Osteocyte- and late osteoblast-derived NOTUM reduces cortical bone mass in mice

Nilsson, Karin; Henning, Petra; Shahawy, Maha El; Wu, Jianyao; Koskela, Antti; Tuukkanen, Juha; Lerner, Ulf H.; Ohlsson, Claes; Movérare‐Skrtic, Sofia

doi:10.1152/ajpendo.00565.2020

Cited by 8 publications

(7 citation statements)

References 23 publications

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“…55 We detected strong expression of Notum in cultured osteoblasts, which is not surprising given high expression levels described in osteocytes and mature osteoblasts in vivo. 55 Notum deletion in murine osteocytes/late osteoblasts resulted in increased cortical bone mass, which was expected given its role as a Wnt inhibitor. 55 Evidence suggests that the actions of Notum are specific to modulation of Wnt signaling and thus effects on lipid metabolism are unlikely.…”

Section: Induction Of Er Stress With Tunicamycin Was Shown To Inducesupporting

confidence: 62%

“…55 Notum deletion in murine osteocytes/late osteoblasts resulted in increased cortical bone mass, which was expected given its role as a Wnt inhibitor. 55 Evidence suggests that the actions of Notum are specific to modulation of Wnt signaling and thus effects on lipid metabolism are unlikely. Further studies are needed to elucidate the role of Lipase A and hepatic lipase in bone, and to determine whether osteoblast lipases are acting cell autonomously, or contributing to lipid metabolism globally.…”

Section: Induction Of Er Stress With Tunicamycin Was Shown To Inducementioning

confidence: 79%

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Lipolysis products from triglyceride‐rich lipoproteins induce stress protein ATF3 in osteoblasts

Rutkowsky,

Wong,

Toupadakis

et al. 2023

Journal Orthopaedic Research

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High fat diets overwhelm the physiological mechanisms for absorption, storage, and utilization of triglycerides (TG); consequently TG, TG‐rich lipoproteins (TGRL), and TGRL remnants accumulate, circulate systemically, producing dyslipidemia. This associates with, or is causative for increased atherosclerotic cardiovascular risk, ischemic stroke, fatty liver disease, and pancreatitis. TGRL hydrolysis by endothelial surface‐bound lipoprotein lipase (LPL) generates metabolites like free fatty acids which have proinflammatory properties. While osteoblasts utilize fatty acids as an energy source, dyslipidemia is associated with negative effects on the skeleton. In this study we investigated the effects of TGRL lipolysis products (TGRL‐LP) on expression of a stress responsive transcription factor, termed activating transcription factor 3 (ATF3), reactive oxygen species (ROS), ATF3 target genes, and angiopoietin‐like 4 (Angptl4) in osteoblasts. As ATF3 negatively associates with osteoblast differentiation, we also investigated the skeletal effects of global ATF3 deletion in mice. TGRL‐LP increased expression of Atf3, proinflammatory proteins Ptgs2 and IL‐6, and induced ROS in MC3T3‐E1 osteoblastic cells. Angptl4 is an endogenous inhibitor of LPL which was transcriptionally induced by TGRL‐LP, while recombinant Angptl4 prevented TG‐driven Atf3 induction. Atf3 global knockout male mice demonstrated increased trabecular and cortical microarchitectural parameters. In summary, we find that TGRL‐LP induce osteoblastic cell stress as evidenced by expression of ATF3, which may contribute to the negative impact of dyslipidemia in the skeleton. Further, concomitant induction of Angptl4 in osteoblasts might play a protective role by reducing local lipolysis.

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Section: Induction Of Er Stress With Tunicamycin Was Shown To Inducesupporting

confidence: 62%

Section: Induction Of Er Stress With Tunicamycin Was Shown To Inducementioning

confidence: 79%

Lipolysis products from triglyceride‐rich lipoproteins induce stress protein ATF3 in osteoblasts

Rutkowsky,

Wong,

Toupadakis

et al. 2023

Journal Orthopaedic Research

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“…Trabecular and cortical bone may respond differently to treatments, and certain WNT signaling pathways have the capacity to regulate the trabecular and the cortical bone compartments separately ( 11 – 13 ). Previous studies have demonstrated that osteoblast-derived WNT16 and the secreted WNT inhibiting lipase NOTUM are major regulators specifically of cortical bone mass ( 11 , 32 , 33 , 36 ). In contrast, WNT10b and the extracellular WNT signaling modulator RSPO3 mainly regulate trabecular bone mass ( 12 , 22 ).…”

Section: Discussionmentioning

confidence: 99%

Estradiol and RSPO3 regulate vertebral trabecular bone mass independent of each other

Nilsson

Gustafsson

et al. 2022

American Journal of Physiology-Endocrinology and Metabolism

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Osteoporosis is an age-dependent serious skeletal disease that leads to great suffering for the patient and high social costs, especially as the global population reaches higher age. Decreasing estrogen levels after menopause result in a substantial bone loss and increased fracture risk, while estrogen treatment improves bone mass in women. RSPO3, a secreted protein that modulates WNT signaling, increases trabecular bone mass and strength in the vertebrae of mice, and is associated with trabecular density and risk of distal forearm fractures in humans. The aim of the present study was to determine if RSPO3 is involved in the bone-sparing effect of estrogens. We first observed that estradiol (E2) treatment increases RSPO3 expression in bone of ovariectomized (OVX) mice, supporting a possible role of RSPO3 in the bone-sparing effect of estrogens. As RSPO3 is mainly expressed by osteoblasts in the bone, we used a mouse model devoid of osteoblast-derived RSPO3 (Runx2‑creRspo3flox/flox mice) to determine if RSPO3 is required for the bone-sparing effect of E2 in OVX mice. We confirmed that osteoblast-specific RSPO3 inactivation results in a substantial reduction in trabecular bone mass and strength in the vertebrae. However, E2 increased vertebral trabecular bone mass and strength similarly in mice devoid of osteoblast-derived RSPO3 and control mice. Unexpectedly, osteoblast-derived RSPO3 was needed for the full estrogenic response on cortical bone thickness. In conclusion, although osteoblast-derived RSPO3 is a crucial regulator of vertebral trabecular bone, it is required for a full estrogenic effect on cortical, but not trabecular, bone in OVX mice. Thus, estradiol and RSPO3 regulate vertebral trabecular bone mass independent of each other.

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“…Karin H Nilsson et al. demonstrated that late osteoblast‐derived NOTUM reduces cortical bone mass (Nilsson et al., 2021). Therefore, NOTUM is crucial for Foxf1 osteogenic differentiation of BMSCs.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, we found that NOTUM reduced cell growth and cell transfer, and inhibited osteogenic differentiation of BMSCs. Karin H Nilsson et al demonstrated that late osteoblast-derived NOTUM reduces cortical bone mass (Nilsson et al, 2021). Therefore, NOTUM is crucial for Foxf1 osteogenic differentiation of BMSCs.…”

Section: Discussionmentioning

confidence: 99%

The expression of NOTUM in replantation of severed fingers may be an important treatment factor

Xiao

Ye³

et al. 2022

Annals of Human Genetics

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Background: After years of development, digital replantation has become a mature treatment. Although the NOTUM gene has been shown to be involved in the formation of vertebrate nerves, whether it contributes to the osteogenic mechanism of severed finger replantation remains unknown. In response to this, this study investigates the specific details of NOTUM involvement in replantation of severed fingers. Methods: The experimental subjects are patients with replantation of severed fingers from Shulan International Medical College of Shulan (Hangzhou) Hospital affiliated to Zhejiang Shuren University. In addition to using bone marrow mesenchymal stem cells (BMSCs) as an in vitro system, this experiment also involves quantitative polymerase chain reaction, microarray analysis, cell counting Kit-8, ethynyl deoxyuridine staining and Western blot analysis. Results:The expression level of NOTUM in the severed finger replantation group is lower than that in the normal group. NOTUM inhibits cell growth and cell transfer, osteogenic differentiation and β-catenin gene expression in BMSCs. Luciferase reporter assay illustrated that β-catenin wild type closely correlated with NOTUM. The inhibition of β-catenin increases the effects of NOTUM on cell growth, cell transfer and osteogenic differentiation of BMSCs. Conclusions:Considering that NOTUM can inhibit cell growth, cell transfer, osteogenic differentiation of BMSCs, as well as the gene expression of β-catenin, it may be a biomarker of osteogenic differentiation and a potential therapeutic target for replantation of severed fingers.

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Osteocyte- and late osteoblast-derived NOTUM reduces cortical bone mass in mice

Cited by 8 publications

References 23 publications

Lipolysis products from triglyceride‐rich lipoproteins induce stress protein ATF3 in osteoblasts

Lipolysis products from triglyceride‐rich lipoproteins induce stress protein ATF3 in osteoblasts

Estradiol and RSPO3 regulate vertebral trabecular bone mass independent of each other

The expression of NOTUM in replantation of severed fingers may be an important treatment factor

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