Pathogenic variants in GNPTAB and GNPTG encoding distinct subunits of GlcNAc-1-phosphotransferase differentially impact bone resorption in patients with mucolipidosis type II and III

Abstract Purpose Pathogenic variants in GNPTAB and GNPTG, encoding different subunits of GlcNAc-1-phosphotransferase, cause mucolipidosis (ML) II, MLIII alpha/beta, and MLIII gamma. This study aimed to investigate the cellular and molecular bases underlying skeletal abnormalities in patients with MLII and MLIII. Methods We analyzed bone biopsies from patients with MLIII alpha/beta or MLIII gamma by undecalcified histology and histomorphometry. The skeletal status of Gnptgkoand Gnptab-deficient mice was determined and complemented by biochemical analysis of primary Gnptgko bone cells. The clinical relevance of the mouse data was underscored by systematic urinary collagen crosslinks quantification in patients with MLII, MLIII alpha/beta, and MLIII gamma. Results The analysis of iliac crest biopsies revealed that bone remodeling is impaired in patients with GNPTAB-associated MLIII alpha/beta but not with GNPTG-associated MLIII gamma. Opposed to Gnptab-deficient mice, skeletal remodeling is not affected in Gnptgko mice. Most importantly, patients with variants in GNPTAB but not in GNPTG exhibited increased bone resorption. Conclusion The gene-specific impact on bone remodeling in human individuals and in mice proposes distinct molecular functions of the GlcNAc-1-phosphotransferase subunits in bone cells. We therefore appeal for the necessity to classify MLIII based on genetic in addition to clinical criteria to ensure appropriate therapy.

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The Development of Molecular Biology of Osteoporosis

International Journal of Molecular Sciences ◽

10.3390/ijms22158182 ◽

2021 ◽

Vol 22 (15) ◽

pp. 8182

Author(s):

Yongguang Gao ◽

Suryaji Patil ◽

Jingxian Jia

Keyword(s):

Bone Resorption ◽

Molecular Biology ◽

Bone Formation ◽

Bone Mass ◽

Bone Remodeling ◽

Bone Cells ◽

Cell Activity ◽

Bone Cell ◽

Bone Disorders ◽

Molecular Aspects

Osteoporosis is one of the major bone disorders that affects both women and men, and causes bone deterioration and bone strength. Bone remodeling maintains bone mass and mineral homeostasis through the balanced action of osteoblasts and osteoclasts, which are responsible for bone formation and bone resorption, respectively. The imbalance in bone remodeling is known to be the main cause of osteoporosis. The imbalance can be the result of the action of various molecules produced by one bone cell that acts on other bone cells and influence cell activity. The understanding of the effect of these molecules on bone can help identify new targets and therapeutics to prevent and treat bone disorders. In this article, we have focused on molecules that are produced by osteoblasts, osteocytes, and osteoclasts and their mechanism of action on these cells. We have also summarized the different pharmacological osteoporosis treatments that target different molecular aspects of these bone cells to minimize osteoporosis.

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Biology of Bone Tissue: Structure, Function, and Factors That Influence Bone Cells

BioMed Research International ◽

10.1155/2015/421746 ◽

2015 ◽

Vol 2015 ◽

pp. 1-17 ◽

Cited By ~ 424

Author(s):

Rinaldo Florencio-Silva ◽

Gisela Rodrigues da Silva Sasso ◽

Estela Sasso-Cerri ◽

Manuel Jesus Simões ◽

Paulo Sérgio Cerri

Keyword(s):

Bone Resorption ◽

Bone Formation ◽

Bone Tissue ◽

Bone Remodeling ◽

Bone Cells ◽

Current Data ◽

Bone Diseases ◽

Bone Homeostasis ◽

Bone Biology ◽

Structure And Functions

Bone tissue is continuously remodeled through the concerted actions of bone cells, which include bone resorption by osteoclasts and bone formation by osteoblasts, whereas osteocytes act as mechanosensors and orchestrators of the bone remodeling process. This process is under the control of local (e.g., growth factors and cytokines) and systemic (e.g., calcitonin and estrogens) factors that all together contribute for bone homeostasis. An imbalance between bone resorption and formation can result in bone diseases including osteoporosis. Recently, it has been recognized that, during bone remodeling, there are an intricate communication among bone cells. For instance, the coupling from bone resorption to bone formation is achieved by interaction between osteoclasts and osteoblasts. Moreover, osteocytes produce factors that influence osteoblast and osteoclast activities, whereas osteocyte apoptosis is followed by osteoclastic bone resorption. The increasing knowledge about the structure and functions of bone cells contributed to a better understanding of bone biology. It has been suggested that there is a complex communication between bone cells and other organs, indicating the dynamic nature of bone tissue. In this review, we discuss the current data about the structure and functions of bone cells and the factors that influence bone remodeling.

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Communications Between Bone Marrow Macrophages and Bone Cells in Bone Remodeling

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2020.598263 ◽

2020 ◽

Vol 8 ◽

Author(s):

Kaixuan Chen ◽

Yurui Jiao ◽

Ling Liu ◽

Mei Huang ◽

Chen He ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Stem Cells ◽

Bone Marrow ◽

Bone Resorption ◽

Bone Remodeling ◽

Bone Cells ◽

Therapeutic Approaches ◽

Tightly Coupled ◽

Mensenchymal Stem Cells

The mammalian skeleton is a metabolically active organ that continuously undergoes bone remodeling, a process of tightly coupled bone resorption and formation throughout life. Recent studies have expanded our knowledge about the interactions between cells within bone marrow in bone remodeling. Macrophages resident in bone (BMMs) can regulate bone metabolism via secreting numbers of cytokines and exosomes. This review summarizes the current understanding of factors, exosomes, and hormones that involved in the communications between BMMs and other bone cells including mensenchymal stem cells, osteoblasts, osteocytes, and so on. We also discuss the role of BMMs and potential therapeutic approaches targeting BMMs in bone remodeling related diseases such as osteoporosis, osteoarthritis, rheumatoid arthritis, and osteosarcoma.

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Minireview: Osteoprotective Action of Estrogens Is Mediated by Osteoclastic Estrogen Receptor-α

Molecular Endocrinology ◽

10.1210/me.2009-0238 ◽

2010 ◽

Vol 24 (5) ◽

pp. 877-885 ◽

Cited By ~ 43

Author(s):

Yuuki Imai ◽

Shino Kondoh ◽

Alexander Kouzmenko ◽

Shigeaki Kato

Keyword(s):

Estrogen Receptor ◽

Bone Resorption ◽

Bone Remodeling ◽

Bone Cells ◽

Developed Countries ◽

Estrogen Deficiency ◽

Estrogen Signaling ◽

Estrogen Action ◽

Health Maintenance ◽

Enhanced Production

Abstract The osteoprotective action of estrogen in women has drawn considerable attention because estrogen deficiency-induced osteoporosis became one of the most widely spread diseases in developed countries. In men, the significance of estrogen action for bone health maintenance is also apparent from the osteoporotic phenotype seen in male patients with genetically impaired estrogen signaling. Severe bone loss and high bone turnover, including typical osteofeatures seen in postmenopausal women, can also be recapitulated in rodents after ovariectomy. However, the expected osteoporotic phenotype is not observed in female mice deficient in estrogen receptor (ER)-α or -β or both, even though the degenerative defects are clearly seen in other estrogen target tissues together with up-regulated levels of circulating testosterone. It has also been reported that estrogens may attenuate bone remodeling by cell autonomous suppressive effects on osteoblastogenesis and osteoclastogenesis. Hence, the effects of estrogens in bone appear to be complex, and the molecular role of bone estrogen receptors in osteoprotective estrogen action remains unclear. Instead, it has been proposed that estrogens indirectly control bone remodeling. For example, the enhanced production of cytokines under estrogen deficiency induces bone resorption through stimulation of osteoclastogenesis. However, the osteoporotic phenotype without systemic defects has been recapitulated in female (but not in male) mice by osteoclast-specific ablation of the ERα, proving that bone cells represent direct targets for estrogen action. An aberrant accumulation of mature osteoclasts in these female mutants indicates that in females, the inhibitory action of estrogens on bone resorption is mediated by the osteoclastic ERα through the shortened lifespan of osteoclasts.

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Identifying genes that regulate bone remodeling as potential therapeutic targets

Journal of Experimental Medicine ◽

10.1084/jem.20050354 ◽

2005 ◽

Vol 201 (6) ◽

pp. 841-843 ◽

Cited By ~ 43

Author(s):

Stephen M. Krane

Keyword(s):

Bone Resorption ◽

Bone Loss ◽

Bone Remodeling ◽

Osteoblast Differentiation ◽

Osteoclast Differentiation ◽

Protein Signaling ◽

Coupled Process ◽

Systemic Factors ◽

And Function ◽

Deficient Mice

Bone remodeling, a coupled process involving bone resorption and formation, is initiated by mechanical signals and is controlled by local and systemic factors that regulate osteoblast and osteoclast differentiation and function. An excess of resorption over formation leads to the bone loss and increased propensity to fracture that is characteristic of osteoporosis. A newly described inhibitor of osteoblast differentiation, Ciz, interferes with bone morphogenic protein signaling. As a consequence, Ciz-deficient mice develop increased bone mass.

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PERAN ESTROGEN PADA REMODELING TULANG

JURNAL BIOMEDIK (JBM) ◽

10.35790/jbm.4.3.2012.1210 ◽

2013 ◽

Vol 4 (3) ◽

Author(s):

Iknes Sihombing ◽

Sunny Wangko ◽

Sonny J.R. Kalangi

Keyword(s):

Vitamin D ◽

Hormone Replacement Therapy ◽

Bone Resorption ◽

Bone Remodeling ◽

Bone Cells ◽

Hormone Replacement ◽

Vitamine D ◽

Estrogen Action ◽

Slowing Down ◽

Fracture Risks

Abstract: Bone tissues experience continual regeneration of their extracellular components by overhauling the old components. This process is called bone remodeling, which involves several kinds of bone cells. The most important bone cells related to the bone remodeling are osteoblasts, osteocytes, and osteoclats. The bone remodeling is influenced by estrogen. This hormone inhibits bone resorption, resulting in slowing down the osteoporosis process. This antiresorptive effect can be provided also by the estrogen action on osteoblasts, which indirectly influences osteoclast activities. Estrogen has been proved to slow down the decrease of bone mass and fracture risks in women with osteoporosis. Hormone replacement therapy, aimed at replacing estrogen deficiency, consists of phytoestrogen and progesteron; besides that, calcium and vitamine D are needed, too. Keywords: estrogen, bone remodeling, osteoblast, osteocyte, osteoclast. Abstrak: Tulang merupakan jaringan yang terus menerus melakukan regenerasi komponen-komponen ekstrasel dengan cara menghancurkan komponen tulang yang sudah tua dan menggantikannya dengan yang baru. Proses ini disebut remodeling tulang, yang melibatkan kerja sel-sel tulang tertentu. Sel-sel dalam tulang yang terutama berhubungan dengan pembentukan dan resorpsi tulang ialah osteoblas, osteosit, dan osteoklas. Remodeling tulang dipengaruhi oleh hormon estrogen. Hormon ini menekan resorpsi tulang sehingga dapat menghambat proses kerapuhan tulang. Efek antiresorptif tersebut dapat pula dihasilkan melalui kerjanya pada osteoblas, yang secara tidak langsung mempengaruhi aktivitas osteoklas. Estrogen terbukti dapat mengurangi laju penurunan massa tulang dan risiko fraktur pada wanita dengan osteoporosis. Terapi sulih hormon yang digunakan untuk mengganti defisisensi estrogen ialah fitoestrogen, progesteron, selain itu juga kalsium dan vitamin D. Kata kunci: estrogen, remodeling tulang, osteoblas, osteosit, osteoklas.

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Diagnostic difficulties and possibilities of NF1-like syndromes in childhood

BMC Pediatrics ◽

10.1186/s12887-021-02791-0 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Eva Pinti ◽

Krisztina Nemeth ◽

Krisztina Staub ◽

Anna Lengyel ◽

Gyorgy Fekete ◽

...

Keyword(s):

Diagnostic Criteria ◽

Neurofibromatosis Type ◽

Early Years ◽

Diagnostic Efficiency ◽

Clinical Criteria ◽

Pathogenic Variants ◽

Clinical Diagnostic ◽

Long Time ◽

Diagnostic Difficulties ◽

Clinical Diagnostic Criteria

Abstract Background Neurofibromatosis type 1 (NF1), which is caused by heterozygous inactivating pathogenic variants in the NF1, has poor phenotypic expressivity in the early years of life and there are numerous conditions, including many other tumor predisposition syndromes, that can mimic its appearance. These are collectively termed NF1-like syndromes and are also connected by their genetic background. Therefore, the NF1’s clinical diagnostic efficiency in childhood could be difficult and commonly should be completed with genetic testing. Methods To estimate the number of syndromes/conditions that could mimic NF1, we compiled them through an extensive search of the scientific literature. To test the utility of NF1’s National Institutes of Health (NIH) clinical diagnostic criteria, which have been in use for a long time, we analyzed the data of a 40-member pediatric cohort with symptoms of the NF1-like syndromes’ overlapping phenotype and performed NF1 genetic test, and established the average age when diagnostic suspicion arises. To facilitate timely identification, we compiled strongly suggestive phenotypic features and anamnestic data. Results In our cohort the utility of NF1’s clinical diagnostic criteria were very limited (sensitivity: 80%, specificity: 30%). Only 53% of children with clinically diagnosed NF1 had a detectable NF1 pathogenic variation, whereas 40% of patients without fulfilled clinical criteria tested positive. The average age at first genetic counseling was 9 years, and 40% of children were referred after at least one tumor had already been diagnosed. These results highlight the need to improve NF1-like syndromes’ diagnostic efficiency in childhood. We collected the most extensive spectrum of NF1-like syndromes to help the physicians in differential diagnosis. We recommend the detailed, non-invasive clinical evaluation of patients before referring them to a clinical geneticist. Conclusions Early diagnosis of NF1-like syndromes can help to prevent severe complications by appropriate monitoring and management. We propose a potential screening, diagnostic and management strategy based on our findings and recent scientific knowledge.

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Renal Proximal Tubule Cell Cannabinoid-1 Receptor Regulates Bone Remodeling and Mass via a Kidney-to-Bone Axis

Cells ◽

10.3390/cells10020414 ◽

2021 ◽

Vol 10 (2) ◽

pp. 414

Author(s):

Saja Baraghithy ◽

Yael Soae ◽

Dekel Assaf ◽

Liad Hinden ◽

Shiran Udi ◽

...

Keyword(s):

Bone Mass ◽

Proximal Tubule ◽

Bone Remodeling ◽

Kidney Function ◽

Bone Cells ◽

Critical Role ◽

Renal Proximal Tubule ◽

Proximal Tubule Cell ◽

Protective Effects ◽

Cannabinoid 1 Receptor

The renal proximal tubule cells (RPTCs), well-known for maintaining glucose and mineral homeostasis, play a critical role in the regulation of kidney function and bone remodeling. Deterioration in RPTC function may therefore lead to the development of diabetic kidney disease (DKD) and osteoporosis. Previously, we have shown that the cannabinoid-1 receptor (CB1R) modulates both kidney function as well as bone remodeling and mass via its direct role in RPTCs and bone cells, respectively. Here we employed genetic and pharmacological approaches that target CB1R, and found that its specific nullification in RPTCs preserves bone mass and remodeling both under normo- and hyper-glycemic conditions, and that its chronic blockade prevents the development of diabetes-induced bone loss. These protective effects of negatively targeting CB1R specifically in RPTCs were associated with its ability to modulate erythropoietin (EPO) synthesis, a hormone known to affect bone mass and remodeling. Our findings highlight a novel molecular mechanism by which CB1R in RPTCs remotely regulates skeletal homeostasis via a kidney-to-bone axis that involves EPO.

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Estrogen Decreases Cytoskeletal Organization by Forming an ERα/SHP2/c-Src Complex in Osteoclasts to Protect against Ovariectomy-Induced Bone Loss in Mice

Antioxidants ◽

10.3390/antiox10040619 ◽

2021 ◽

Vol 10 (4) ◽

pp. 619

Author(s):

Hyun-Jung Park ◽

Malihatosadat Gholam-Zadeh ◽

Sun-Young Yoon ◽

Jae-Hee Suh ◽

Hye-Seon Choi

Keyword(s):

Bone Resorption ◽

Bone Loss ◽

Ring Formation ◽

Tartrate Resistant Acid Phosphatase ◽

Actin Ring ◽

Collagen Crosslinks ◽

Trap Staining ◽

Src Activation

Loss of ovarian function is closely related to estrogen (E2) deficiency, which is responsible for increased osteoclast (OC) differentiation and activity. We aimed to investigate the action mechanism of E2 to decrease bone resorption in OCs to protect from ovariectomy (OVX)-induced bone loss in mice. In vivo, tartrate-resistant acid phosphatase (TRAP) staining in femur and serum carboxy-terminal collagen crosslinks-1 (CTX-1) were analyzed upon E2 injection after OVX in mice. In vitro, OCs were analyzed by TRAP staining, actin ring formation, carboxymethylation, determination of reactive oxygen species (ROS) level, and immunoprecipitation coupled with Western blot. In vivo and in vitro, E2 decreased OC size more dramatically than OC number and Methyl-piperidino-pyrazole hydrate dihydrochloride (MPPD), an estrogen receptor alpha (ERα) antagonist, augmented the OC size. ERα was found in plasma membranes and E2/ERα signaling affected receptor activator of nuclear factor κB ligand (RANKL)-induced actin ring formation by rapidly decreasing a proto-oncogene tyrosine-protein kinase, cellular sarcoma (c-Src) (Y416) phosphorylation in OCs. E2 exposure decreased physical interactions between NADPH oxidase 1 (NOX1) and the oxidized form of c-Src homology 2 (SH2)-containing protein tyrosine phosphatase 2 (SHP2), leading to higher levels of reduced SHP2. ERα formed a complex with the reduced form of SHP2 and c-Src to decrease c-Src activation upon E2 exposure, which blocked a signal for actin ring formation by decreased Vav guanine nucleotide exchange factor 3 (Vav3) (p–Y) and Ras-related C3 botulinum toxin substrate 1 (Rac1) (GTP) activation in OCs. E2/ERα signals consistently inhibited bone resorption in vitro. In conclusion, our study suggests that E2-binding to ERα forms a complex with SHP2/c-Src to attenuate c-Src activation that was induced upon RANKL stimulation in a non-genomic manner, resulting in an impaired actin ring formation and reducing bone resorption.

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