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Bone Research

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https://www.readbyqxmd.com/read/30038821/oxidized-phospholipids-are-ligands-for-lrp6
#1
Lei Wang, Yu Chai, Changjun Li, Haiyun Liu, Weiping Su, Xiaonan Liu, Bing Yu, Weiqi Lei, Bin Yu, Janet L Crane, Xu Cao, Mei Wan
Low-density lipoprotein receptor-related protein 6 (LRP6) is a co-receptor for Wnt signaling and can be recruited by multiple growth factors/hormones to their receptors facilitating intracellular signaling activation. The ligands that bind directly to LRP6 have not been identified. Here, we report that bioactive oxidized phospholipids (oxPLs) are native ligands of LRP6, but not the closely related LRP5. oxPLs are products of lipid oxidation involving in pathological conditions such as hyperlipidemia, atherosclerosis, and inflammation...
2018: Bone Research
https://www.readbyqxmd.com/read/30038820/ciliary-parathyroid-hormone-signaling-activates-transforming-growth-factor-%C3%AE-to-maintain-intervertebral-disc-homeostasis-during-aging
#2
Liwei Zheng, Yong Cao, Shuangfei Ni, Huabin Qi, Zemin Ling, Xin Xu, Xuenong Zou, Tianding Wu, Ruoxian Deng, Bo Hu, Bo Gao, Hao Chen, Yusheng Li, Jianxi Zhu, Francis Tintani, Shadpour Demehri, Amit Jain, Khaled M Kebaish, Shenghui Liao, Cheryle A Séguin, Janet L Crane, Mei Wan, Hongbin Lu, Paul D Sponseller, Lee H Riley, Xuedong Zhou, Jianzhong Hu, Xu Cao
Degenerative disc disease (DDD) is associated with intervertebral disc degeneration of spinal instability. Here, we report that the cilia of nucleus pulposus (NP) cells mediate mechanotransduction to maintain anabolic activity in the discs. We found that mechanical stress promotes transport of parathyroid hormone 1 receptor (PTH1R) to the cilia and enhances parathyroid hormone (PTH) signaling in NP cells. PTH induces transcription of integrin αv β6 to activate the transforming growth factor (TGF)-β-connective tissue growth factor (CCN2)-matrix proteins signaling cascade...
2018: Bone Research
https://www.readbyqxmd.com/read/30002945/dietary-fat-associated-osteoarthritic-chondrocytes-gain-resistance-to-lipotoxicity-through-pkck2-stamp2-fsp27
#3
Sung Won Lee, Jee Hyun Rho, Sang Yeob Lee, Won Tae Chung, Yoo Jin Oh, Jung Ha Kim, Seung Hee Yoo, Woo Young Kwon, Ju Yong Bae, Su Young Seo, Hokeun Sun, Hye Young Kim, Young Hyun Yoo
Free fatty acids (FFAs), which are elevated with metabolic syndrome, are considered the principal offender exerting lipotoxicity. Few previous studies have reported a causal relationship between FFAs and osteoarthritis pathogenesis. However, the molecular mechanism by which FFAs exert lipotoxicity and induce osteoarthritis remains largely unknown. We here observed that oleate at the usual clinical range does not exert lipotoxicity while oleate at high pathological ranges exerted lipotoxicity through apoptosis in articular chondrocytes...
2018: Bone Research
https://www.readbyqxmd.com/read/29928541/the-art-of-building-bone-emerging-role-of-chondrocyte-to-osteoblast-transdifferentiation-in-endochondral-ossification
#4
Patrick Aghajanian, Subburaman Mohan
There is a worldwide epidemic of skeletal diseases causing not only a public health issue but also accounting for a sizable portion of healthcare expenditures. The vertebrate skeleton is known to be formed by mesenchymal cells condensing into tissue elements (patterning phase) followed by their differentiation into cartilage (chondrocytes) or bone (osteoblasts) cells within the condensations. During the growth and remodeling phase, bone is formed directly via intramembranous ossification or through a cartilage to bone conversion via endochondral ossification routes...
2018: Bone Research
https://www.readbyqxmd.com/read/29872550/yap-promotes-osteogenesis-and-suppresses-adipogenic-differentiation-by-regulating-%C3%AE-catenin-signaling
#5
EDITORIAL
Jin-Xiu Pan, Lei Xiong, Kai Zhao, Peng Zeng, Bo Wang, Fu-Lei Tang, Dong Sun, Hao-Han Guo, Xiao Yang, Shun Cui, Wen-Fang Xia, Lin Mei, Wen-Cheng Xiong
YAP (yes-associated protein) is a transcriptional factor that is negatively regulated by Hippo pathway, a conserved pathway for the development and size control of multiple organs. The exact function of YAP in bone homeostasis remains controversial. Here we provide evidence for YAP's function in promoting osteogenesis, suppressing adipogenesis, and thus maintaining bone homeostasis. YAP is selectively expressed in osteoblast (OB)-lineage cells. Conditionally knocking out Yap in the OB lineage in mice reduces cell proliferation and OB differentiation and increases adipocyte formation, resulting in a trabecular bone loss...
2018: Bone Research
https://www.readbyqxmd.com/read/29844946/bone-loss-from-wnt-inhibition-mitigated-by-concurrent-alendronate-therapy
#6
Babita Madan, Mitchell J McDonald, Gabrielle E Foxa, Cassandra R Diegel, Bart O Williams, David M Virshup
Dysregulated Wnt signaling is associated with the pathogenesis of cancers, fibrosis, and vascular diseases. Inhibition of Wnt signaling has shown efficacy in various pre-clinical models of these disorders. One of the key challenges in developing targeted anti-cancer drugs is to balance efficacy with on-target toxicity. Given the crucial role Wnts play in the differentiation of osteoblasts and osteoclasts, acute inhibition of Wnt signaling is likely to affect bone homeostasis. In this study, we evaluated the skeletal effect of small molecule inhibitor of an o-acyl transferase porcupine (PORCN) that prevents Wnt signaling by blocking the secretion of all Wnts...
2018: Bone Research
https://www.readbyqxmd.com/read/29844945/paracrine-and-endocrine-actions-of-bone-the-functions-of-secretory-proteins-from-osteoblasts-osteocytes-and-osteoclasts
#7
REVIEW
Yujiao Han, Xiuling You, Wenhui Xing, Zhong Zhang, Weiguo Zou
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...
2018: Bone Research
https://www.readbyqxmd.com/read/29736302/rheumatoid-arthritis-pathological-mechanisms-and-modern-pharmacologic-therapies
#8
REVIEW
Qiang Guo, Yuxiang Wang, Dan Xu, Johannes Nossent, Nathan J Pavlos, Jiake Xu
Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease that primarily affects the lining of the synovial joints and is associated with progressive disability, premature death, and socioeconomic burdens. A better understanding of how the pathological mechanisms drive the deterioration of RA progress in individuals is urgently required in order to develop therapies that will effectively treat patients at each stage of the disease progress. Here we dissect the etiology and pathology at specific stages: (i) triggering, (ii) maturation, (iii) targeting, and (iv) fulminant stage, concomitant with hyperplastic synovium, cartilage damage, bone erosion, and systemic consequences...
2018: Bone Research
https://www.readbyqxmd.com/read/29707403/histone-demethylase-lsd1-regulates-bone-mass-by-controlling-wnt7b-and-bmp2-signaling-in-osteoblasts
#9
Jun Sun, Joerg Ermann, Ningning Niu, Guang Yan, Yang Yang, Yujiang Shi, Weiguo Zou
Multiple regulatory mechanisms control osteoblast differentiation and function to ensure unperturbed skeletal formation and remodeling. In this study we identify histone lysine-specific demethylase 1(LSD1/KDM1A) as a key epigenetic regulator of osteoblast differentiation. Knockdown of LSD1 promoted osteoblast differentiation of human mesenchymal stem cells (hMSCs) in vitro and mice lacking LSD1 in mesenchymal cells displayed increased bone mass secondary to accelerated osteoblast differentiation. Mechanistic in vitro studies revealed that LSD1 epigenetically regulates the expression of WNT7B and BMP2...
2018: Bone Research
https://www.readbyqxmd.com/read/29707402/molecularly-specific-detection-of-bacterial-lipoteichoic-acid-for-diagnosis-of-prosthetic-joint-infection-of-the-bone
#10
Julie E Pickett, John M Thompson, Agnieszka Sadowska, Christine Tkaczyk, Bret R Sellman, Andrea Minola, Davide Corti, Antonio Lanzavecchia, Lloyd S Miller, Daniel Lj Thorek
Discriminating sterile inflammation from infection, especially in cases of aseptic loosening versus an actual prosthetic joint infection, is challenging and has significant treatment implications. Our goal was to evaluate a novel human monoclonal antibody (mAb) probe directed against the Gram-positive bacterial surface molecule lipoteichoic acid (LTA). Specificity and affinity were assessed in vitro. We then radiolabeled the anti-LTA mAb and evaluated its effectiveness as a diagnostic imaging tool for detecting infection via immunoPET imaging in an in vivo mouse model of prosthetic joint infection (PJI)...
2018: Bone Research
https://www.readbyqxmd.com/read/29644115/shp2-regulates-skeletal-cell-fate-by-modifying-sox9-expression-and-transcriptional-activity
#11
Chunlin Zuo, Lijun Wang, Raghavendra M Kamalesh, Margot E Bowen, Douglas C Moore, Mark S Dooner, Anthony M Reginato, Qian Wu, Christoph Schorl, Yueming Song, Matthew L Warman, Benjamin G Neel, Michael G Ehrlich, Wentian Yang
Chondrocytes and osteoblasts differentiate from a common mesenchymal precursor, the osteochondroprogenitor (OCP), and help build the vertebrate skeleton. The signaling pathways that control lineage commitment for OCPs are incompletely understood. We asked whether the ubiquitously expressed protein-tyrosine phosphatase SHP2 (encoded by Ptpn11 ) affects skeletal lineage commitment by conditionally deleting Ptpn11 in mouse limb and head mesenchyme using "Cre-loxP"-mediated gene excision. SHP2-deficient mice have increased cartilage mass and deficient ossification, suggesting that SHP2-deficient OCPs become chondrocytes and not osteoblasts...
2018: Bone Research
https://www.readbyqxmd.com/read/29644114/super-enhancer-inhibitors-suppress-myc-driven-transcriptional-amplification-and-tumor-progression-in-osteosarcoma
#12
Demeng Chen, Zhiqiang Zhao, Zixin Huang, Du-Chu Chen, Xin-Xing Zhu, Yi-Ze Wang, Ya-Wei Yan, Shaojun Tang, Subha Madhavan, Weiyi Ni, Zhan-Peng Huang, Wen Li, Weidong Ji, Huangxuan Shen, Shuibin Lin, Yi-Zhou Jiang
Osteosarcoma is the most common primary bone sarcoma that mostly occurs in young adults. The causes of osteosarcoma are heterogeneous and still not fully understood. Identification of novel, important oncogenic factors in osteosarcoma and development of better, effective therapeutic approaches are in urgent need for better treatment of osteosarcoma patients. In this study, we uncovered that the oncogene MYC is significantly upregulated in metastastic osteosarcoma samples. In addition, high MYC expression is associated with poor survival of osteosarcoma patients...
2018: Bone Research
https://www.readbyqxmd.com/read/29619270/chip-regulates-bone-mass-by-targeting-multiple-traf-family-members-in-bone-marrow-stromal-cells
#13
Tingyu Wang, Shan Li, Dan Yi, Guang-Qian Zhou, Zhijie Chang, Peter X Ma, Guozhi Xiao, Di Chen
Carboxyl terminus of Hsp70-interacting protein (CHIP or STUB1) is an E3 ligase and regulates the stability of several proteins which are involved in different cellular functions. Our previous studies demonstrated that Chip deficient mice display bone loss phenotype due to increased osteoclast formation through enhancing TRAF6 activity in osteoclasts. In this study we provide novel evidence about the function of CHIP. We found that osteoblast differentiation and bone formation were also decreased in Chip KO mice...
2018: Bone Research
https://www.readbyqxmd.com/read/29619269/omentin-1-prevents-inflammation-induced-osteoporosis-by-downregulating-the-pro-inflammatory-cytokines
#14
Shan-Shan Rao, Yin Hu, Ping-Li Xie, Jia Cao, Zhen-Xing Wang, Jiang-Hua Liu, Hao Yin, Jie Huang, Yi-Juan Tan, Juan Luo, Ming-Jie Luo, Si-Yuan Tang, Tuan-Hui Chen, Ling-Qing Yuan, Er-Yuan Liao, Ran Xu, Zheng-Zhao Liu, Chun-Yuan Chen, Hui Xie
Osteoporosis is a frequent complication of chronic inflammatory diseases and increases in the pro-inflammatory cytokines make an important contribution to bone loss by promoting bone resorption and impairing bone formation. Omentin-1 is a newly identified adipocytokine that has anti-inflammatory effects, but little is known about the role of omentin-1 in inflammatory osteoporosis. Here we generated global omentin-1 knockout ( omentin-1 -/- ) mice and demonstrated that depletion of omentin-1 induces inflammatory bone loss-like phenotypes in mice, as defined by abnormally elevated pro-inflammatory cytokines, increased osteoclast formation and bone tissue destruction, as well as impaired osteogenic activities...
2018: Bone Research
https://www.readbyqxmd.com/read/29619268/enhancer-variants-reveal-a-conserved-transcription-factor-network-governed-by-pu-1-during-osteoclast-differentiation
#15
Heather A Carey, Blake E Hildreth, Jennifer A Geisler, Mara C Nickel, Jennifer Cabrera, Sankha Ghosh, Yue Jiang, Jing Yan, James Lee, Sandeep Makam, Nicholas A Young, Giancarlo R Valiente, Wael N Jarjour, Kun Huang, Thomas J Rosol, Ramiro E Toribio, Julia F Charles, Michael C Ostrowski, Sudarshana M Sharma
Genome-wide association studies (GWASs) have been instrumental in understanding complex phenotypic traits. However, they have rarely been used to understand lineage-specific pathways and functions that contribute to the trait. In this study, by integrating lineage-specific enhancers from mesenchymal and myeloid compartments with bone mineral density loci, we were able to segregate osteoblast- and osteoclast (OC)-specific functions. Specifically, in OCs, a PU.1-dependent transcription factor (TF) network was revealed...
2018: Bone Research
https://www.readbyqxmd.com/read/29581909/mechanically-induced-ca-2-oscillations-in-osteocytes-release-extracellular-vesicles-and-enhance-bone-formation
#16
Andrea E Morrell, Genevieve N Brown, Samuel T Robinson, Rachel L Sattler, Andrew D Baik, Gehua Zhen, Xu Cao, Lynda F Bonewald, Weiyang Jin, Lance C Kam, X Edward Guo
The vast osteocytic network is believed to orchestrate bone metabolic activity in response to mechanical stimuli through production of sclerostin, RANKL, and osteoprotegerin (OPG). However, the mechanisms of osteocyte mechanotransduction remain poorly understood. We've previously shown that osteocyte mechanosensitivity is encoded through unique intracellular calcium (Ca2+ ) dynamics. Here, by simultaneously monitoring Ca2+ and actin dynamics in single cells exposed to fluid shear flow, we detected actin network contractions immediately upon onset of flow-induced Ca2+ transients, which were facilitated by smooth muscle myosin and further confirmed in native osteocytes ex vivo...
2018: Bone Research
https://www.readbyqxmd.com/read/29507819/igf-i-induced-phosphorylation-of-pth-receptor-enhances-osteoblast-to-osteocyte-transition
#17
Tao Qiu, Janet L Crane, Liang Xie, Lingling Xian, Hui Xie, Xu Cao
Parathyroid hormone (PTH) regulates bone remodeling by activating PTH type 1 receptor (PTH1R) in osteoblasts/osteocytes. Insulin-like growth factor type 1 (IGF-1) stimulates mesenchymal stem cell differentiation to osteoblasts. However, little is known about the signaling mechanisms that regulates the osteoblast-to-osteocyte transition. Here we report that PTH and IGF-I synergistically enhance osteoblast-to-osteocyte differentiation. We identified that a specific tyrosine residue, Y494, on the cytoplasmic domain of PTH1R can be phosphorylated by insulin-like growth factor type I receptor (IGF1R) in vitro...
2018: Bone Research
https://www.readbyqxmd.com/read/29507818/lrp1-in-osteoblasts-controls-osteoclast-activity-and-protects-against-osteoporosis-by-limiting-pdgf-rankl-signaling
#18
Alexander Bartelt, Friederike Behler-Janbeck, F Timo Beil, Till Koehne, Brigitte Müller, Tobias Schmidt, Markus Heine, Laura Ochs, Tayfun Yilmaz, Martin Dietrich, Jan P Tuckermann, Michael Amling, Joachim Herz, Thorsten Schinke, Joerg Heeren, Andreas Niemeier
Skeletal health relies on architectural integrity and sufficient bone mass, which are maintained through a tightly regulated equilibrium of bone resorption by osteoclasts and bone formation by osteoblasts. Genetic studies have linked the gene coding for low-density lipoprotein receptor-related protein1 (Lrp1) to bone traits but whether these associations are based on a causal molecular relationship is unknown. Here, we show that Lrp1 in osteoblasts is a novel regulator of osteoclast activity and bone mass. Mice lacking Lrp1 specifically in the osteoblast lineage displayed normal osteoblast function but severe osteoporosis due to highly increased osteoclast numbers and bone resorption...
2018: Bone Research
https://www.readbyqxmd.com/read/29507817/engineering-3d-approaches-to-model-the-dynamic-microenvironments-of-cancer-bone-metastasis
#19
REVIEW
Han Qiao, Tingting Tang
Cancer metastasis to bone is a three-dimensional (3D), multistep, dynamic process that requires the sequential involvement of three microenvironments, namely, the primary tumour microenvironment, the circulation microenvironment and the bone microenvironment. Engineered 3D approaches allow for a vivid recapitulation of in vivo cancerous microenvironments in vitro, in which the biological behaviours of cancer cells can be assessed under different metastatic conditions. Therefore, modelling bone metastasis microenvironments with 3D cultures is imperative for advancing cancer research and anti-cancer treatment strategies...
2018: Bone Research
https://www.readbyqxmd.com/read/29423331/transforming-growth-factor-%C3%AE-in-stem-cells-and-tissue-homeostasis
#20
Xin Xu, Liwei Zheng, Quan Yuan, Gehua Zhen, Janet L Crane, Xuedong Zhou, Xu Cao
TGF-β 1-3 are unique multi-functional growth factors that are only expressed in mammals, and mainly secreted and stored as a latent complex in the extracellular matrix (ECM). The biological functions of TGF-β in adults can only be delivered after ligand activation, mostly in response to environmental perturbations. Although involved in multiple biological and pathological processes of the human body, the exact roles of TGF-β in maintaining stem cells and tissue homeostasis have not been well-documented until recent advances, which delineate their functions in a given context...
2018: Bone Research
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