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Cellular mechanism of decreased bone in Brtl mouse model of OI: imbalance of decreased osteoblast function and increased osteoclasts and their precursors.

The Brtl mouse, a knock-in model for moderately severe osteogenesis imperfecta (OI), has a G349C substitution in half of type I collagen alp … atio is maintained. TRACP(+) precursors are markedly elevated in Brtl marrow cultures and form more osteoclasts, suggesting that osteoclast increases arise from more RANK-expressing precursors. We conclude that osteoblasts and osteoclasts are unsynchronized in Brtl bone. This cellular imbalance results in declining BFR as Brtl ages, consistent with reduced fe …

The effects of colony-stimulating factor-1 on the number and ultrastructure of osteoclasts in toothless (tl) rats and osteopetrotic (op) mice.

The role of colony-stimulating factor-1 (CSF-1 or M-CSF) in osteoclast development is illustrated by observations that administration of exogenous CSF-1 increases osteoclast number and improves the skeletal sclerosis of two osteopetrotic mutations, toothless (tl) in the rat and osteopetrotic (op) in the mouse. We examined the effects of CSF-1 treatment on the number and ultrastructure of osteoclasts in the tibial metaphysis of normal and mutant animals of both stocks to understand the similarities and differences between these two mutations. Osteoclasts from normal animals of both stocks were …

The skeletal effects of colony-stimulating factor-1 in toothless (osteopetrotic) rats: persistent metaphyseal sclerosis and the failure to restore subepiphyseal osteoclasts.

Toothless (tl), one of four osteopetrotic mutations in the rat, is characterized by few osteoclasts, undetectable bone resorption, and failure of correction by bone marrow transplantation. We recently reported that CSF-1 treatment improves these skeletal problems but that metaphyseal sclerosis persists. In the present study we demonstrate that optimal reduction of the skeletal sclerosis in tl rats following CSF-1 treatment has lower and upper dosage thresholds and that skeletal sclerosis returns after CSF-1 withdrawal. Osteoclasts increase significantly in tl rats after CSF-1 treatment, but co…

Effects of (5R)-5-Hydroxytriptolide Against Rheumatoid Arthritis: Intervention on the Transformation of Bone Marrow Cells Induced Osteoclasts Bone Erosion and Angiogenesis.

Rheumatoid arthritis (RA) is characterized by chronic synovitis, leading to joint cartilage and bone erosion. While current treatments aim to control inflammation, no specific drug prevents joint structure damage. This study set out to explore the efficacy of (5R)-5-hydroxytriptolide (LLDT-8), which targets osteoclasts known to be closely related to RA-induced erosion. We evaluated morphological changes of bone marrow cells and identified the induced osteoclasts by TRAP staining. LLDT-8’s inhibitory effect on the bone erosion activity of osteoclasts was assessed by resorption pit assay and the…

Tumor-derived exosomal lncRNA-MIR193BHG promotes bone metastasis of breast cancer by targeting the miR-489-3p/DNMT3A signaling axis in osteoclasts.

BACKGROUND: Breast cancer exhibits high incidence and mortality among women, with distant metastasis, especially bone metastasis, being the leading cause of death. Despite advances in adjuvant therapies, bone metastasis remains a challenge for patient survival and quality of life. Exosomes, small vesicles capable of mediating intercellular communication, play a crucial role in tumor metastasis. RESULTS: This study investigated the role of tumor-derived exosomal long noncoding RNA (lncRNA)-MIR193BHG in breast cancer bone metastasis. LncRNA-MIR193BHG was delivered to osteoclasts via exosomes an…

Complement C3a promotes the formation of osteoclasts by inhibiting Sirt1 to activate the PI3K/PDK1/SGK3 pathway in patients with multiple myeloma.

BACKGROUND: Myeloma bone disease (MBD) is the most common complication of multiple myeloma (MM). Our previous study showed that the complement C3a activates osteoclasts to participate in the pathogenesis of MBD; however, its mechanism of action is diverse and complex. Studies have shown that the Sirtuin (Sirt) family of proteins (i.e., Sirt1-7) are expressed in human bone and cartilage, and participate in bone metabolic balance. METHODS AND RESULTS: We measured the levels of complement C3a, Sirt1, osteoclast-related genes, and bone disease-related biological indicators using enzyme-linked imm…

Extracellular Vesicles From Prostate Cancer-Corrupted Osteoclasts Drive a Chain Reaction of Inflammatory Osteolysis and Tumour Progression at the Bone Metastatic Site.

Advanced-stage prostate cancer (PCa) frequently causes bone metastases, resulting in a poor prognosis and a 5-year survival rate of 30%. PCa … communication and actively function in the bone microenvironment. We report that PCa cells corrupt osteoclasts (OCs) via their secretomes, inducing a pathological phenotype. EVs from pathological OCs activate bone-resorbing OCs and suppress bone-forming osteoblasts (OBs), leading to bone destruction. Pathological OCs increased IL-1β secretion and produced EV …

Conditional Deletion of Gremlin-1 in Cathepsin K-expressing Mature Osteoclasts Altered the Skeletal Response to Calcium Depletion in Sex-Dependent Manner.

This study assessed the novel concept that osteoclast-derived Grem1 has regulatory functions in the skeletal response to calcium stress using an osteoclastic Grem1 conditional knockout (cKO) mouse model. The calcium stress was initiated by feeding cKO mutants and wildtype (WT) littermates a calcium-deficient diet for 2 weeks. Deletion of Grem1 in mature osteoclasts did not affect developmental bone growth nor basal bone turnover. In response to calcium depletion, male cKO mutants showed greater increases in osteoclastic resorption and trabecular bone loss than male WT littermates, indicating a…

Anti-Osteoporotic Activity of Harpagoside by Upregulation of the BMP2 and Wnt Signaling Pathways in Osteoblasts and Suppression of Differentiation in Osteoclasts.

Harpagoside (1) is an iridoid glycoside isolated from the radix of Harpagophytum procumbens var. sublobatum, commonly called Devil's claw. The anti-osteoporotic effect of 1 was investigated in both in vitro cell cultures and in vivo using an ovariectomized (OVX) mouse model. Compound 1 induced bone formation by stimulating osteoblast proliferation, alkaline phosphatase activity, and mineralization in osteoblastic MC3T3-E1 cells. Treatment with 1 increased the mRNA and protein expression of bone formation biomarkers through regulation of the BMP2 and Wnt signaling pathway in MC3T3-E1 cells. Com

Osteopontin signals through calcium and nuclear factor of activated T cells (NFAT) in osteoclasts: a novel RGD-dependent pathway promoting cell survival.

Osteopontin (OPN), an integrin-binding extracellular matrix glycoprotein, enhances osteoclast activity; however, its mechanisms of action are elusive. The Ca(2+)-dependent transcription factor NFATc1 is essential for osteoclast differentiation. We assessed the effects of OPN on NFATc1, which translocates to nuclei upon activation. Osteoclasts from neonatal rabbits and rats were plated on coverslips, uncoated or coated with OPN or bovine albumin. OPN enhanced the proportion of osteoclasts exhibiting nuclear NFATc1. An RGD-containing, integrin-blocking peptide prevented the translocation of NFAT…

Substance P increases production of proinflammatory cytokines and formation of osteoclasts in dental pulp fibroblasts in patients with severe orthodontic root resorption.

INTRODUCTION: The objective of this study was to determine the extent to which substance P (SP) increases proinflammatory cytokine productio … after 24 hours by using ELISA kits. Furthermore, culture supernatants were added to cultured human osteoclasts, and osteoclast formation was observed after tartrate-resistant acid phosphatase (TRAP) staining and the formation of resorption cavities. RESULTS: Stimulation with SP increased the levels of IL-1beta, IL-6, and TNF-alpha, in a time- and concentrat …

Recruitment of osteoclasts in the mandibular condyle of growing osteopetrotic (op/op) mice after a single injection of macrophage colony-stimulating factor.

The purpose was to elucidate histological changes in the mandibular condyle and ramus in growing osteopetrotic (op/op) mice after a single i … ugh the numbers were substantially different for all ages. The uninjected op/op mice had no visible osteoclasts until 15 days and their number then increased significantly from 60 to 90 days of age. These results were considered due to the difference in biological responses of bony structures to M-CSF injection in the op/op mice. The influences of mechanical …

Tartrate-resistant acid phosphatase activity in tibial osteoclasts and cells elicited by ectopic bone and suture implants in normal and osteopetrotic rats.

Bone-induced multinucleated cells have been suggested as surrogates for the study of osteoclastic lineage and function. This study evaluates this proposal by comparing acid phosphatase localization in tibial osteoclasts (in situ) with that of cell populations elicited by subcutaneous implantation of devitalized trabecular bone chips from two week old rats and suture into normal and osteopetrotic (ia) rats, emphasizing tartrate-resistant acid phosphatase, an osteoclastic marker. The ia rat mutation of osteopetrosis is characterized by defective osteoclasts which typically express enhanced TRAP …

Clinical characteristics and survival outcomes for undifferentiated carcinoma with/without osteoclast-like giant cells of the pancreas.

Undifferentiated carcinoma of the pancreas (UCP) are extremely rare entities and there is currently no standardized treatment guideline for it, with its characteristics and prognosis remaining unclear. UCP with osteoclast-like giant cells (OGCs) and without OGCs represent two different pathological types of pancreatic ductal adenocarcinoma. This study aimed to improve our understanding of these entities with a focus on the comparison between these two entities. Patients diagnosed with undifferentiated carcinoma with osteoclast-like giant cells of the pancreas (UCOGCP) and UCP without OGCs (non

The Neuro-Bone Axis in Metastatic Progression: Innervation, Neuro-Immune-Osteoclast Crosstalk, and Therapeutic Opportunities.

Bone metastases represent a major cause of morbidity in advanced cancers, yet the neural regulation of metastatic growth within bone remains largely unexplored. The skeletal system is richly innervated by sensory and sympathetic nerve fibers that influence bone remodeling, hematopoiesis, and immune surveillance. Emerging evidence suggests that disseminated tumor cells exploit these neural circuits to create a growth-permissive microenvironment. Tumor-secreted neurotrophic factors can induce nerve sprouting, while sympathetic activation via β-adrenergic receptors promotes osteoclastogenesis, im

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… Norepinephrine binds β2-adrenergic receptors expressed mainly on osteoblasts but also on osteoclasts [ 16 , 17 , 19 ]. … Semaphorin 4D (Sema4D), produced from osteoclasts, and its receptor, Plexin B1, impede osteoblast differentiation and are associated with bone metastasis; Sema4D is overexpressed in breast cancer cells and facilitates skeletal metastases, partly through osteoclast activation and osteoblast suppression …

In silico exploration of osteoclast precursor inhibition for preventing rapid bone loss after denosumab discontinuation.

Denosumab is a potent anti-resorptive drug for osteoporosis treatment that increases bone mass and reduces fracture risk. However, its discontinuation causes a rebound phenomenon where bone is rapidly lost by activated resorption, possibly because of the accumulation of osteoclast precursors. Here, we propose a therapeutic strategy wherein osteoclast precursor apoptosis is induced to prevent the rebound. To investigate the efficacy of this undeveloped osteoclast precursor inhibitor (OCPI), we performed in silico experiments with denosumab treatment followed by OCPI or alendronate. The accumula

Icariin alleviates ovariectomy-induced osteoporosis by promoting M2 macrophage polarization and suppressing osteoclast activation.

BACKGROUND: Osteoporosis is a prevalent skeletal disorder marked by reduced bone strength and increased fragility, especially in postmenopausal women and older adults. Icariin (ICA), a natural flavonoid, has been reported to stimulate osteoblastogenesis and suppress osteoclast activity. METHODS: Female BALB/c mice underwent bilateral ovariectomy (OVX) or sham surgery and were maintained for 12 weeks. ICA (80 mg/kg in distilled water, oral gavage) was administered once daily from postoperative week 1 through week 12. Femoral bone mineral density (BMD) and trabecular architecture were evaluated

Interleukin-33 drives abnormal bone remodeling in ankylosing spondylitis via inhibition of osteoclast differentiation.

OBJECTIVES: Interleukin (IL)-33 has been shown to be abnormally expressed in patients diagnosed with ankylosing spondylitis (AS). However, t … tients with AS. Accordingly, the IL-33/p38/NFATc1 axis may offer a crucial mechanistic link between osteoclasts and osteoblasts for understanding the pathological bone remodeling characteristics of AS.

Undifferentiated Carcinoma with Osteoclast-Like Giant Cells Associated with Carcinoma In Situ of the Main Pancreatic Duct.

INTRODUCTION: Undifferentiated carcinoma with osteoclast-like giant cells (UC-OGC) of the pancreas is an extremely rare subtype of pancreatic malignancy, accounting for less than 1% of cases and generally associated with a poor prognosis. Its histogenesis and progression remain incompletely understood. We report a rare case in which UC-OGC appeared to be associated with carcinoma in situ (CIS) of the main pancreatic duct and achieved long-term disease-free survival after curative resection. CASE PRESENTATION: A 52-year-old man was referred for evaluation of a pancreatic cyst. Imaging revealed