitro and in vivo,thus creating a positive feedback regulatory loop.Finally,estrogen deficiency induced by ovariectomy drastically decreases expression of Kindlin-2 protein in osteocytes embedded in the bone matrix and Kindlin-2 loss essentially abolishes the PTH anabolic activity in bone in ovariectomized mice.Thus,we demonstrate that Kindlin-2 functions as an intrinsic component of the PTH1R signaling pathway in osteoblastic cells to regulate bone mass accrual and homeostasis. | Xuekun Fu Bo Zhou Qinnan Yan Chu Tao Lei Qin Xiaohao Wu Sixiong Lin Sheng Chen Yumei Lai Xuenong Zou Zengwu Shao Meiqing Wang Di Chen Wenfei Jin Youqiang Song Huiling Cao Ge Zhang Guozhi Xiao | 2021 | Signal Transduction and Targeted Therapy2021，6，1： | 0 |
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