In vitro osteoclastogenesis from Gaucher patients' cells correlates with bone mineral density but not with Chitotriosidase

Bondar, Constanza; Mucci, Juan Marcos; Crivaro, Andrea; Ormazabal, Maximiliano; Ceci, Romina; Oliveri, Beatriz; González, Diana; Rozenfeld, Paula

doi:10.1016/j.bone.2017.07.020

Cited by 10 publications

(12 citation statements)

References 39 publications

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“…We used α‐MEM and 10% FBS to culture RAW264.7 cells. Human peripheral blood mononuclear cells (PBMCs) were isolated from the peripheral blood from healthy volunteers as described, and the cells were cultured with α‐MEM containing 10% FBS, 50 ng/mL RANKL, and 30 ng/mL M‐CSF. To investigate the effects of JWH133 on osteoclast differentiation, PBMCs, BMMs or RAW264.7 cells were stimulated with RANKL with or without JWH133 (1µM).…”

Section: Methodsmentioning

confidence: 99%

Cannabinoid Receptor 2 Agonist Prevents Local and Systemic Inflammatory Bone Destruction in Rheumatoid Arthritis

Zhu

Bai

et al. 2018

Journal of Bone and Mineral Research

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Cannabinoid receptor 2 (CB2) has been implicated as an important clinical regulator of inflammation and malignant osteolysis. Here, we observed that CB2 expression was markedly higher in the collagen‐induced arthritis (CIA) mice synovium and bone tissues than in the noninflamed synovium and bone tissues. The CB2 selective agonist (JWH133) but not antagonist (SR144528) suppressed CIA in mice without toxic effects, as demonstrated by the decreased synovial hyperplasia, inflammatory responses, cartilage damage, and periarticular and systemic bone destruction. JWH133 treatment decreased the infiltration of pro‐inflammatory M1‐like macrophages and repolarized macrophages from the M1 to M2 phenotype. Similarly, activation of CB2 increased the expression of anti‐inflammatory cytokine interleukin (IL)‐10 and reduced the expression of pro‐inflammatory cytokines, including tumor necrosis factor‐α (TNF‐α), IL‐1β, and IL‐6. In addition, JWH133 treatment attenuated osteoclast formation and osteoclastic bone resorption, and reduced the expression of receptor activators of the nuclear factor‐κB (NF‐κB) ligand (RANKL), matrix metallopeptidase‐9 (MMP‐9), tartrate‐resistant acid phosphatase (TRAP), cathepsin K (CTSK), and nuclear factor of activated T‐cells 1 (NFAT‐1) in CIA mice and osteoclast precursors, which were obviously blocked by pretreatment with SR144528. Mechanistically, JWH133 inhibited RANKL‐induced NF‐κB activation in the osteoclast precursors. We found that JWH133 ameliorates pathologic bone destruction in CIA mice via the inhibition of osteoclastogenesis and modulation of inflammatory responses, thereby highlighting its potential as a treatment for human rheumatoid arthritis. © 2018 American Society for Bone and Mineral Research.

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Section: Methodsmentioning

confidence: 99%

Cannabinoid Receptor 2 Agonist Prevents Local and Systemic Inflammatory Bone Destruction in Rheumatoid Arthritis

Zhu

Bai

et al. 2018

Journal of Bone and Mineral Research

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“…Later on, the same authors proposed that the extralysosomal glucocerebrosidase GBA2 transformed the increased levels in serum of GlcCer and, mainly, GlcSph in sphingosine, which inhibited osteoblast survival . Despite this previous evidence, other studies confirmed a correlation between bone features and the osteoclast number in GD …”

Section: Gaucher Diseasementioning

confidence: 98%

Bone development and remodeling in metabolic disorders

Serra-Vinardell

Roca-Ayats

De-Ugarte

et al. 2019

J of Inher Metab Disea

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There are many metabolic disorders that present with bone phenotypes. In some cases, the pathological bone symptoms are the main features of the disease whereas in others they are a secondary characteristic. In general, the generation of the bone problems in these disorders is not well understood and the therapeutic options for them are scarce. Bone development occurs in the early stages of embryonic development where the bone formation, or osteogenesis, takes place. This osteogenesis can be produced through the direct transformation of the pre‐existing mesenchymal cells into bone tissue (intramembranous ossification) or by the replacement of the cartilage by bone (endochondral ossification). In contrast, bone remodeling takes place during the bone's growth, after the bone development, and continues throughout the whole life. The remodeling involves the removal of mineralized bone by osteoclasts followed by the formation of bone matrix by the osteoblasts, which subsequently becomes mineralized. In some metabolic diseases, bone pathological features are associated with bone development problems but in others they are associated with bone remodeling. Here, we describe three examples of impaired bone development or remodeling in metabolic diseases, including work by others and the results from our research. In particular, we will focus on hereditary multiple exostosis (or osteochondromatosis), Gaucher disease, and the susceptibility to atypical femoral fracture in patients treated with bisphosphonates for several years.

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“…[14][15][16] The role of GlcCer has been suggested in metabolic disorders, such as obesity and insulin resistance. 19,20 Although osteoclast malfunctions in impaired bone remodeling in GD have been suggested as a cause due to the presence of Gaucher cells, osteoblast dysfunction has been reported to be important in the bone diseases of GD. GD has various symptoms, including hepatomegaly, splenomegaly, and bone defects.…”

Section: Introductionmentioning

confidence: 99%

Glucosylceramide synthase regulates adipo‐osteogenic differentiation through synergistic activation of PPARγ with GlcCer

et al. 2019

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Abbreviations: A/B, N-terminal regulatory domain; AIM, adipogenic induction medium; ALP, alkaline phosphatase; AMP-DNM, N-(5-adamantane-1-ylmethoxy-pentyl)-deoxynojirimycin; aP2, adipocyte protein 2; ATF2, activating transcription factor 2; BMP2, bone morphogenetic protein 2; BV, bone volume; C/EBPα, CCAAT-enhancer binding protein α AbstractDysregulation of the adipo-osteogenic differentiation balance of mesenchymal stem cells (MSCs), which are common progenitor cells of adipocytes and osteoblasts, has been associated with many pathophysiologic diseases, such as obesity, osteopenia, and osteoporosis. Growing evidence suggests that lipid metabolism is crucial for maintaining stem cell homeostasis and cell differentiation; however, the detailed underlying mechanisms are largely unknown. Here, we demonstrate that glucosylceramide (GlcCer) and its synthase, glucosylceramide synthase (GCS), are key determinants of MSC differentiation into adipocytes or osteoblasts. GCS expression was increased during adipogenesis and decreased during osteogenesis. Targeting GCS using RNA interference or a chemical inhibitor enhanced osteogenesis and inhibited adipogenesis by controlling the transcriptional activity of peroxisome proliferator-activated receptor γ (PPARγ). Treatment with GlcCer sufficiently rescued adipogenesis and inhibited osteogenesis in GCS knockdown MSCs. Mechanistically, GlcCer interacted directly with PPARγ through A/B domain and synergistically enhanced rosiglitazone-induced PPARγ activation without changing PPARγ expression, thereby treatment with exogenous GlcCer increased adipogenesis and inhibited osteogenesis. Animal studies demonstrated that inhibiting GCS reduced adipocyte formation in white adipose tissues under normal chow diet and high-fat diet feeding and accelerated bone repair in a calvarial defect model. Taken together, our findings identify a novel lipid metabolic regulator for the control of MSC differentiation and may have important therapeutic implications.

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In vitro osteoclastogenesis from Gaucher patients' cells correlates with bone mineral density but not with Chitotriosidase

Cited by 10 publications

References 39 publications

Cannabinoid Receptor 2 Agonist Prevents Local and Systemic Inflammatory Bone Destruction in Rheumatoid Arthritis

Cannabinoid Receptor 2 Agonist Prevents Local and Systemic Inflammatory Bone Destruction in Rheumatoid Arthritis

Bone development and remodeling in metabolic disorders

Glucosylceramide synthase regulates adipo‐osteogenic differentiation through synergistic activation of PPARγ with GlcCer

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