The high-density lipoprotein receptor Scarb1 is required for normal bone differentiation in vivo and in vitro

Tourkova, Irina L.; Dobrowolski, Steven F.; Secunda, Cassandra; Zaidi, Mone; Papadimitriou-Olivgeri, Ioanna; Papachristou, Dionysios J.; Blair, Harry C.

doi:10.1038/s41374-019-0311-0

Cited by 14 publications

(12 citation statements)

References 23 publications

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“…In contrast, others have recently shown that Scarb1 knockout mice have lower bone mass and lower bone formation rate at 16 weeks, suggesting that Scarb1 is required for osteoblast differentiation and bone acquisition. ( 35 ) Be that as it may, the global nature of the Scarb1 deletion in these later mouse models cannot exclude the possibility that other cell types contribute to the bone phenotype. Last, based on in vitro observations, recent studies suggested that OxLDL and synthetic OxPL may promote endocytosis of LRP6—a Wnt receptor that plays a prominent role in osteoblastogenesis.…”

Section: Discussionmentioning

confidence: 99%

A Neutralizing Antibody Targeting Oxidized Phospholipids Promotes Bone Anabolism in Chow-Fed Young Adult Mice

Palmieri

Kim

Gómez-Acevedo

et al. 2020

Journal of Bone and Mineral Research

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Oxidized phospholipids containing phosphocholine (OxPL) are pro‐inflammatory lipid peroxidation products that bind to scavenger receptors (SRs), such as Scarb1, and toll‐like receptors (TLRs). Excessive OxPL, as found in oxidized low‐density lipoprotein (OxLDL), overwhelm these defense mechanisms and become pathogenic in atherosclerosis, nonalcoholic steatohepatitis (NASH), and osteoporosis. We previously reported that the innate IgM natural antibody E06 binds to OxPL and neutralizes their deleterious effects; expression of the single‐chain (scFv) form of the antigen‐binding domain of E06 (E06‐scFv) as a transgene increases trabecular bone in male mice. We show herein that E06‐scFv increases trabecular and cortical bone in female and male mice by increasing bone formation and decreasing osteoblast apoptosis in vivo. Homozygous E06‐scFv mice have higher bone mass than hemizygous, showing a dose effect of the transgene. To investigate how OxPL restrain bone formation under physiologic conditions, we measured the levels of SRs and TLRs that bind OxPL. We found that osteoblastic cells primarily express Scarb1. Moreover, OxLDL‐induced apoptosis and reduced differentiation were prevented in bone marrow–derived or calvaria‐derived osteoblasts from Scarb1 knockout mice. Because Scarb1‐deficient mice are reported to have high bone mass, our results suggest that E06 may promote bone anabolism in healthy young mice, at least in part, by neutralizing OxPL, which in turn promote Scarb1‐mediated apoptosis of osteoblasts or osteoblast precursors. © 2020 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR)..

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Section: Discussionmentioning

confidence: 99%

A Neutralizing Antibody Targeting Oxidized Phospholipids Promotes Bone Anabolism in Chow-Fed Young Adult Mice

Palmieri

Kim

Gómez-Acevedo

et al. 2020

Journal of Bone and Mineral Research

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“…Furthermore, it was found that the high-density lipoprotein (HDL) type B scavenger receptor (Scarb1) knockout in bone MSCs affected their potential to undergo osteoblast differentiation ( Tourkova et al, 2019 ). Importantly, another study using the same Scarb1 KO mouse model reported a compensatory level of adrenocorticotropic hormone (ACTH) levels for GC homeostasis which in turn affected trabeculae mass.…”

Section: Discussionmentioning

confidence: 99%

A Core Omnigenic Non-coding Trait Governing Dex-Induced Osteoporotic Effects Identified Without DEXA

et al. 2021

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Iatrogenic glucocorticoid (GC)-induced osteoporosis (GIO) is an idiosyncratic form of secondary osteoporosis. Genetic predisposition among individuals may give rise to variant degree of phenotypic changes but there has yet been a documented unified pathway to explain the idiosyncrasy. In this study, we argue that the susceptibility to epigenetic changes governing molecular cross talks along the BMP and PI3K/Akt pathway may underline how genetic background dictate GC-induced bone loss. Concordantly, osteoblasts from BALB/c or C57BL/6 neonatal mice were treated with dexamethasone for transcriptome profiling. Furthermore, we also confirmed that GC-pre-conditioned mesenchymal stem cells (MSCs) would give rise to defective osteogenesis by instigating epigenetic changes which affected the accessibility of enhancer marks. In line with these epigenetic changes, we propose that GC modulates a key regulatory network involving the scavenger receptor Cd36 in osteoblasts pre-conditioning pharmacological idiosyncrasy in GIO.

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“…After incubation overnight, non-adherent cells, including monocytic osteoclast precursors, were removed from adherent stromal cells and re-plated, with continued growth in m-CSF to favor survival of cells of monocytic lineage. 11,12 These cells were then used in experiments to evaluate calcium signaling, gene expression, and RANKL-induced differentiation.…”

Section: Cell Culture and Osteoclast Differentiationmentioning

confidence: 99%

The function of the calcium channel Orai1 in osteoclast development

et al. 2021

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To determine the intrinsic role of Orai1 in osteoclast development, Orai1-floxed mice were bred with LysMcre mice to delete Orai1 from the myeloid lineage. PCR, in situ labelling and Western analysis showed Orai1 deletion in myeloid-lineage cells, including osteoclasts, as expected. Surprisingly, bone resorption was maintained in vivo, despite loss of multinucleated osteoclasts; instead, a large number of mononuclear cells bearing tartrate resistant acid phosphatase were observed on cell surfaces.An in vitro resorption assay confirmed that RANKL-treated Orai1 null cells, also TRAP-positive but mononuclear, degraded matrix, albeit at a reduced rate compared to wild type osteoclasts. This shows that mononuclear osteoclasts can degrade bone, albeit less efficiently. Further unexpected findings included that Orai1 fl/fl -LysMcre vertebrae showed slightly reduced bone density in 16-week-old mice, despite Orai1 deletion only in myeloid cells; however, this mild difference resolved with age. In summary, in vitro analysis showed a severe defect in osteoclast multinucleation in Orai1 negative mononuclear cells, consistent with prior studies using less targeted strategies, but with evidence of resorption in vivo and unexpected secondary effects on bone formation leaving bone mass largely unaffected. 2 of 15 | ROBINSON et al.

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The high-density lipoprotein receptor Scarb1 is required for normal bone differentiation in vivo and in vitro

Cited by 14 publications

References 23 publications

A Neutralizing Antibody Targeting Oxidized Phospholipids Promotes Bone Anabolism in Chow-Fed Young Adult Mice

A Neutralizing Antibody Targeting Oxidized Phospholipids Promotes Bone Anabolism in Chow-Fed Young Adult Mice

A Core Omnigenic Non-coding Trait Governing Dex-Induced Osteoporotic Effects Identified Without DEXA

The function of the calcium channel Orai1 in osteoclast development

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