Osteoclast Apoptosis Research Articles

Bone-seeking nanoplatform co-delivering cisplatin and zoledronate for synergistic therapy of breast cancer bone metastasis and bone resorption

The “vicious cycle” established between tumor growth and osteolysis aggravates the process of breast cancer bone metastasis, leading to life-threatening skeletal-related events that severely reduce survival and quality of life. To effectively interrupt the “vicious cycle”, innovative therapeutic strategies that not only reduce osteolysis but also relieve tumor burden are urgently needed. Herein, a bone-seeking moiety, alendronate (ALN), functionalized coordination polymer nanoparticles (DZ@ALN) co-delivering cisplatin prodrug (DSP) and antiresorptive agent zoledronate (ZOL) via Zn2+ crosslinking for combination therapy was reported. The versatile DZ@ALN with a diameter of about 40 nm can cross the fissure in the bone marrow sinus capillaries, and possesses an excellent bone-seeking ability both in vitro and in vivo. Additionally, DZ@ALN could synergistically inhibit the proliferation of cancer cells, suppress the formation of osteoclast-like cells and induce the apoptosis of osteoclasts in vitro. Importantly, it could preferentially accumulate in bone affected site, remarkably inhibit the proliferation of tumor cells, relieving bone pain, and significantly inhibit the activation of osteoclasts, protecting the bone from destruction in vivo, eventually leading to the breakdown of “vicious cycle” without inducing obvious systemic toxicity. This innovative nanoagent combines chemotherapy and osteolysis inhibition, exhibiting an inspiring strategy for effective treatment of bone metastasis.

Mycobacterium tuberculosis infection increases the number of osteoclasts and inhibits osteoclast apoptosis by regulating TNF-α-mediated osteoclast autophagy.

Osteoarticular tuberculosis, a chronic inflammatory disease characterized by Mycobacterium tuberculosis (M.tb) infection, has become a serious problem in China. The present study was conducted to determine the mechanism of action of tumor necrosis factor (TNF)-α in the pathogenesis of osteoarticular tuberculosis. The number of osteoclasts in osteoarticular tuberculosis tissue samples was detected by tartrate-resistant acid phosphatase staining. Autophagy and apoptosis of osteoclasts were detected by western blotting, reverse transcription-quantitative PCR, transmission electron microscopy and TUNEL staining. The results showed that autophagy and the number of osteoclasts increased in the lesions of patients with osteoarticular tuberculosis compared with osteoarthritis samples. Moreover, activation of osteoclast autophagy inhibited the apoptosis of osteoclasts infected with M.tb, and increased the expression level of TNF-α. The results showed that TNF-α enhanced the autophagic activity of M.tb-infected osteoclasts and inhibited cell apoptosis. These findings indicated that M.tb infection induced osteoclast production and inhibited osteoclast apoptosis by regulating TNF-α-mediated osteoclast autophagy, revealing a new mechanism for TNF-α in the pathogenesis of osteoarticular tuberculosis.

MiR‑27a‑3p negatively regulates osteogenic differentiation of MC3T3‑E1 preosteoblasts by targeting osterix.

Osteoporosis is a complex multifactorial disorder characterized by microarchitectural deterioration, low bone mass, and increased risk of fractures or broken bones. Balanced bone remodeling is tightly regulated by the differentiation, activity and apoptosis of bone-forming osteoblasts and bone-resorbing osteoclasts. MicroRNAs (miRs) are dysregulated in osteoporosis, but whether they control osteogenic differentiation and skeletal biology, or could serve as therapeutic targets remains to be elucidated. The present study identified miR-27a-3p as a critical suppressor of osteoblastogenesis. Bioinformatics analysis and luciferase reporter assays demonstrated that miR-27a-3p directly targeted and controlled the expression of osterix (Osx), an early response gene essential for bone formation, through its 3′-untranslated region. miR-27a-3p functionally inhibited the differentiation of preosteoblasts by decreasing Osx expression, which synergistically contributed to bone formation. miR-27a-3p level was significantly decreased during osteogenic differentiation and increased in the serum of patients with osteoporosis. Together, miR-27a-3p contributed to diminished osteogenic function during osteogenic differentiation and might thus serve as a therapeutic target and diagnostic biomarker for osteoporosis.

NECROSE MANDIBULAR ASSOCIADA AO USO DE BIFOSFONATO: RELATO DE CASO

Introdução: Os bifosfonatos são medicamentos que objetivam reduzir a reabsorção óssea por provocarem a apoptose de osteoclastos. Por essa razão, são frequentemente empregados em pacientes com osteoporose e no tratamento do câncer. Contudo, apesar dos benefícios associados ao tratamento com bifosfonatos, esses medicamentos vêm sendo relacionados a osteonecrose maxilo-mandibular, materializando-se como um preocupante quadro de interesse à saúde pública. Objetivo: Apresentar um caso clínico de osteonecrose mandibular associada ao uso de bifosfanato, após extração de um elemento dentário, bem como contribuir com as discussões sobre as possibilidades terapêuticas desta enfermidade. Descrição do caso: Paciente do sexo masculino, 59 anos, encaminhado ao serviço de Cirurgia e Traumatologia Bucomaxilofacial dois meses após a extração do elemento dentário 45. O diagnóstico foi de Osteonecrose Maxilomandibular Relacionada a Bifosfonatos (OMRB), optando-se, inicialmente, pela remoção dos traumas existentes, como também o cuidado com a área exposta. Posteriormente, optou-se pela remoção do segmento ósseo necrótico. Conclusões: A complexa fisiopatologia da OMRB, exige dos cirurgiões dentistas a tomada de medidas em tempo oportuno e que cause o mínimo transtorno à vida dos pacientes. Assim, deve-se avaliar o estado da lesão, havendo indicação de terapia conservadora para os achados precoces. O desbridamento cirúrgico é aconselhado para o tratamento da doença avançada e não responsiva.
 Palavras-Chave: Bifosfonatos; Osteonecrose; Mandíbula.

Epothilone B prevents lipopolysaccharide-induced inflammatory osteolysis through suppressing osteoclastogenesis via STAT3 signaling pathway.

Inflammatory osteolysis is a common osteolytic specificity that occurs during infectious orthopaedic surgery and is characterized by an imbalance in bone homeostasis due to excessive osteoclast bone resorption activity. Epothilone B (Epo B) induced α-tubulin polymerization and enhanced microtubule stability, which also played an essential role in anti-inflammatory effect on the regulation of many diseases. However, its effects on skeletal system have rarely been investigated. Our study demonstrated that Epo B inhibited osteoclastogenesis in vitro and prevented inflammatory osteolysis in vivo. Further analysis showed that Epo B also markedly induced mature osteoclasts apoptosis during osteoclastogenesis. Mechanistically, Epo B directly suppressed osteoclastogenesis by the inhibitory regulation of the phosphorylation and activation of PI3K/Akt/STAT3 signaling directly, and the suppressive regulation of the CD9/gp130/STAT3 signaling pathway indirectly. The negative regulatory effect on STAT3 signaling further restrained the translocation of NF-κB p65 and NFATc1 from the cytosol to the nuclei during RANKL stimulation. Additionally, the expression of osteoclast specific genes was also significantly attenuated during osteoclast fusion and differentiation. Taken together, these findings illustrated that Epo B protected against LPS-induced bone destruction through inhibiting osteoclastogenesis via regulating the STAT3 dependent signaling pathway.

Conditional Knockout of PKC-δ in Osteoclasts Favors Bone Mass Accrual in Males Due to Decreased Osteoclast Function.

Protein kinase C delta (PKC-δ) functions as an important regulator in bone metabolism. However, the precise involvement of PKC-δ in the regulation of osteoclasts remains elusive. We generated an osteoclast specific PKC-δ knockout mouse strain to investigate the function of PKC-δ in osteoclast biology. Bone phenotype was investigated using microcomputed tomography. Osteoclast and osteoblast parameters were assessed using bone histomorphometry, and analysis of osteoclast formation and function with osteoclastogensis and hydroxyapatite resorption assays. The molecular mechanisms by which PKC-δ regulated osteoclast function were dissected by Western Blotting, TUNEL assay, transfection and transcriptome sequencing. We found that ablation of PKC-δ in osteoclasts resulted in an increase in trabecular and cortical bone volume in male mice, however, the bone mass phenotype was not observed in female mice. This was accompanied by decreased osteoclast number and surface, and Cathepsin-K protein levels in vivo, as well as decreased osteoclast formation and resorption in vitro in a male-specific manner. PKC-δ regulated androgen receptor transcription by binding to its promoter, moreover, PKC-δ conditional knockout did not increase osteoclast apoptosis but increased MAPK signaling and enhanced androgen receptor transcription and expression, finally leding to significant alterations in gene expression and signaling changes related to extracellular matrix proteins specifically in male mice. In conclusion, PKC-δ plays an important role in osteoclast formation and function in a male-specific manner. Our work reveals a previously unknown target for treatment of gender-related bone diseases.

Inflammatory environments disrupt both bone formation and bone resorption

Abstract Inflammation has been associated with bone diseases such as osteoporosis and osteoarthritis. Bone loss were reported in the patients of several inflammatory diseases, such as rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease. However, how inflammation influence bone metabolism remains elusive. The bone loss in inflammatory environments are widely considered as the results of osteoclast overactivation which leads to excessive bone resorption. We previously discovered that osteoclasts induced from RAW macrophage treated with RANKL exhibited different cell properties and gene expression profile with undifferentiated macrophage. In this research we examined the excessive bone resorption hypothesis in in vitro systems. RANKL stimulated differentiation of RAW cells into bone-resorptive osteoclasts, and induction of pre-osteoblasts (MC-3T3 E1) into mature osteoblasts are utilized in this research. Inflammatory environments are mimic by treating cultured osteoclast or osteoblast with conditioned medium collected from bone marrow derived macrophage primed with LPS or interferon-γ. The pro-inflammatory cytokines inhibit the proliferation and disrupt the expression of genes that are needed for bone formation, such as osteocalcin and collagen. On the other hand, inflammatory environments did not activate osteoclast, nor promote bone resorption. Instead, pro-inflammatory cytokines inhibit osteoclastogenesis and bone resorption, induce mitochondrial dysfunctions and lead to apoptosis of osteoclast. These results indicated that the bone loss developed in the inflammatory environments might be due to the disruption of both bone formation and bone resorption.

Notch Signaling in Skeletal Development, Homeostasis and Pathogenesis.

Skeletal development is a complex process which requires the tight regulation of gene activation and suppression in response to local signaling pathways. Among these pathways, Notch signaling is implicated in governing cell fate determination, proliferation, differentiation and apoptosis of skeletal cells-osteoblasts, osteoclasts, osteocytes and chondrocytes. Moreover, human genetic mutations in Notch components emphasize the critical roles of Notch signaling in skeletal development and homeostasis. In this review, we focus on the physiological roles of Notch signaling in skeletogenesis, postnatal bone and cartilage homeostasis and fracture repair. We also discuss the pathological gain- and loss-of-function of Notch signaling in bone and cartilage, resulting in osteosarcoma and age-related degenerative diseases, such as osteoporosis and osteoarthritis. Understanding the physiological and pathological function of Notch signaling in skeletal tissues using animal models and human genetics will provide new insights into disease pathogenesis and offer novel approaches for the treatment of bone/cartilage diseases.

Oleoylethanolamide Exhibits GPR119-Dependent Inhibition of Osteoclast Function and GPR119-Independent Promotion of Osteoclast Apoptosis.

Oleoylethanolamide (OEA), a bioactive lipid in bone, is known as an endogenous ligand for G protein-coupled receptor 119 (GPR119). Here, we explored the effects of OEA on osteoclast differentiation, function, and survival. While OEA inhibits osteoclast resorptive function by disrupting actin cytoskeleton, it does not affect receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast differentiation. OEA attenuates osteoclast spreading, blocks actin ring formation, and eventually impairs bone resorption. Mechanistically, OEA inhibits Rac activation in response to macrophage colony-stimulating factor (M-CSF), but not RANKL. Furthermore, the OEA-mediated cytoskeletal disorganization is abrogated by GPR119 knockdown using small hairpin RNA (shRNA), indicating that GPR119 is pivotal for osteoclast cytoskeletal organization. In addition, OEA induces apoptosis in both control and GPR119 shRNA- transduced osteoclasts, suggesting that GPR119 is not required for osteoclast apoptosis. Collectively, our findings reveal that OEA has inhibitory effects on osteoclast function and survival of mature osteoclasts via GPR119-dependent and GPR119-independent pathways, respectively.

The protective effects of microRNA-26a in steroid-induced osteonecrosis of the femoral head by repressing EZH2

ABSTRACT Recently, the role of microRNAs (miRs) in human diseases has been verified. This study was determined to explore the protective effects of microRNA-26a (miR-26a) in steroid-induced osteonecrosis of the femoral head (SONFH) with the involvement of enhancer of zeste homologue 2 (EZH2). Femoral head (FH) samples from SONFH patients and patients with femoral neck fracture were collected, and rat SONFH models were established by Escherichia coli endotoxin combining with large dose steroid pulse assay. The hemorheology, blood lipid, inflammatory factors, and pathologic changes were measured by a series of experiments. Moreover, the detection of osteoblasts, osteoclasts, miR-26a expression, EZH2 expression, osteoprotegerin (OPG) and osteoprotegerin ligand (OPGL), and the apoptosis of osteocytes were conducted. The target relation between miR-26a and EZH2 was clarified by bioinformatics and dual-luciferase reporter gene assay. MiR-26a was poorly expressed, while EZH2 was highly expressed in SONFH, and the elevation of miR-26a could repress EZH2 expression. Elevated miR-26a and reduced EZH2 were able to decelerate the apoptosis of osteocytes, increase osteoblasts, and decrease osteoclasts, resulting in a repression of SONFH progression. Additionally, EZH2 was a target gene of miR-26a. Furthermore, the elevation of EZH2 could reverse the repression of SONFH progression that is induced by elevated miR-26a. We found that up-regulation of miR-26a and knockdown of EZH2 could suppress the development of SONFH, which would contribute to the therapy of SONFH.

A bone remodeling model governed by cellular micromechanics and physiologically based pharmacokinetics

This study describes a mathematical model for bone remodeling that integrates the bone cells activities with the pharmacological dynamics for bone-seeking agents. The evolution of bone cells population involves the osteoblast-osteoclast signaling mediated by biochemical factors and receives both mechanical stimulus evaluated at the microscale and pharmacological regulation. A physiologically based pharmacokinetic model (PBPK) for bone-seeking agents was developed to provide the drug concentration on bone sites and feed the remodeling algorithm. The drug effect on bone was reproduced coupling three different strategies: modification of the RANKL expression, increase the osteoclast apoptosis and change in the rate of differentiation of preosteoblasts. Computational simulations were performed in the PBPK model considering different dosing regimens. A 3D finite element model of a proximal femur was generated and the simulation of the bone remodeling algorithm were implemented in Matlab. The results indicate that the proposed integrated model is able to capture adequately the expected adaptive behavior of bone subjected to mechanical and pharmacological stimulus. The model demonstrated to have potential for use as a platform to investigate therapies and may help in the study of new drugs for bone diseases.

Re-appraising the potential of naringin for natural, novel orthopedic biotherapies.

Naringin is a naturally occurring flavonoid found in plants of the Citrus genus that has historically been used in traditional Chinese medical regimens for the treatment of osteoporosis. Naringin modulates signaling through numerous molecular pathways critical to musculoskeletal development, cellular differentiation, and inflammation. Administration of naringin increases in vitro expression of bone morphogenetic proteins (BMPs) and activation of the Wnt/β-catenin and extracellular signal-related kinase (Erk) pathways, thereby promoting osteoblastic proliferation and differentiation from stem cell precursors for bone formation. Naringin also inhibits osteoclastogenesis by both modifying RANK/RANKL interactions and inducing apoptosis in osteoclasts in vitro. In addition, naringin acts on the estrogen receptor in bone to mimic the native bone-preserving effects of estrogen, with few systemic side effects on other estrogen-sensitive tissues. The efficacy of naringin therapy in reducing the osteolysis characteristic of common musculoskeletal pathologies such as osteoporosis, degenerative joint disease, and osteomyelitis, as well as inflammatory conditions affecting bone such as diabetes mellitus, has been extensively demonstrated in vitro and in animal models. Naringin thus represents a naturally abundant, cost-efficient agent whose potential for use in novel musculoskeletal biotherapies warrants re-visiting and further exploration through human studies. Here, we review the cellular mechanisms of action that have been elucidated regarding the action of naringin on bone resident cells and the bone microenvironment, in vivo evidence of naringin’s osteostimulative and chondroprotective properties in the setting of osteolytic bone disease, and current limitations in the development of naringin-containing translational therapies for common musculoskeletal conditions.

Interleukin-20 Bidirectionally Regulates Osteoclast Survival, Apoptosis, Differentiation and Function Through the TRAF6-Mediated NF-κB, MAPK and AKT Signaling Pathways

Interleukin-20 Bidirectionally Regulates Osteoclast Survival, Apoptosis, Differentiation and Function Through the TRAF6-Mediated NF-κB, MAPK and AKT Signaling Pathways

RETRACTED ARTICLE: LncRNA TUG1 was upregulated in osteoporosisand regulates the proliferation and apoptosis of osteoclasts

BackgroundLong non-coding RNA (LncRNA) TUG1 plays critical roles in thedevelopment of human cancers. Its inhibition has been proved to participate inankylosing spondylitis, which is an inverse pathological procedure ofosteoporosis. In the present study, we aim to investigate the role of lncRNATUG1 in ankylosing spondylitis.Materials and methodsExpressions of lncRNA TUG1 in plasma of 98 patients withosteoporosis and 60 healthy participants were detected by real-time quantitativePCR (RT-qPCR). Diagnostic values of lncRNA CASC11 for osteoclasts were performedby the ROC curve with osteoporosis patients as positive and healthy participantsas negative. All experiments were repeated 3 times. Mean ± standard deviationwas calculated.ResultsWe found that plasma lncRNA TUG1 was upregulated in osteoporosispatients than in healthy participants. Upregulation of plasma lncRNA TUG1distinguished osteoporosis patients from healthy participants. LncRNA TUG1 levelincreased with the advances of clinical stages. Over-expression of lncRNA TUG1promoted the proliferation and inhibited the apoptosis of mice osteoclasts,while lncRNA TUG1 siRNA silencing played an opposite role. In addition, lncRNATUG1 over-expression led to downregulated PTEN, while lncRNA TUG1 siRNAsilencing played an opposite role.ConclusionTherefore, lncRNA TUG1 is upregulated in osteoporosis and regulatesthe proliferation and apoptosis of osteoclasts. lncRNA TUG1 knockdown may serveas a promising therapeutic target for osteoporosis by inhibiting theproliferation and promoting the apoptosis of osteoclasts through PTEN.

Environmental hypoxia causes growth retardation, osteoclast differentiation and calcium dyshomeostasis in juvenile rainbow trout (Oncorhynchus mykiss)

Hypoxia generally refers to a dissolved oxygen (DO) level that is less than 2–3 mg/L. With ongoing global warming and environment pollution, environmental or geological studies showed hypoxia frequently occurs in global aquatic systems including ocean, river, estuaries and coasts. A preliminary study was performed to evaluate hypoxia tolerant of rainbow trout (Oncorhynchus mykiss) with parameters of mortality, behavior, endocrine and metabolite, identifying three DO levels including normoxia (Ctrl, 7.0 mg/L), non-lethal hypoxia (NH, 4.5 mg/L) and lethal hypoxia (LH, 3.0 mg/L). Furthermore, trout was treated by Ctrl, NH and LH for six hours to mimic the acute hypoxia in wild and/or farming conditions. A significantly higher mortality was observed in LH group. Trout of NH and LH showed stressful responses with unnormal swimming, increased serum cortisol and up-regulated gill hif1α transcription. Despite trout of NH and LH increased the oxygen delivery abilities by increasing the serum hemoglobin levels, the anerobic metabolism were inevitably observed with increased lactate. This study also showed a prolonged influence of NH and LH on growth after 30-days’ recovery. Based on RNA-Seq data, different expression genes (DEGs) associated with stress, apoptosis, antioxidant, chaperone, growth, calcium and vitamin D metabolism were identified. Enrichment analysis showed DEGs were clustered in osteoclast differentiation, apoptosis and intracellular signaling transduction pathways. Results further showed NH and LH significantly decreased bone calcium content and disrupted the growth hormone-insulin-like growth factor (GH-IGF) axis. Our study might contribute to a better understanding of the effects of hypoxia on rainbow trout.

Diterpenoids from the aerial parts of Flueggea acicularis and their activity against RANKL-induced osteoclastogenesis.

Compounds 1-11 were isolated from the aerial parts of Flueggea acicularis Croizz Webster, including three new rearranged clesistanthane diterpenoids fluacinoids A-C (1-3) and five new norditerpenoid fluacinoids D-H (4-8). The new compounds were identified from spectroscopic data combined with single crystal X-ray diffraction analysis, modified Mosher's methods, and ECD data analyses. All the isolated compounds were evaluated for their activities on RANKL-induced osteoclastogenesis in bone marrow monocytes (BMMs). Compound 6 showed the most potent inhibition against osteoclast differentiation (IC50, 0.7μM) and decreased the expression level of osteoclast-related genes. Moreover, compound 6 prompted the apoptosis of osteoclasts. Compound 6 also suppressed RANKL-induced NF-κB activation. This study reveals that norditerpenoids may be resource for anti-osteoporosis agents.

Protocatechuic acid attenuates anterior cruciate ligament transection-induced osteoarthritis by suppressing osteoclastogenesis.

Osteoarthritis (OA) is related to over-proliferation or differentiation of osteoclasts. Although protocatechuic acid (PCA) has been identified to inhibit osteoclast differentiation and stimulate apoptosis in mature osteoclasts, whether it can relieve OA is still unknown. The present study aimed to investigate the effect of PCA on anterior cruciate ligament transection (ACLT)-induced OA and the potential mechanisms of action behind this effect. ACLT was performed on rats, which were then treated with or without PCA. C-terminal telopeptide of type I collagen (CTX–I) and CTX–II were tested in knee joint protein extracts by ELISA. Damage to cartilage was evaluated using Safranin-O/Fast Green staining. Osteoclast-related gene and protein expression was assessed through reverse transcription-quantitative PCR and western blotting. Tartrate-resistant acid phosphatase (TRAP) staining and functional bone resorption pit assays were performed using RAW264.7 murine macrophage cells to determine the effects of PCA on osteoclastic formation and function, respectively, in vitro. Finally, the activity of osteoclastogenesis-related signaling pathways was evaluated by western blotting. Levels of CTX–II were relatively decreased and Safranin-O/fast green staining indicated milder changes in the articular cartilage in the PCA treatment group. PCA downregulated osteoclast specific markers and suppressed receptor activator of nuclear factor-κB ligand-induced formation of TRAP-positive multinucleated cells, bone-resorption and pit formation. Mitogen-activated protein kinase (MAPK) and Akt signaling as well as the downstream factors, were downregulated by PCA. In conclusion, the present study demonstrated that PCA attenuated ACLT-induced OA by suppressing osteoclastogenesis by inhibiting the MAPK, ATK and NF-κB signaling pathways.

MiRNA-483–5p is involved in the pathogenesis of osteoporosis by promoting osteoclast differentiation

AimsThe study aimed to investigate the roles of miR-483–5p and IGF2 in osteoclast formation. MethodsBlood and bone tissues were collected from osteoporosis and non-osteoporosis patients with hip fractures for gene expression analysis. CD14 + peripheral blood mononuclear cells (PBMCs) were isolated for differentiating osteoclasts. MiR-483–5p mimic and inhibitor was transfected into CD14 + PBMCs, respectively. Predicted by TargetScan and verified by Dual-luciferase reporter assay system, insulin-like growth factor-2 (IGF2) could be targeted by miR-483–5p. IGF2 expression vector was co-transfected with miR-483–5p mimic to study the role of IGF2 in miR-483–5p affecting osteoclast differentiation. Flow cytometry was performed for cell apoptosis analysis. ResultsHigh-expressed miR-483–5p and low-expressed IGF2 were frequently found in the serums and bone tissues derived from osteoporotic patients. We found that up-regulation of miR-483–5p in CD14 + PBMCs notably increased the number of TRAP-positive cells, at the same time, the expression levels of TRAP, nuclear factor of activated T-cells (NFATc1), cytoplasmic 1 (NFAT2) and Cathepsin K (CTSK) were also up-regulated. However, overexpressed IGF2 effectively reversed such effects produced by up-regulation of miR-483–5p on osteoclastogenesis-related factors in CD14 + PBMCs. Moreover, forced expression of IGF2 could also enhance apoptosis of osteoclasts reduced by miR-483–5p. ConclusionsOur study suggests that miRNA-483–5p is involved in the pathogenesis of osteoporosis by promoting osteoclast differentiation.

Ferulic acid, a natural polyphenol, protects against osteoporosis by activating SIRT1 and NF-κB in neonatal rats with glucocorticoid-induced osteoporosis

Osteoporosis is a chronic disease whose symptoms include a reduction in bone strength, osteopenia, and damage to the bone microstructure. Ferulic acids are natural polyphenols present in various fruits that suppress the fusion and apoptosis of mature osteoclasts. Rats were divided into sham, control (osteoporosis), 10 mg/kg body weight ferulic acid, 20 mg/kg body weight ferulic acid, and 30 mg/kg body weight ferulic acid treatment groups. Osteoporosis was induced in neonatal by administration of dexamethasone (glucocorticoids). Bone mineral density (BMD), osteocalcin and alkaline phosphatase (ALP) levels, bone mechanical parameters, and mRNA and protein levels of sirtuin1 (SIRT1) and nuclear factor kappa-B (NF-κB) in the osteoporotic neonatal rats were assessed. Histopathological analysis was also conducted. Treatment with 20 and 30 mg/kg body weight ferulic acid increased BMD by 25% and 141.7%, respectively, but reduced ALP and osteocalcin levels. Furthermore, treatment with 20 or 30 mg/kg body weight ferulic acid significantly reduced the pixel intensity and significantly increased the peak load and ultimate stiffness. Ferulic acid significantly increased the mRNA and protein levels of SIRT1 and reduced those of NF-κB. Finally, the histopathological analysis showed that ferulic acid increased BMD. In summary, ferulic acid exhibited protective effects against osteoporosis in neonatal rats.

Prevention Of Skeletal Related Events In Multiple Myeloma: Focus On The RANK-L Pathway In The Treatment Of Multiple Myeloma.

More than 90% of patients with multiple myeloma (MM) have osteolytic bone lesions which increase the risk of skeletal-related events (SRE). The cytokine milieu in the bone marrow microenvironment (BMME) of MM plays a key role in myeloma bone disease by impairing the balance between osteoclastogenesis and osteoblastogenesis. This is orchestrated by the malignant plasma cell (MPC) with the ultimate outcome of MPC proliferation and survival at the expense of excess osteoclast activation resulting in osteolytic bone lesions. Prevention of SRE is currently accomplished by the inhibition of osteoclasts. Bisphosphonates (BPs) are pyrophosphate analogues that cause apoptosis of osteoclasts and have been proven to prevent and delay SRE. Denosumab, a fully humanized monoclonal antibody that binds and inhibits receptor activator of nuclear factor-ĸB ligand (RANKL), a key molecule in the BMME crucial for osteoclastogenesis, is also approved for the prevention of SRE in MM. The addition of BPs and denosumab to standard MM treatment affords a survival benefit for patients with MM. Specifically, the addition of denosumab to standard MM treatments results in superior PFS compared to BPs, highlighting the key role of the RANKL pathway in MM. This review focuses on the pathophysiology of myeloma bone disease as well as on the importance of targeting the RANK-L pathway for the treatment of MM and prevention of SRE.