Regulation Of Bone Resorption Research Articles

Ubiquitin-specific peptidases: Players in bone metabolism.

Osteoporosis is an ageing-related disease, that has become a major public health problem and its pathogenesis has not yet been fully elucidated. Substantial evidence suggests a strong link between overall age-related disease progression and epigenetic modifications throughout the life cycle. As an important epigenetic modification, ubiquitination is extensively involved in various physiological processes, and its role in bone metabolism has attracted increasing attention. Ubiquitination can be reversed by deubiquitinases, which counteract protein ubiquitination degradation. As the largest and most structurally diverse cysteinase family of deubiquitinating enzymes, ubiquitin-specific proteases (USPs), comprising the largest and most structurally diverse cysteine kinase family of deubiquitinating enzymes, have been found to be important players in maintaining the balance between bone formation and resorption. The aim of this review is to explore recent findings highlighting the regulatory functions of USPs in bone metabolism and provide insight into the molecular mechanisms governing their actions during bone loss. An in-deep understanding of USPs-mediated regulation of bone formation and bone resorption will provide a scientific rationale for the discovery and development of novel USP-targeted therapeutic strategies for osteoporosis.

Effect of T cells on bone.

Bone and immune systems mutually influence each other by sharing a variety of regulatory molecules and the tissue microenvironment. The interdisciplinary research field "osteoimmunology" has illuminated the complex and dynamic interactions between the two systems in the maintenance of tissue homeostasis as well as in the development of immune and skeletal disorders. T cells play a central role in the immune response by secreting various immune factors and stimulating other immune cells and structural cells such as fibroblasts and epithelial cells, thereby contributing to pathogen elimination and pathogenesis of immune diseases. The finding on regulation of osteoclastic bone resorption by activated CD4+ T cells in rheumatoid arthritis was one of the driving forces for the development of osteoimmunology. With advances in research on helper T cell subsets and rare lymphoid cells such as γδ T cells in the immunology field, it is becoming clear that various types of T cells exert multiple effects on bone metabolism depending on immune context. Understanding the diverse effects of T cells on bone is essential for deciphering the osteoimmune regulatory network in various biological settings.

HBP/O-GlcNAcylation Metabolic Axis Regulates Bone Resorption Outcome

Osteoclasts play a key role in the regulation of bone mass and are highly active metabolically. Here we show that a metabolic reprogramming toward the hexosamine biosynthetic pathway (HBP) is required not only for osteoclast differentiation but also to determine the bone resorption mode during physiological and pathological bone remodeling. We found that pharmacological inhibition of O-GlcNAc transferase (OGT) significantly reduced protein O-GlcNAcylation and osteoclast differentiation. Accordingly, genetic deletion of OGT also inhibited osteoclast formation and downregulated critical markers related to osteoclasts differentiation and function (NFATc1, αvintegrin, cathepsin K). Indeed, cells treated with OSMI-1, an OGT inhibitor, also reduced nuclear translocation of NFATc1. Furthermore, the addition of exogenous N-acetylglucosamine (GlcNAc) strongly increased osteoclast formation and demineralization ability. Strikingly, our data show for the first time that O-GlcNAcylation facilitates an aggressive trench resorption mode in human cells. The incubation of osteoclasts with exogenous GlcNAc increases the percentage of erosion by trench while having no effect on pit resorption mode. Through time-lapse recording, we documented that osteoclasts making trenches moving across the bone surface are sensitive to GlcNAcylation. Finally, osteoclast-specific Ogt-deficient mice show increased bone density and reduced inflammation-induced bone loss during apical periodontitis model. We show that osteoclast-specific Ogt-deficient mice are less susceptible to develop bacterial-induced periapical lesion. Consistent with this, Ogt-deleted mice showed a decreased number of tartrate-resistant acid phosphatase-positive cells lining the apical periodontitis site. In summary, here we describe a hitherto undiscovered role of the HBP/O-GlcNAcylation axis tuning resorption mode and dictating bone resorption outcome.

Fatty Acid Excess Increases Lipid Droplet Size and Modifies Gene Expression in Osteocytes

The relationship between obesity and bone remains controversial, although recent studies suggest that obesity can confer an increased risk of osteoporosis resulting in bone fractures in skeletal sites such as the wrist. Osteocytes are the most numerous bone cells functioning as key regulators of bone formation, resorption, and renal phosphate homeostasis; therefore, they likely play an important role in obesity-induced skeletal pathology. Cells exposed to excess free fatty acids (FA) in obesity strive to detoxify the cytotoxic free FA by taking up and storing free FA into lipid droplets (LD). It is unknown how osteocytes respond to FA and how this would affect their functions.
 In this study, we assessed the effects of FA overload on osteocytes using two cell lines, MLO-Y4 and IDG-SW3. We hypothesized that normal osteocyte energy metabolism is disrupted by excess FA, resulting in increased lipid storage and abnormal osteocyte function. To study this, MLO-Y4 cells were treated with palmitate to induce LD accumulation, and then stained to quantify LD. To determine palmitate’s effects on osteocyte function, we performed qPCR analysis for lipid accumulation genes and osteocyte markers. To examine LD formation in IDG-SW3 mature osteocytes, LipidSpot fluorescent staining was performed; preliminary observations show LD accumulation.
 Using this in vitro system, MLO-Y4 cells under fatty acid overload demonstrated a greater percent area and size of LDs. RT-qPCR analysis showed an increase in lipid storage genes, Dgat2 (1.5- fold, p<0.001) and Cidec (4-fold, p<0.05). Opg, an inhibitor of osteoclast differentiation, was decreased (0.75-fold, p<0.01), whereas there was no change in Rankl, an inducer of osteoclast differentiation. Dmp1, an early osteocyte marker which plays a role in matrix mineralization, was increased (2-fold, p<0.05). This indicates that FA most likely disrupts osteocyte metabolism through increased lipid storage, which may alter osteocyte function to promote osteoclast activity leading to bone loss.

A Novel Prenylflavonoid Icariside I Ameliorates Estrogen Deficiency-Induced Osteoporosis via Simultaneous Regulation of Osteoblast and Osteoclast Differentiation.

Regulation of osteoblast-mediated bone formation and osteoclast-mediated bone resorption is crucial for bone health. Currently, most clinical drugs for osteoporosis treatment such as bisphosphonates are commonly used to inhibit bone resorption but unable to promote bone formation. In this study, we discovered for the first time that icariside I (GH01), a novel prenylflavonoid isolated from Epimedium, can effectively ameliorate estrogen deficiency-induced osteoporosis with enhancement of trabecular and cortical bone in an ovariectomy (OVX) mouse model. Mechanistically, our in vitro results showed that GH01 repressed osteoclast differentiation and resorption through inhibition of RANKL-induced TRAF6-MAPK-p38-NFATc1 cascade. Simultaneously, we also found that GH01 dose-dependently promoted osteoblast differentiation and formation by inhibiting adipogenesis and accelerating energy metabolism of osteoblasts. In addition, both in vitro and in vivo studies also suggested that GH01 is not only a non-toxic natural small molecule but also beneficial for restoration of liver injury in OVX mice. These results demonstrated that GH01 has great potential for osteoporosis treatment by simultaneous regulation of osteoblast and osteoclast differentiation.

Nano-formulations for bone-specific delivery of siRNA for CrkII silencing-induced regulation of bone formation and resorption to maximize therapeutic potential for bone-related diseases.

CrkII, a member of the adaptor protein family, is known to participate in bone homeostasis via the regulation of osteoclasts and osteoblasts. Therefore, silencing CrkII would beneficially impact the bone microenvironment. In this study, CrkII siRNA encapsulated by a bone-targeting peptide (AspSerSer)6-liposome was evaluated for its therapeutic applications using a receptor activator of nuclear factor kappa-B ligand (RANKL)-induced bone loss model. (AspSerSer)6-liposome-siCrkII maintained its gene-silencing ability in both osteoclasts and osteoblasts in vitro and significantly reduced osteoclast formation while increasing osteoblast differentiation in vitro. Fluorescence image analyses showed that the (AspSerSer)6-liposome-siCrkII was present largely in bone, where it remained present for up to 24 hours and was cleared by 48 hours, even when systemically administrated. Importantly, microcomputed-tomography revealed that bone loss induced by RANKL administration was recovered by systemic administration of (AspSerSer)6-liposome-siCrkII. Collectively, the findings of this study suggest that (AspSerSer)6-liposome-siCrkII is a promising therapeutic strategy for the development of treatments for bone diseases, as it overcomes the adverse effects derived from ubiquitous expression via bone-specific delivery of siRNA.

Oral Administration of Mice with Cell Extracts of Recombinant Lactococcus lactis IL1403 Expressing Mouse Receptor Activator of NF-kB Ligand (RANKL).

Receptor activator of NF-kB ligand (RANKL) is known to play a major role in bone metabolism and the immune system, and its recombinant form has been expressed in bacterial systems for research since the last two decades. However, most of these recombinant forms are used after purification or directly using living cells. Here, there were cell extracts of recombinant Lactococcus lactis expressing mouse RANKL (mRANKL) used to evaluate its biological activity in mice. Mice were divided into three groups that were fed phosphate-buffered saline (PBS), wild-type L. lactis IL1403 (WT_CE), and recombinant L. lactis expressing mRANKL (mRANKL_CE). The small intestinal transcriptome and fecal microbiome were then profiled. The biological activity of mRANKL_CE was confirmed by studying RANK-RANKL signaling in vitro and in vivo. For small intestinal transcriptome, differentially expressed genes (DEGs) were identified in the mRANKL_CE group, and no DEGs were found in the WT_CE group. In the PBS vs. mRANKL_CE gene enrichment analysis, upregulated genes were enriched for heat shock protein binding, regulation of bone resorption, and calcium ion binding. In the gut microbiome analysis, there were no critical changes among the three groups. However, Lactobacillus and Sphingomonas were more abundant in the mRANKL_CE group than in the other two groups. Our results indicate that cell extracts of mRANKL_CE can play an effective role without a significant impact on the intestine. This strategy may be useful for the development of protein drugs.

ODP599 Modulation of Wnt/b-catenin and Autophagy in an in vitro Model of Glucocorticoid-induced Osteoporosis

Abstract Background During bone aging and osteoporosis, formation and resorption are not tightly coupled; the main cells involved in bone remodeling are osteoblasts and osteoclast but also osteocytes play a pivotal role in this process. Osteocytes are the most abundant cell type in bone and are mainly responsible for sensing mechanical signals on the bones, controlling osteoblast and osteoclast activities through cell-to-cell communication and via secreted factors. In particular, osteocytes regulate bone resorption, thanks to the production of RANKL, reducing osteoclast activity. Ellagic acid, a natural polyphenolic compound derived from pomegranate, could modulate cell function via specific estrogen receptor b; activation of ERb plays a critical role in bone remodeling suppressing osteoclast differentiation and function, promoting osteoblast proliferation through the Wnt/b-catenin pathway, increasing osteoprotegerin levels. In addition, stimulation of ERb plays an anti-inflammatory effect, increasing the expression of IL-10 and reducing the expression of proinflammatory cytokines, such as IL-1β and TNF-α, and can regulate the expression of autophagy inhibiting the PI3K/Akt/mTOR pathway. The hypothesis here tested is that ellagic acid, through ERb modulation, could induce Wnt/b-catenin and autophagy pathways in osteocytes challenged with dexamethasone to mimic glucocorticoid-induced osteoporosis. Materials and methods The osteocyte cells MLO-A5 were differentiated into osteocytes under appropriate culturing conditions. Cells were treated with Ellagic acid (1µM) following dexamethasone (1µM) challenge for 24h to induce an in vitro model of osteoporosis. At the end of the treatment period, cell viability was evaluated by MTT assay; qPCR was performed to evaluate the expression of the genes involved in osteocyte function (SOST, RANKL, Destrin and Dmp1) and Wnt/B-catenin signaling pathway (Wnt5a, Wnt10b, B-Catenin and DKK1); Western Blot was performed to evaluate the expression of proteins involved in apoptosis (cleaved-Caspase3) and autophagy (Beclin-1, LC3 and p62). In addition, the expression of Sclerostin and nuclear translocation of B-Catenin was evaluated by immunofluorescence. Results Ellagic acid reduced the gene expression of SOST, RANKL, Dmp1 and increased the expression of Destrin compared to untreated cells stimulated with dexamethasone; caused a significant increase of Wnt5a, Wnt10b and B-Catenin expression and reduced significantly the expression of DKK1. CGS21680 inhibited dexamethasone-induced apoptosis, reducing the expression of Caspase3, and increased the expression of Beclin-1 and LC3 compared to cell treated with dexamethasone. Finally, treatment with Ellagic acid stimulated the nuclear translocation of B-Catenin, promoting the transcription of genes involved in osteogenesis. Conclusion These preliminary data suggest that stimulation of ERb through Ellagic acid could modulate bone remodelling through activation of Wnt/b-catenin pathway and autophagy, providing evidence on the possible use of this natural compound as a new therapeutic approach for osteoporosis. Presentation: No date and time listed

Acyloxyacyl hydrolase deficiency induces chronic inflammation and bone loss in male mice.

Hormonal homeostasis is essential in bone remodeling. Recent studies have shown that the treatment of intestinal inflammation can result in the regulation of bone resorption in distant bones. Increased intestinal permeability may lead to systemic inflammation and bone loss, also known as gut-bone axis. However, the underlying mechanism remains to be elucidated. Lipopolysaccharide (LPS) is a component of gram-negative bacteria that can increase osteoclastic differentiation in vitro. Acyloxyacyl hydrolase (AOAH) is a specific degrading enzyme of LPS, but little is known about the role of AOAH in bone metabolism. In this study, adult Aoah-/- mice showed a chronic inflammatory state and osteopenic phenotype analyzed by micro-CT and HE staining. Tartrate-resistant acid phosphatase (TRAP) staining of femurs showed an increase in TRAP-positive cells from Aoah-/- mice. AOAH depletion enhanced the osteoclast differentiation and bone resorption capacity of bone marrow-derived macrophages (BMMs). The enhanced osteoclast differentiation and bone resorption capacity of Aoah-/- BMMs were reversed by rAOAH. In conclusion, the chronic inflammatory state of adult Aoah-/- mice promotes bone resorption. AOAH participates in bone metabolism, which is mainly mediated by inhibiting osteoclast differentiation. LPS may be a key mediator of the gut-bone axis, and targeting AOAH may represent a feasible strategy for the treatment of chronic inflammatory bone resorption. KEY MESSAGES : AOAH knockout mice exhibited chronic inflammation mediated by LPS, and LPS may also serve as an important mediator in the regulation of bone metabolism in the gut-bone axis. AOAH regulated bone resorption by blocking the osteoclast differentiation via classical ERK and JNK pathways. rAOAH could rescue the enhanced osteoclast differentiation caused by AOAH deficiency.

The crosstalk between MYC and mTORC1 during osteoclastogenesis.

Osteoclasts are bone-resorbing cells that undergo extensive changes in morphology throughout their differentiation. Altered osteoclast differentiation and activity lead to changes in pathological bone resorption. The mammalian target of rapamycin (mTOR) is a kinase, and aberrant mTOR complex 1 (mTORC1) signaling is associated with altered bone homeostasis. The activation of mTORC1 is biphasically regulated during osteoclastogenesis; however, the mechanism behind mTORC1-mediated regulation of osteoclastogenesis and bone resorption is incompletely understood. Here, we found that MYC coordinates the dynamic regulation of mTORC1 activation during osteoclastogenesis. MYC-deficiency blocked the early activation of mTORC1 and also reversed the decreased activity of mTORC1 at the late stage of osteoclastogenesis. The suppression of mTORC1 activity by rapamycin in mature osteoclasts enhances bone resorption activity despite the indispensable role of high mTORC1 activation in osteoclast formation in both mouse and human cells. Mechanistically, MYC induces Growth arrest and DNA damage-inducible protein (GADD34) expression and suppresses mTORC1 activity at the late phase of osteoclastogenesis. Taken together, our findings identify a MYC-GADD34 axis as an upstream regulator of dynamic mTORC1 activation in osteoclastogenesis and highlight the interplay between MYC and mTORC1 pathways in determining osteoclast activity.

Nε-Carboxymethyl-Lysine Mediates Vascular Calcification in Diabetes Caused by Impaired Osteoclastic Resorption Activity Through NFATc1-GNPTAB.

Nε-carboxymethyl-lysine (CML) is closely associated with vascular calcification in diabetes. Osteoclasts are the only cells with bone resorption activity that have the potential to reverse calcification. This study aimed to investigate the mechanism of CML in the bone resorption activity of macrophage-derived osteoclasts in diabetic calcified plaques. Macrophage-derived osteoclasts were found to be present in calcified plaques of the anterior tibial artery in patients with diabetic amputation. Furthermore, in vitro studies showed that CML induced the differentiation of macrophages into osteoclasts, although, the bone resorption activity of these macrophage-derived osteoclasts was impaired. CML significantly increased the levels of NFATc1and GNPTAB. In vivo studies showed that there was more calcium deposition and less TRAP was less in the CML group while this effect was reversed after silencing of NFATc1. In conclusion, CML mediates NFATc1-GNPTAB to regulate bone resorption activity of osteoclasts in diabetic calcified plaques. CML promotes macrophage differentiation into osteoclasts, but their function is impaired in diabetic calcified plaques through NFATc1-GNPTAB, which eventually leads to the further progression of vascular calcification in diabetes.

Phospholipase D2 controls bone homeostasis by modulating M-CSF-dependent osteoclastic cell migration and microtubule stability

Phospholipase D2 (PLD2), a signaling protein, plays a central role in cellular communication and various biological processes. Here, we show that PLD2 contributes to bone homeostasis by regulating bone resorption through osteoclastic cell migration and microtubule-dependent cytoskeletal organization. Pld2-deficient mice exhibited a low bone mass attributed to increased osteoclast function without altered osteoblast activity. While Pld2 deficiency did not affect osteoclast differentiation, its absence promoted the migration of osteoclast lineage cells through a mechanism involving M-CSF-induced activation of the PI3K–Akt–GSK3β signaling pathway. The absence of Pld2 also boosted osteoclast spreading and actin ring formation, resulting in elevated bone resorption. Furthermore, Pld2 deletion increased microtubule acetylation and stability, which were later restored by treatment with a specific inhibitor of Akt, an essential molecule for microtubule stabilization and osteoclast bone resorption activity. Interestingly, PLD2 interacted with the M-CSF receptor (c-Fms) and PI3K, and the association between PLD2 and c-Fms was reduced in response to M-CSF. Altogether, our findings indicate that PLD2 regulates bone homeostasis by modulating osteoclastic cell migration and microtubule stability via the M-CSF-dependent PI3K–Akt–GSK3β axis.

Dietary Effects of Nanopowder Eggshells on Mineral Contents, Bone Turnover Biomarkers, and Regulators of Bone Resorption in Healthy Rats and Ovariectomy-Induced Osteoporosis Rat Model.

Postmenopausal osteoporosis is a critical issue for female health worldwide. This current study was designed to evaluate the role of nanopowder eggshell (NPES) in healthy and ovariectomy-induced osteoporosis rats. Fifty-six female rats were divided into healthy rats (35) and ovariectomized rats (21). The healthy rats were subdivided into five groups (G1-G5) and received one of the following treatments: saline, 20 or 40mg/kg of calcium carbonate, and 20 or 40mg/kg of NPES. The 21 ovariectomized rats were divided into three groups (G6-G8) and received either saline, 40mg/kg of calcium carbonate, or 40mg/kg of NPES. Biochemical and histopathological assessments of bone formation and resorption were performed. Biomarkers of bone formation (calcium and osteocalcin (OCN)) and calcium content in left femur ashes were significantly higher in healthy rats given 40-mg/kg NPES than in healthy control rats and healthy rats given 40-mg/kg calcium carbonate. The ovariectomized groups had significantly lower levels of vitamin D3, OCN, and osteoprotegerin (OPG) than the healthy control. Alanine transaminase (ALT), alkaline phosphatase (ALP), and receptor activator of nuclear factor-κB ligand (RANKL) were significantly increased in the ovariectomized group than in the healthy control group. Treatment with NPES and calcium carbonate reduced liver enzymes in ovariectomized rats. NPES treatment significantly increased Vit D3, OCN, OPG, and bone ash mineral content (calcium, magnesium, zinc, and phosphorus) in ovariectomized rats. NPES also increased femur cortical thickness, osteoblast number, and collagen fiber. The current study suggests that NPES can modulate bone turnover biomarkers and increase bone trace elements. Moreover, NPES alleviates bone resorption in ovariectomy-induced osteoporosis.

GsαR201C and estrogen reveal different subsets of bone marrow adiponectin expressing osteogenic cells

The Gsα/cAMP signaling pathway mediates the effect of a variety of hormones and factors that regulate the homeostasis of the post-natal skeleton. Hence, the dysregulated activity of Gsα due to gain-of-function mutations (R201C/R201H) results in severe architectural and functional derangements of the entire bone/bone marrow organ. While the consequences of gain-of-function mutations of Gsα have been extensively investigated in osteoblasts and in bone marrow osteoprogenitor cells at various differentiation stages, their effect in adipogenically-committed bone marrow stromal cells has remained unaddressed. We generated a mouse model with expression of GsαR201C driven by the Adiponectin (Adq) promoter. Adq-GsαR201C mice developed a complex combination of metaphyseal, diaphyseal and cortical bone changes. In the metaphysis, GsαR201C caused an early phase of bone resorption followed by bone deposition. Metaphyseal bone formation was sustained by cells that were traced by Adq-Cre and eventually resulted in a high trabecular bone mass phenotype. In the diaphysis, GsαR201C, in combination with estrogen, triggered the osteogenic activity of Adq-Cre-targeted perivascular bone marrow stromal cells leading to intramedullary bone formation. Finally, consistent with the previously unnoticed presence of Adq-Cre-marked pericytes in intraosseous blood vessels, GsαR201C caused the development of a lytic phenotype that affected both cortical (increased porosity) and trabecular (tunneling resorption) bone. These results provide the first evidence that the Adq-cell network in the skeleton not only regulates bone resorption but also contributes to bone formation, and that the Gsα/cAMP pathway is a major modulator of both functions.

Pathogenetic and diagnostic role of osteoprotegerin in the combined course of osteoarthritis and obesity

In recent years, it has been proven that the formation of OA can occur against the background of impaired bone metabolism.
 Bone remodeling is considered as a continuous complex process aimed at eliminating microdamages and updating the bone matrix. A key link in the regulation of this process is the system RANK / RANKL / OPG (osteoprotegerin), which provides a balance of activity of osteoblasts and osteoclasts. It blocks the interaction between RANK and RANKL by intercepting the RANKL ligand, which inhibits osteoclast development and reduces bone resorption.
 Thus, these properties of OPG can be considered as one of the pathogenetic factors in patients with dystrophic joint lesions.
 Objective: to investigate the content and role of osteoprotegerin in young patients with osteoarthritis, which occurs against the background of changes in body weight.
 Materials and methods. The study involved 75 young patients (mean age - 30.92 ± 0.546 years) with overweight or obesity, who in the previous stages of the study was diagnosed with osteoarthritis (main group). The comparison group was represented by 50 patients with osteoarthritis and normal body weight. The age of patients was 30.95 ± 0.545 years; as in the previous group, men predominated - 64% and 36% respectively.
 Benchmarks of osteoprotegerin were obtained in a study of 37 relatively healthy individuals of the same age and sex.
 The level of osteoprotegerin was determined by enzyme-linked immunosorbent assay using the FineTest EH0247 reagent kit, China.
 The outcomes were processed by the methods of variation statistics using the computer program STATISTICA.Results and discussion. When determining the content of OPG in the serum of patients of the main group was found to increase to 124.03 pg / ml, against control - 65.64 pg / ml. In the group of patients with isolated OA, this value was 92.29 pg / ml. Meaning that, in OA, running on the background of altered BMI, the content of OPG is likely to increase, both in relation to the norm and the results of the comparison group (p <0,001).
 The formation and course of osteoarthritis is accompanied by an increase in osteoprotegerin, the content of which depends on the degree of obesity and the radiological stage of the process.
 Conclusions: The course of osteoarthritis is accompanied by an increase in osteoprotegerin, which is considered a negative regulator of bone resorption.
 In osteoarthritis, which occurs against the background of changes in body mass index, a direct correlation with the degree of obesity.
 Changes in osteoprotegerin in patients with osteoarthritis depend on the radiological stage of joint damage and are most pronounced in individuals with stage 2 obesity and stage 2 radiological changes

Regulation of osteoclast-mediated bone resorption by microRNA.

Osteoclast-mediated bone resorption is responsible for bone metabolic diseases, negatively impacting people's health and life. It has been demonstrated that microRNA influences the differentiation of osteoclasts by regulating the signaling pathways during osteoclast-mediated bone resorption. So far, the involved mechanisms have not been fully elucidated. This review introduced the pathways involved in osteoclastogenesis and summarized the related microRNAs binding to their specific targets to mediate the downstream pathways in osteoclast-mediated bone resorption. We also discuss the clinical potential of targeting microRNAs to treat osteoclast-mediated bone resorption as well as the challenges of avoiding potential side effects and producing efficient delivery methods.

Icariin self-crosslinked network functionalized strontium-doped bioceramic scaffolds synergistically enhanced the healing of osteoporotic bone defects

The regeneration of osteoporotic defects remains a great challenge in clinic, due to the capacity of bone regeneration is seriously impaired and bone resorption is overactivated. Although extensive scaffolds are developed to regenerate and remodel osteoporotic bone defects, satisfactory repairing effect has not been achieved yet. Developing a multi-functional scaffold with clinical application prospects is extremely urgent. Herein, an icariin self-crosslinked network functionalized Sr-doped biphasic calcium phosphate bioceramic (IC/Sr-BCP) was developed in an easy and convenient way. The in vitro results showed that both icariin and Sr 2+ could sustained-release from the IC/Sr-BCP scaffold and create an instructive microenvironment for synergistically promoting osteogenesis through activating Wnt/β-catenin and BMP-2/Smad pathways. In addition, osteoclastogenesis was significantly suppressed by icariin and Sr 2+ resulting from the inhibition of nuclear factor-κB (NF-κB) and p38 mitogen-activated protein kinase (p38-MAPK) pathways. The in vivo results suggested that the IC/Sr-BCP scaffold exhibited dual regulation of bone formation and resorption , achieving the synergistic enhancement on bone regeneration than which with only one agent (Sr-BCP or IC/BCP). Moreover, the results also elaborated the underlying mechanisms of these beneficial effects. We believe that it provides a promising strategy for clinical treatment by means of designing multi-functional scaffolds (IC/Sr-BCP) to repair osteoporotic defects.

The Paget's disease of bone risk gene PML is a negative regulator of osteoclast differentiation and bone resorption.

ABSTRACTPaget's disease of bone (PDB) is characterized by focal increases in bone remodelling. Genome-wide association studies identified a susceptibility locus for PDB tagged by rs5742915, which is located within the PML gene. Here, we have assessed the candidacy of PML as the predisposing gene for PDB at this locus. We found that the PDB-risk allele of rs5742915 was associated with lower PML expression and that PML expression in blood cells from individuals with PDB was lower than in controls. The differentiation, survival and resorptive activity of osteoclasts prepared from Pml−/− mice was increased compared with wild type. Furthermore, the inhibitory effect of IFN-γ on osteoclast formation from Pml−/− was significantly blunted compared with wild type. Bone nodule formation was also increased in osteoblasts from Pml−/− mice when compared with wild type. Although microCT analysis of trabecular bone showed no differences between Pml−/− mice and wild type, bone histomorphometry showed that Pml−/− mice had high bone turnover with increased indices of bone resorption and increased mineral apposition rate. These data indicate that reduced expression of PML predisposes an individual to PDB and identify PML as a novel regulator of bone metabolism. This article has an associated First Person interview with the first author of the paper.

First person – Sachin Wani

ABSTRACTFirst Person is a series of interviews with the first authors of a selection of papers published in Disease Models & Mechanisms, helping early-career researchers promote themselves alongside their papers. Sachin Wani is first author on ‘The Paget's disease of bone risk gene PML is a negative regulator of osteoclast differentiation and bone resorption’, published in DMM. Sachin is a research assistant (postdoctoral) in the lab of Prof. Omar Albagha at University of Edinburgh, Edinburgh, UK, where he applies knowledge of biomedical science to the investigation of health, development, biological function and disease.

Rab34 plays a critical role as a bidirectional regulator of osteoclastogenesis.

Accumulating evidence suggests that Rab GTPases representing the largest branch of Ras superfamily have recently emerged as the core factors for the regulation of osteoclastogenesis through modulating vesicular transport amongst specific subcellular compartments. Among these, Rab34 GTPase has been identified to be important for the post-Golgi secretory pathway and for phagocytosis; nevertheless, its specific role in osteoclastogenesis has been completely obscure. Here, upon the in vitro model of osteoclast formation derived from murine macrophages like RAW-D cells or bone marrow-derived macrophages, we reveal that Rab34 regulates osteoclastogenesis bidirectionally. More specifically, Rab34 serves as a negative regulator of osteoclast differentiation by promoting the lysosome-induced proteolysis of two osteoclastogenic surface receptors, c-fms and RANK, via the axis of early endosomes-late endosomes-lysosomes, leading to alleviate the transcriptional activity of two of the master regulator of osteoclast differentiation, c-fos and NFATc-1, eventually attenuating osteoclast differentiation and bone resorption. Besides, Rab34 plays a crucial role in modulating the secretory network of lysosome-related proteases including matrix metalloprotease 9 and Cathepsin K across the ruffled borders of osteoclasts, contributing to the regulation of bone resorption.