Targeting skeletal endothelium to ameliorate bone loss

Xu, Ren; Yallowitz, Alisha R.; Qin, An; Wu, Zhuhao; Shin, Dong Yeon; Kim, Jung-Min; Debnath, Shawon; Ji, Gang; Bostrom, Mathias P.; Yang, Xu; Zhang, Chao; Han, Dong; Kermani, Pouneh; Lalani, Sarfaraz; Li, Na; Liu, Yifang; Poulos, Michael G.; Wach, Amanda; Zhang, Yi; Inoue, Kenzo; Lorenzo, Annarita Di; Zhao, Baohong; Butler, Jerry F.; Shim, Jae-Hyuck; Glimcher, Laurie H.; Greenblatt, Matthew B.

doi:10.1038/s41591-018-0020-z

Cited by 263 publications

(310 citation statements)

References 52 publications

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“…These results complement published studies demonstrating that deletion of Slit3 in cathepsin K–expressing cells decreased bone formation rate and trabecular bone volume, although osteoclast number and eroded surface were also increased in this mouse model . Although the impact of osteoblast lineage–derived SLIT3 on the skeleton remains somewhat controversial, our data firmly support the concept that osteoclast‐derived coupling factors, including SLIT3, play an important role in skeletal homeostasis.…”

Section: Discussionsupporting

confidence: 91%

“…Given that deletion of Srgap2 in the myeloid lineage caused an increase in bone formation, we considered potential clastokines that may mediate such a response. Recently, SLIT3 was identified by two different groups as an osteoclast‐derived and osteoblast‐derived bone anabolic factor that acts in a paracrine fashion . Western blot analysis confirmed that SLIT3 protein was induced in BMMs cultured in the presence of M‐CSF and RANKL; moreover, expression of SLIT3 was greater in differentiated osteoclasts from Srgap2‐cKO mice compared to control (Fig.…”

Section: Resultsmentioning

confidence: 66%

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Rac1 Inhibition Via Srgap2 Restrains Inflammatory Osteoclastogenesis and Limits the Clastokine, SLIT3

Shin

Kupferman

Schmidt

et al. 2019

Journal of Bone and Mineral Research

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The Rac1‐specific guanosine triphosphatase (GTPase)‐activating protein Slit‐Robo GAP2 (Srgap2) is dramatically upregulated during RANKL‐induced osteoclastogenesis. Srgap2 interacts with the cell membrane to locally inhibit activity of Rac1. In this study, we determined the role of Srgap2 in the myeloid lineage on bone homeostasis and the osteoclastic response to TNFα treatment. The bone phenotype of mice specifically lacking Srgap2 in the myeloid lineage (Srgap2 f/f:LysM‐Cre; Srgap2 conditional knockout [cKO]) was investigated using histomorphometric analysis, in vitro cultures and Western blot analysis. Similar methods were used to determine the impact of TNFα challenge on osteoclast formation in Srgap2 cKO mice. Bone parameters in male Srgap2 cKO mice were unaffected. However, female cKO mice displayed higher trabecular bone volume due to increased osteoblast surface and bone formation rate, whereas osteoclastic parameters were unaltered. In vitro, cells from Srgap2 cKO had strongly enhanced Rac1 activation, but RANKL‐induced osteoclast formation was unaffected. In contrast, conditioned medium from Srgap2 cKO osteoclasts promoted osteoblast differentiation and had increased levels of the bone anabolic clastokine SLIT3, providing a possible mechanism for increased bone formation in vivo. Rac1 is rapidly activated by the inflammatory cytokine TNFα. Supracalvarial injection of TNFα caused an augmented osteoclastic response in Srgap2 cKO mice. In vitro, cells from Srgap2 cKO mice displayed increased osteoclast formation in response to TNFα. We conclude that Srgap2 plays a prominent role in limiting osteoclastogenesis during inflammation through Rac1, and restricts expression of the paracrine clastokine SLIT3, a positive regulator of bone formation. © 2019 American Society for Bone and Mineral Research.

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Section: Discussionsupporting

confidence: 91%

Section: Resultsmentioning

confidence: 66%

Rac1 Inhibition Via Srgap2 Restrains Inflammatory Osteoclastogenesis and Limits the Clastokine, SLIT3

Shin

Kupferman

Schmidt

et al. 2019

Journal of Bone and Mineral Research

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“…The related pathophysiological changes include cancer, cardiovascular diseases, neurological diseases, metabolic syndrome, and motor system diseases . Osteoporosis is a debilitating chronic bone disease accompanied by increased bone loss and a high risk of fracture and is the most common reason for fracture among the elderly . Currently, numerous drugs have been produced to treat osteoporosis by inhibiting bone resorption, although they offer few benefits to bone formation and fail to reverse bone loss .…”

Section: Mechanisms Underlying Melatonin's Action On Osteoporosismentioning

confidence: 99%

“…These networks promote downstream osteogenetic molecules (eg, ALP, BMP2, and osteoprotegerin) and osteolysis molecules (TNF-α, ROS, IL-1β, IL-6) the most common reason for fracture among the elderly. [49][50][51][52][53][54] Currently, numerous drugs have been produced to treat osteoporosis by inhibiting bone resorption, although they offer few benefits to bone formation and fail to reverse bone loss. 55 Moreover, conventional therapies have their own adverse effects, such as osteonecrosis, 56 atrial fibrillation, 57 esophageal cancer, 58 eczema, 59 cellulitis, 60 deep venous thrombosis, 33 and osteosarcoma, 61 all of which may contribute to a lack of compliance.…”

Section: Melatonin Maintains Metabolic Homeostasis In Bonementioning

confidence: 99%

Melatonin: Another avenue for treating osteoporosis?

Tian

Jiang

et al. 2019

Journal of Pineal Research

111

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Melatonin is a signal molecule that modulates the biological circadian rhythms of vertebrates. Melatonin deficiency is thought to be associated with several disorders, including insomnia, cancer, and cardiovascular and neurodegenerative diseases. Accumulating evidence has also indicated that melatonin may be involved in the homeostasis of bone metabolism. Age‐related reductions in melatonin are considered to be critical factors in bone loss and osteoporosis with aging. Thus, serum melatonin levels might serve as a biomarker for the early detection and prevention of osteoporosis. Compared to conventional antiosteoporosis medicines, which primarily inhibit bone loss, melatonin both suppresses bone loss and promotes new bone formation. Mechanistically, by activating melatonin receptor 2 (MT2), melatonin upregulates the gene expression of alkaline phosphatase (ALP), bone morphogenetic protein 2 (BMP2), BMP6, osteocalcin, and osteoprotegerin to promote osteogenesis while inhibiting the receptor activator of NF‐kB ligand (RANKL) pathway to suppress osteolysis. In view of the distinct actions of melatonin on bone metabolism, we hypothesize that melatonin may be a novel remedy for the prevention and clinical treatment of osteoporosis.

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“…Recently, researchers have identified a new type of vessel, termed type H vessels, which show strong expression of CD31 and endomucin (Emcn) in the endothelium . These vessels couple the opposing processes of bone absorption and formation . Although the relative abundance of these specific vessels is low, many osteoprogenitor cells are distributed around them .…”

Section: Introductionmentioning

confidence: 99%

Nuciferine prevents bone loss by disrupting multinucleated osteoclast formation and promoting type H vessel formation

et al. 2020

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Recently, type H vessels were reported to couple angiogenesis and osteogenesis during osteoclastogenesis, and tartrate‐resistant acid phosphatase (Trap)+ preosteoclasts were found to secrete increased PDGF‐BB to promote type H vessel formation. Therefore, utilization of type H vessels may be a strategy to treat diseases involving bone loss. In the present study, we found that nuciferine, a natural bioactive compound, has various effects, including inhibiting osteoclastogenesis and promoting type H vessel formation. Nuciferine inhibited osteoclastogenesis and bone resorption but increased the relative number of Trap+ preosteoclasts. Nuciferine restrained the expression of osteoclast‐specific genes and proteins, promoted PDGF‐BB production and potentiated related angiogenic activities by inhibiting the MAPK and NF‐κB signaling pathways in vitro. We confirmed the bone‐protective effects of nuciferine in ovariectomized mice and found that nuciferine treatment increased the PDGF‐BB concentration and the number of type H vessels in the femur. In conclusion, our results demonstrated that nuciferine can decrease multinucleated osteoclast formation and promote type H vessel formation through preservation of Trap+ preosteoclasts via inhibition of the MAPK and NF‐κB signaling pathways and may be an excellent agent for the treatment of diseases involving bone loss.

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Targeting skeletal endothelium to ameliorate bone loss

Cited by 263 publications

References 52 publications

Rac1 Inhibition Via Srgap2 Restrains Inflammatory Osteoclastogenesis and Limits the Clastokine, SLIT3

Rac1 Inhibition Via Srgap2 Restrains Inflammatory Osteoclastogenesis and Limits the Clastokine, SLIT3

Melatonin: Another avenue for treating osteoporosis?

Nuciferine prevents bone loss by disrupting multinucleated osteoclast formation and promoting type H vessel formation

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