Osteocyte RANKL is required for cortical bone loss with age and is induced by senescence

Kim, Ha‐Neui; Xiong, Jinhu; MacLeod, Ryan S.; Iyer, Srividhya; Fujiwara, Yuko; Cawley, Keisha M.; Han, Li; He, Yonghan; Thostenson, Jeff D.; Ferreira, Elisabeth; Jilka, Robert L.; Zhou, Daohong; Almeida, Maria; O’Brien, Charles A.

doi:10.1172/jci.insight.138815

Cited by 67 publications

(60 citation statements)

References 35 publications

(55 reference statements)

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“…We have previously reported that the increase in osteoclast number with aging is associated with an increase in RANKL expression by osteocytes; and, this source of RANKL is indispensable for the age-related loss of bone at endocortical and intracortical surfaces (50).…”

Section: Discussionmentioning

confidence: 99%

“…We have previously reported that the increase in osteoclast number with aging is associated with an increase in RANKL expression by osteocytes; this source of RANKL is indispensable for the age-related loss of bone at endocortical and intracortical surfaces ( 50 ). Several studies have shown that RANKL promotes mitochondria activity in osteoclast progenitor cells via multiple mechanisms, including increased mitochondria biogenesis and stimulation of OxPhos ( 16 – 21 ).…”

Section: Discussionmentioning

confidence: 99%

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Mitochondrial Sirt3 contributes to the bone loss caused by aging or estrogen deficiency

Wen¹,

Krager²,

Richardson³

et al. 2021

JCI Insight

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Altered mitochondria activity in osteoblasts and osteoclast has been implicated in the loss of bone mass associated with aging and estrogen deficiency -the two most common causes of osteoporosis. However, the mechanisms that control mitochondrial metabolism in bone cells during health or disease remain unknown. The mitochondrial deacetylase Sirtuin-3 (Sirt3) has been earlier implicated in age-related diseases. Here, we show that deletion of Sirt3 had no effect on the skeleton of young mice but attenuated the age-related loss of bone mass in both sexes.This effect was associated with impaired bone resorption. Osteoclast progenitors from aged Sirt3 null mice were able to differentiate into osteoclasts. Albeit, the differentiated cells exhibited impaired polykaryon formation and resorptive activity as well as decreased oxidative phosphorylation and mitophagy. The Sirt3 inhibitor LC-0296 recapitulated the effects of Sirt3 deletion in osteoclast formation and mitochondrial function, and its administration to aging mice increased bone mass. Deletion of Sirt3 also attenuated the increase in bone resorption and loss of bone mass caused by estrogen deficiency. These findings suggest that Sirt3 inhibition and the resulting impairment of osteoclast mitochondrial function could be a novel therapeutic intervention for the two most important causes of osteoporosis.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Mitochondrial Sirt3 contributes to the bone loss caused by aging or estrogen deficiency

Wen¹,

Krager²,

Richardson³

et al. 2021

JCI Insight

Self Cite

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“…An increase in osteoclast number and bone resorption are critical components of age‐related cortical bone loss and porosity (Li et al, 2015 ; Piemontese et al, 2017 ; Ucer et al, 2017 ). The increase in osteoclasts is associated with increased expression of RANKL by senescent osteocytes (Kim et al, 2020 ), and blocking RANKL completely prevents cortical bone loss in aged mice (Kim et al, 2020 ). Our previous work showed that E06‐scFv does not alter the osteoclast number at the endocortical surface (Ambrogini et al, 2018 ; Palmieri et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Neutralization of oxidized phospholipids attenuates age‐associated bone loss in mice

et al. 2021

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Oxidized phospholipids (OxPLs) are pro‐inflammatory molecules that affect bone remodeling under physiological conditions. Transgenic expression of a single‐chain variable fragment (scFv) of the antigen‐binding domain of E06, an IgM natural antibody that recognizes the phosphocholine (PC) moiety of OxPLs, increases trabecular and cortical bone in adult male and female mice by increasing bone formation. OxPLs increase with age, while natural antibodies decrease. Age‐related bone loss is associated with increased oxidative stress and lipid peroxidation and is characterized by a decline in osteoblast number and bone formation, raising the possibility that increased OxPLs, together with the decline of natural antibodies, contribute to age‐related bone loss. We show here that transgenic expression of E06‐scFv attenuated the age‐associated loss of spinal, femoral, and total bone mineral density in both female and male mice aged up to 22 and 24 months, respectively. E06‐scFv attenuated the age‐associated decline in trabecular bone, but not cortical bone, and this effect was associated with an increase in osteoblasts and a decrease in osteoclasts. Furthermore, RNA‐seq analysis showed that E06‐scFv increased Wnt10b expression in vertebral bone in aged mice, indicating that blocking OxPLs increases Wnt signaling. Unlike age‐related bone loss, E06‐scFv did not attenuate the bone loss caused by estrogen deficiency or unloading in adult mice. These results demonstrate that OxPLs contribute to age‐associated bone loss. Neutralization of OxPLs, therefore, is a promising therapeutic target for senile osteoporosis, as well as atherosclerosis and non‐alcoholic steatohepatitis (NASH), two other conditions shown to be attenuated by E06‐scFv in mice.

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“…In addition, aged MSCs produce high amounts of CXCL2 and CXCL5 chemokines, which contribute to the senescence-associated secretory phenotype (SASP) ( Helbling et al, 2019 ). RANKL, an osteoclastogenic cytokine, has been shown to be increasingly secreted by MSCs in aged mice ( Lin et al, 2017 ), leading to bone loss ( Kim et al, 2020 ). Cellular senescence also leads to a decrease in Optineurin (OPTN), an autophagy receptor therefore contributing to osteoporosis alongside with accumulation of the OPTN substrate fatty acid binding protein 3 (FABP3) ( Liu et al, 2020 ).…”

Section: Msc Changes In Aging Bone Marrowmentioning

confidence: 99%

Dynamic Changes of the Bone Marrow Niche: Mesenchymal Stromal Cells and Their Progeny During Aging and Leukemia

Woods

Guezguez

2021

Front. Cell Dev. Biol.

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Mesenchymal stromal cells (MSCs) are a heterogenous cell population found in a wide range of tissues in the body, known for their nutrient-producing and immunomodulatory functions. In the bone marrow (BM), these MSCs are critical for the regulation of hematopoietic stem cells (HSC) that are responsible for daily blood production and functional immunity throughout an entire organism’s lifespan. Alongside other stromal cells, MSCs form a specialized microenvironment BM tissue called “niche” that tightly controls HSC self-renewal and differentiation. In addition, MSCs are crucial players in maintaining bone integrity and supply of hormonal nutrients due to their capacity to differentiate into osteoblasts and adipocytes which also contribute to cellular composition of the BM niche. However, MSCs are known to encompass a large heterogenous cell population that remains elusive and poorly defined. In this review, we focus on deciphering the BM-MSC biology through recent advances in single-cell identification of hierarchical subsets with distinct functionalities and transcriptional profiles. We also discuss the contribution of MSCs and their osteo-adipo progeny in modulating the complex direct cell-to-cell or indirect soluble factors-mediated interactions of the BM HSC niche during homeostasis, aging and myeloid malignancies. Lastly, we examine the therapeutic potential of MSCs for rejuvenation and anti-tumor remedy in clinical settings.

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Osteocyte RANKL is required for cortical bone loss with age and is induced by senescence

Cited by 67 publications

References 35 publications

Mitochondrial Sirt3 contributes to the bone loss caused by aging or estrogen deficiency

Mitochondrial Sirt3 contributes to the bone loss caused by aging or estrogen deficiency

Neutralization of oxidized phospholipids attenuates age‐associated bone loss in mice

Dynamic Changes of the Bone Marrow Niche: Mesenchymal Stromal Cells and Their Progeny During Aging and Leukemia

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