Increased autophagy in EphrinB2-deficient osteocytes is associated with elevated secondary mineralization and brittle bone

Vrahnas, Christina; Blank, Martha; Dite, Toby A.; Tatarczuch, Liliana; Ansari, Niloufar; Crimeen‐Irwin, Blessing; Nguyen, Huynh Quoc; Forwood, Mark R.; Hu, Yifang; Ikegame, Mika; Bambery, Keith R.; Petibois, Cyril; Mackie, Eleanor J.; Tobin, Mark J.; Smyth, Gordon K.; Oakhill, Jonathan S.; Martın, Thomas; Sims, Natalie A.

doi:10.1038/s41467-019-11373-9

Cited by 54 publications

(41 citation statements)

References 77 publications

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“…This effect could be recapitulated in vivo with a rat mandibular bone defect model, which showed that exogenous addition of OMD could accelerate BMP2-induced bone healing. Mineralized bone forms when collagen-containing osteoid integrates hydroxyapatite crystals 47 . The Masson’s trichrome staining potentially indicated that OMD accelerated mineral accrual when bone was remodeled.…”

Section: Discussionmentioning

confidence: 99%

Osteomodulin positively regulates osteogenesis through interaction with BMP2

et al. 2021

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Osteomodulin (OMD), a member of the small leucine-rich proteoglycan family, distributes in mineralized tissues and is positively regulated by bone morphogenetic protein 2 (BMP2). However, the exact function of OMD during mineralization and its association with BMP2 remain poorly understood. Herein, the expression pattern of OMD during osteogenesis was investigated in human dental pulp stem cells. Silencing OMD gene significantly suppressed the alkaline phosphatase activity, mineralized nodule formation and osteogenesis-associated gene transcription. Besides, OMD could enhance BMP2-induced expression of SP7 and RUNX2 with concentration dependence in vitro. Rat mandibular bone defect model revealed that scaffolds injected with the combination of OMD and suboptimal BMP2 exhibited more mature and abundant mineralized bone than that treated with OMD or suboptimal BMP2 alone. Mechanistically, OMD could bind to BMP2 via its terminal leucine-rich repeats and formed complexes with BMP2 and its membrane receptors, thus promoting BMP/SMAD signal transduction. In addition, OMD was a putative target gene of SMAD4, which plays a pivotal role in this pathway. Collectively, these data elucidate that OMD may act as a positive coordinator in osteogenesis through BMP2/SMADs signaling.

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Section: Discussionmentioning

confidence: 99%

Osteomodulin positively regulates osteogenesis through interaction with BMP2

et al. 2021

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“…On the contrary, ephrinB2 enhanced osteogenic differentiation through EphB4 of osteoblasts, which is a forward signaling (108,110). Osteocytes with the absence of ephrinB2 increased more autophagosomes both in vivo and in vitro (111).…”

Section: Ec-contact Regulation In Bone Biology Is Also An Important Mmentioning

confidence: 94%

“…On the contrary, ephrinB2 enhanced osteogenic differentiation through EphB4 of osteoblasts, which is a forward signaling [ 108 , 110 ]. Osteocytes with the absence of ephrinB2 increased more autophagosomes both in vivo and in vitro [ 111 ]. Besides, the stimulation of ephrinB2 affected the production of collagen type II in osteoarthritic chondrocytes, indicating its role in controlling chondrocyte differentiation [ 112 ].…”

Section: Ec-contact Regulation In Bone Biology Is Also An Important Mmentioning

confidence: 99%

Insights into the mechanism of vascular endothelial cells on bone biology

et al. 2021

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In the skeletal system, blood vessels not only function as a conduit system for transporting gases, nutrients, metabolic waste, or cells but also provide multifunctional signal molecules regulating bone development, regeneration, and remodeling. Endothelial cells (ECs) in bone tissues, unlike in other organ tissues, are in direct contact with the pericytes of blood vessels, resulting in a closer connection with peripheral connective tissues. Close-contact ECs contribute to osteogenesis and osteoclastogenesis by secreting various cytokines in the paracrine or juxtacrine pathways. An increasing number of studies have revealed that extracellular vesicles (EVs) derived from ECs can directly regulate maturation process of osteoblasts and osteoclasts. The different pathways focus on targets at different distances, forming the basis of the intimate spatial and temporal link between bone tissue and blood vessels. Here, we provide a systematic review to elaborate on the function of ECs in bone biology and its underlying mechanisms based on three aspects: paracrine, EVs, and juxtacrine. This review proposes the possibility of a therapeutic strategy targeting blood vessels, as an adjuvant treatment for bone disorders.

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“…Cell and mineralized BECM were collected, fixed, with glutaraldehyde, postfixed with 1% osmium tetroxide, dehydrated in an ascending ethanol series, transferred to acetone, and embedded in epoxy resin as previously reported. [ 70 ] After sectioning and staining, the samples were observed by JEM‐1400 TEM (JEOL, Tokyo, Japan) at 120 kV. SAED was performed on electron‐dense granules and extracellular collagen regions by a TF20‐2100F high‐resolution TEM (JEOL, Tokyo Japan) at 6 different points for each sample.…”

Section: Methodsmentioning

confidence: 99%

Autologous Versatile Vesicles‐Incorporated Biomimetic Extracellular Matrix Induces Biomineralization

Wei

Shi

Zhang

et al. 2020

Adv Funct Materials

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Restoring extracellular matrix (ECM) with supportive and osteoinductive abilities is of great significance for bone tissue regeneration. Current approaches involving cell-based scaffolds or nanoparticle-modified biomimic-ECM have been met with additional biosafety concerns. Herein, the natural biomineralization process is first analyzed and is found that mesenchymal stem cells-derived extracellular vesicles (EVs) from early and late stages of osteoinduction play different roles during the mineralization process. The functional EVs hierarchically with blood-derived autohydrogel (AH) are then incorporated to form an osteoinductive biomimetic extracellular matrix (BECM). The alkaline phosphatase-rich EVs are released from the outer layers to induce osteoblast differentiation during early stages. Thereafter, as the degradation of AH occurred, calcium/phosphorus (Ca/P)rich EVs are liberated to promote the nucleation of extracellular mineral crystals. Additionally, BECM contains considerable collagen fibrils that provide additional nucleation sites for crystallites deposition, thus reaching self-mineralization in situ. In conclusion, this research provides a promising, versatile mineralization-instructive platform to tackle the challenges faced in bone-tissue engineering. Scheme 1. Illustration of the BECM induced osteogenesis and biomineralization. In the early stage of mineralization, BECM secreted ALP-rich E-EVs. The E-EVs moved to intracellular mitochondria and provided ALP for phosphate metabolism, contributing to the formation of Ca/P-rich vesicles. Later, with the degradation of BECM, Ca/P-rich L-EVs were released gradually. The L-EVs aligned to extracellular collagen and promoted the nucleation of extracellular mineral crystals. Besides, L-EVs inside BECM aggregate around the internally collagen fibrils and initiated in situ mineralization. Finally, with the complete degradation of BECM, the internal mineralized components were released to the extracellular matrix, promoting the deposition formation together to realize an ideal self-mineralization process for bone tissue regeneration.www.afm-journal.de www.advancedsciencenews.com (3 of 15)

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Increased autophagy in EphrinB2-deficient osteocytes is associated with elevated secondary mineralization and brittle bone

Cited by 54 publications

References 77 publications

Osteomodulin positively regulates osteogenesis through interaction with BMP2

Osteomodulin positively regulates osteogenesis through interaction with BMP2

Insights into the mechanism of vascular endothelial cells on bone biology

Autologous Versatile Vesicles‐Incorporated Biomimetic Extracellular Matrix Induces Biomineralization

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