Hippuric acid and 3‐(3‐hydroxyphenyl) propionic acid inhibit murine osteoclastogenesis through RANKL‐RANK independent pathway

Zhao, Hongyan; Lazarenko, Oxana P.; Chen, Jin‐Ran

doi:10.1002/jcp.28998

Cited by 22 publications

(21 citation statements)

References 40 publications

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“…We treated RAW 264.7 cells under osteoclast differentiation condition with serum collected from LLC-bearing mice and tumor-free control mice. ( Figure 3 g) [ 49 ]. We then determined the expression level of nuclear factor-activated T cells c1 (NFATc1), a master regulator of osteoclast differentiation [ 50 ], and cathepsin K (CTSK), a phenotypic marker of osteoclast [ 51 ].…”

Section: Resultsmentioning

confidence: 99%

Bone Marrow Homeostasis Is Impaired via JAK/STAT and Glucocorticoid Signaling in Cancer Cachexia Model

Choi

Park

et al. 2021

Cancers

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Cancer cachexia is a multifactorial systemic inflammation disease caused by complex interactions between the tumor and host tissues via soluble factors. However, whether cancer cachexia affects the bone marrow, in particular the hematopoietic stem cells (HSCs) and mesenchymal stem cells (MSCs), remains unclear. Here, we investigated the bone marrow and bone in a cancer cachexia animal model generated by transplanting Lewis lung carcinoma cells. The number of bone marrow mononuclear cells (BM-MNCs) started to significantly decrease in the cancer cachectic animal model prior to the discernable loss of muscle and fat. This decrease in BM-MNCs was associated with myeloid skewing in the circulation and the expansion of hematopoietic progenitors in the bone marrow. Bone loss occurred in the cancer cachexia animal model and accompanied the decrease in the bone marrow MSCs that play important roles in both supporting HSCs and maintaining bone homeostasis. Glucocorticoid signaling mediated the decrease in bone marrow MSCs in the cancer cachectic environment. The cancer cachexia environment also skewed the differentiation of the bone marrow MSCs toward adipogenic fate via JAK/STAT as well as glucocorticoid signaling. Our results suggest that the bone loss induced in cancer cachexia is associated with the depletion and the impaired differentiation capacity of the bone marrow MSCs.

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Section: Resultsmentioning

confidence: 99%

Bone Marrow Homeostasis Is Impaired via JAK/STAT and Glucocorticoid Signaling in Cancer Cachexia Model

Choi

Park

et al. 2021

Cancers

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“…We have recently reported an in vitro study suggested that HA and 3-3-PPA inhibit osteoclastogenesis and bone resorption through suppressing GPR109A in pre-osteoclasts 15 . To further search possible membrane GPR109A-mediated actions of HA and 3-3-PPA on inhibition of osteoclastogenesis, we performed an in ex vivo study.…”

Section: Resultsmentioning

confidence: 99%

“…Considering the apparent interactions of diet-derived phenolics and GPR109A on osteoclast function in cell models 15 , we fed BB and HA supplemented diets to male wild type and GPR109A −/− mice for 40 days. Micro-CT determined that bone volume per total tissue volume and trabecular number were significantly higher in GPR109A −/− mice compared with age-matched wild type mice (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…For instance, GPR109A is expressed in murine osteoclasts ( http://biogps.org/#goto=genereport&id=338442 ) and can be induced significantly by inflammatory insults in murine osteoclast precursor bone marrow macrophages. From our previous studies using cell models in which GPR109A expression was modulated 14 , 15 , we have provided evidence that GPR109A plays a role on bone forming cell differentiation. However, until now, the role of GPR109A on osteoclast activity, differentiation and bone resorption in vivo has not been determined.…”

Section: Introductionmentioning

confidence: 84%

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GPR109A mediates the effects of hippuric acid on regulating osteoclastogenesis and bone resorption in mice

et al. 2021

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The G protein-coupled receptor 109 A (GPR109A) is robustly expressed in osteoclastic precursor macrophages. Previous studies suggested that GPR109A mediates effects of diet-derived phenolic acids such as hippuric acid (HA) and 3-(3-hydroxyphenyl) propionic acid (3-3-PPA) on promoting bone formation. However, the role of GPR109A in metabolic bone homeostasis and osteoclast differentiation has not been investigated. Using densitometric, bone histologic and molecular signaling analytic methods, we uncovered that bone mass and strength were significantly higher in tibia and spine of standard rodent diet weaned 4-week-old and 6-month-old GPR109A gene deletion (GPR109A−/−) mice, compared to their wild type controls. Osteoclast numbers in bone and in ex vivo bone marrow cell cultures were significantly decreased in GPR109A−/− mice compared to wild type controls. In accordance with these data, CTX-1 in bone marrow plasma and gene expression of bone resorption markers (TNFα, TRAP, Cathepsin K) were significantly decreased in GPR109A−/− mice, while on the other hand, P1NP was increased in serum from both male and female GPR109A−/− mice compared to their respective controls. GPR109A deletion led to suppressed Wnt/β-catenin signaling in osteoclast precursors to inhibit osteoclast differentiation and activity. Indeed, HA and 3-3-PPA substantially inhibited RANKL-induced GPR109A expression and Wnt/β-catenin signaling in osteoclast precursors and osteoclast differentiation. Resultantly, HA significantly inhibited bone resorption and increased bone mass in wild type mice, but had no additional effects on bone in GPR109A−/− mice compared with their respective untreated control mice. These results suggest an important role for GPR109A during osteoclast differentiation and bone resorption mediating effects of HA and 3-3-PPA on inhibiting bone resorption during skeletal development.

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“…Another half of the hematopoietic nonadherent bone marrow cells were cultured in 96‐well plates (2 × 10 4 cells/well) in the presence of 30 ng/ml of RANKL. As we described previously, ( 37 ) after 5 days for nonadherent bone marrow cell cultures, the cells were fixed with 4% paraformaldehyde and stained for TRAPase activity using a TRAPase staining kit according to the manufacturer's protocols (acid phosphatase leukocyte, procedure No. 386; Sigma‐Aldrich).…”

Section: Methodsmentioning

confidence: 99%

Short‐Term Increased Physical Activity During Early Life Affects High‐Fat Diet–Induced Bone Loss in Young Adult Mice

et al. 2021

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Mechanical stresses associated with physical activity (PA) have beneficial effects on increasing BMD and improving bone quality. However, a high‐fat diet (HFD) and obesity tend to have negative effects on bone, by increasing bone marrow adiposity leading to increased excretion of proinflammatory cytokines, which activate RANKL‐induced bone resorption. In the current study, whether short‐term increased PA via access to voluntary wheel running during early life has persistent and protective effects on HFD‐induced bone resorption was investigated. Sixty 4‐week‐old male C57BL6/J mice were divided into two groups postweaning: without or with PA (access to voluntary running wheel 7–8 km/day) for 4 weeks. After 4 weeks with or without PA, mice were further subdivided into control diet or HFD groups for 8 weeks, and then all animals were switched back to control diet for an additional 4 weeks. Mice from the HFD groups were significantly heavier and obese; however, after 4 weeks of additional control diet their body weights returned to levels of mice on continuous control diet. Using μ‐CT and confirmed by pQCT of tibias and spines ex vivo, it was determined that bone volume and trabecular BMD were significantly increased with PA in control diet animals compared with sedentary animals without access to wheels, and such anabolic effects of PA on bone were sustained after ceasing PA in adult mice. Eight weeks of a HFD deteriorated bone development in mice. Unexpectedly, early‐life PA did not prevent persistent effects of HFD on deteriorating bone quality; in fact, it exacerbated a HFD‐induced inflammation, osteoclastogenesis, and trabecular bone loss in adult mice. In accordance with these data, signal transduction studies revealed that a HFD‐induced Ezh2, DNA methyltransferase 3a, and nuclear factor of activated T‐cells 1 expression were amplified in nonadherent hematopoietic cells. In conclusion, short‐term increased PA in early life is capable of increasing bone mass; however, it alters the HFD‐induced bone marrow hematopoietic cell‐differentiation program to exacerbate increased bone resorption if PA is halted. © 2021 Arkansas Children's Nutrition Center. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

show abstract

Hippuric acid and 3‐(3‐hydroxyphenyl) propionic acid inhibit murine osteoclastogenesis through RANKL‐RANK independent pathway

Cited by 22 publications

References 40 publications

Bone Marrow Homeostasis Is Impaired via JAK/STAT and Glucocorticoid Signaling in Cancer Cachexia Model

Bone Marrow Homeostasis Is Impaired via JAK/STAT and Glucocorticoid Signaling in Cancer Cachexia Model

GPR109A mediates the effects of hippuric acid on regulating osteoclastogenesis and bone resorption in mice

Short‐Term Increased Physical Activity During Early Life Affects High‐Fat Diet–Induced Bone Loss in Young Adult Mice

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