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Pathogenesis of Bone Alterations in Gaucher Disease: The Role of Immune System.

Gaucher, the most prevalent lysosomal disorder, is an autosomal recessive inherited disorder due to a deficiency of glucocerebrosidase. Glucocerebrosidase deficiency leads to the accumulation of glucosylceramide primarily in cells of mononuclear-macrophage lineage. Clinical alterations are visceral, hematological, and skeletal. Bone disorder in Gaucher disease produces defects on bone metabolism and structure and patients suffer from bone pain and crisis. Skeletal problems include osteopenia, osteoporosis, osteolytic lesions, and osteonecrosis. On the other hand a chronic stimulation of the im

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… These processes are strictly regulated in physiological conditions, and this regulation implies the participation of osteocytes, which are the final step of osteoblast differentiation [ 2 ]. … Evidence for osteocyte regulation of bone homeostasis through RANKL expression. Nature Medicine. 2011;17(10):1231–1234. doi: 10.1038/nm.2452. 12. Nakashima T., Kobayashi Y., Yamasaki S., et al. …

Role of Exosomal Non-Coding RNAs in Bone-Related Diseases.

Bone-related diseases seriously affect the lives of patients and carry a heavy economic burden on society. Treatment methods cannot meet the diverse clinical needs of affected patients. Exosomes participate in the occurrence and development of many diseases through intercellular communication, including bone-related diseases. Studies have shown that exosomes can take-up and "package" non-coding RNAs and "deliver" them to recipient cells, thereby regulating the function of recipient cells. The exosomal non-coding RNAs secreted by osteoblasts, osteoclasts, chondrocytes, and other cells are invol

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… These observations indicate that exosomal miRNAs from osteocytic cells can change the differentiation trend of osteoblasts and clasts, thereby inhibiting or promoting bone formation. … Targeted Ablation of Osteocytes Induces Osteoporosis with Defective Mechanotransduction . Cel Metab. 5 ( 6 ), 464 – 475 . 10.1016/j.cmet.2007.05.001 17550781 Théry C. Zitvogel L. Amigorena S. ( 2002 ). Exosomes: Composition, Biogenesis and Function . Nat. Rev. …

Wnt signaling in multiple myeloma: a central player in disease with therapeutic potential.

Multiple myeloma is the second most frequent hematological malignancy in the western world and remains incurable, predominantly due to acquired drug resistance and disease relapse. The highly conserved Wnt signal transduction pathway, which plays a key role in regulating cellular processes of proliferation, differentiation, migration, and stem cell self-renewal, is associated with multiple aspects of disease. Bone homeostasis is severely disturbed by Wnt antagonists that are secreted by the malignant plasma cells in the bone marrow. In the vast majority of patients, this results in osteolytic

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… During this process they can become embedded in the bone tissue, which promotes their terminal differentiation into osteocytes. … These factors diffuse from the osteocyte lacuna, via a canalicular network, to the bone surface, where they inhibit osteoblastic activity [ 57 ]. The main function of osteocytes is to regulate bone mass in the context of mechanical loading. …

Breast cancer metastasis to the bone: mechanisms of bone loss.

Breast cancer frequently metastasizes to the skeleton, interrupting the normal bone remodeling process and causing bone degradation. Osteolytic lesions are the end result of osteoclast activity; however, osteoclast differentiation and activation are mediated by osteoblast production of RANKL (receptor activator for NFκB ligand) and several osteoclastogenic cytokines. Osteoblasts themselves are negatively affected by cancer cells as evidenced by an increase in apoptosis and a decrease in proteins required for new bone formation. Thus, bone loss is due to both increased activation of osteoclasts

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… Osteocytes are terminally differentiated osteoblasts that become embedded in the bone matrix at the end of the deposition phase of remodeling. Once osteoblasts finish bone deposition, they undergo apoptosis, remain in the matrix as osteocytes or revert to thin bone-lining cells. … Osteocytes may act as mechanosensing cells and initiate the process when microfractures and loading are involved. In the context of the current discussion, cancer cells may initiate the process. …

Endocrine sequelae of hematopoietic stem cell transplantation: Effects on mineral homeostasis and bone metabolism.

Hematopoietic stem cell transplantation (HSCT) is an established therapeutic strategy for the treatment of malignant (leukemia and lymphoma) and non-malignant (thalassemia, anemia, and immunodeficiency) hematopoietic diseases. Thanks to the improvement in patient care and the development of more tolerable conditioning treatments, which has extended the applicability of therapy to the elderly, a growing number of patients have successfully benefited from HSCT therapy and, more importantly, HSCT transplant-related mortality has consistently reduced in recent years. However, concomitantly to long

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… Osteocytes respond to estrogen deficiency; the absence of estrogen increases osteocyte apoptosis, resulting in increased concentrations of RANKL, probably released by apoptotic osteocytes or as a result of cell-to-cell signaling between healthy and apoptotic osteocytes, which induces increased bone resorption … The role of estrogen in the control of rat osteocyte apoptosis . J Bone Miner Res ( 1998 ) 13 ( 8 ): 1243–50 . doi: 10.1359/jbmr.1998.13.8.1243 9718192 134 Emerton KB Hu B Woo AA Sinofsky A Hernandez C Majeska RJ . Osteocyte apoptosis and control of bone resorption following ovariectomy in mice . …

Cancer metastasis to the bone: Mechanisms and animal models (Review).

The majority of cancer-related deaths result from tumor metastasis, with bone metastasis occurring in almost all types of malignant tumors. Understanding the mechanism by which tumors metastasize to bone is critical for the identification of novel therapeutic targets. A large amount of research has been carried out using animal models, and these models have been crucial in advancing the fundamental understanding of cancer. However, current models are limited; although they can mimic specific stages of the metastatic process, they are not able to replicate the entire process from tumorigenesis

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… During this process, some osteoblasts are trapped by mineralized bone and differentiate into osteocytes. … Osteocytes secrete Sost, which binds to LRP5, thereby blocking the Wnt-LRP5-β-catenin pathway and inhibiting bone formation. …

The role of myeloid derived suppressor cells in musculoskeletal disorders.

The immune system is closely linked to bone homeostasis and plays a pivotal role in several pathological and inflammatory conditions. Through various pathways it modulates various bone cells and subsequently sustains the physiological bone metabolism. Myeloid-derived suppressor cells (MDSCs) are a group of heterogeneous immature myeloid-derived cells that can exert an immunosuppressive function through a direct cell-to-cell contact, secretion of anti-inflammatory cytokines or specific exosomes. These cells mediate the innate immune response to chronic stress on the skeletal system. In chronic

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… Osteocytes also support the lymphocyte development and show positive impact on B cell generation ( 22 , 23 ). … At the same time, bone regeneration is inhibited by interfering cells supporting the bone metabolism, particularly osteoblasts, osteocytes, and bone marrow mesenchymal stromal cells (BMSCs). …

Animal Models of Multiple Myeloma Bone Disease.

Multiple myeloma (MM) is a clonal B-cell disorder characterized by the proliferation of malignant plasma cells (PCs) in the bone marrow, the presence of monoclonal serum immunoglobulin, and osteolytic lesions. It is the second most common hematological malignancy and considered an incurable disease despite significant treatment improvements. MM bone disease (MMBD) is defined as the presence of one or more osteolytic bone lesions or diffused osteoporosis with compression fracture attributable to the underlying clonal PC disorder. MMBD causes severe morbidity and increases mortality. Cumulative

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… The osteocytes in JJN3 intratibially injected mice expressed high sclerostin levels and significant bone lesions ( Delgado-Calle et al., 2016 ). In addition, the coculture of osteocytes with myeloma cells showed substantial reductions of OPG and OB differentiation markers. … Inhibiting the osteocyte-specific protein sclerostin increases bone mass and fracture resistance in multiple myeloma. Blood 129 3452–3464. 10.1182/blood-2017-03-773341 Mirandola L., Yu Y., Chui K., Jenkins M. R., Cobos E., John C. M., et al. (2011). …

Extracellular Vesicles in Bone Metastasis: Key Players in the Tumor Microenvironment and Promising Therapeutic Targets.

Extracellular vesicles (EVs) are lipid membranous vesicles that are released from every type of cell. It has become clear that EVs are involved in a variety of biological phenomena, including cancer progression, and play critical roles in intracellular communication through the horizontal transfer of cellular cargoes such as proteins, DNA fragments, RNAs including mRNA and non-coding RNAs (microRNA, piRNA, and long non-coding RNA) and lipids. The most common cause of death associated with cancer is metastasis. Recent investigations have revealed that EVs are deeply associated with metastasis.

Interleukin-6 Interweaves the Bone Marrow Microenvironment, Bone Loss, and Multiple Myeloma.

The immune system is strongly linked to the maintenance of healthy bone. Inflammatory cytokines, specifically, are crucial to skeletal homeostasis and any dysregulation can result in detrimental health complications. Interleukins, such as interleukin 6 (IL-6), act as osteoclast differentiation modulators and as such, must be carefully monitored and regulated. IL-6 encourages osteoclastogenesis when bound to progenitors and can cause excessive osteoclastic activity and osteolysis when overly abundant. Numerous bone diseases are tied to IL-6 overexpression, including rheumatoid arthritis, osteop

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… Osteocytes, or other systemic signals, control the balance of bone resorption and formation. Osteocytes, the most abundant cell type in bone, are mechanosensing cells that produce signaling molecules in response to changes in pressure, sheer stress, or BMM chemical signals. … Dallas SL Prideaux M Bonewald LF The osteocyte: an endocrine cell … and more . Endocr Rev. ( 2013 ) 34 : 658 – 90 . 10.1210/er.2012-1026 23612223 PMC3785641 23. …

Osteoporosis: Current and Emerging Therapies Targeted to Immunological Checkpoints.

Osteoporosis is a skeletal pathology characterized by compromised bone strength leading to increased risk of fracture, mainly the spine and hip fractures. Osteoporosis affects more than 200 million people worldwide and because of the skeletal fractures it causes, represents a major cause of morbidity, disability and mortality in older people. Recently, the new discoveries of osteoimmunology have clarified many of the pathogenetic mechanisms of osteoporosis, helping to identify new immunological targets for its treatment opening the way for new and effective therapies with biological drugs. Cur

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… Osteoblasts are the precursors of osteocytes, the structural cells of the bone. … Sclerostin is a glycoprotein also produced by osteocytes and encoded by the SOST gene on the long arm of chromosome 17 that both inhibits bone formation by blocking the Wnt pathway and increases bone resorption through the induction of RANKL production by osteocytes. …

Advanced biomaterial-based approaches for medication-related osteonecrosis of the jaw.

Medication-related osteonecrosis of the jaw (MRONJ) is a debilitating adverse effect linked to anti-resorptive and anti-angiogenic therapies, with an incidence of 4.34 % (6.22 % in oncology patients and 0.59 % in osteoporosis patients) based on a pooled analysis of 92 observational studies (2015-2020), characterized by persistent bone exposure and poor healing. Conventional treatment modalities often yield suboptimal outcomes, with recurrence and procedural morbidity. In recent years, biomaterial-based strategies have emerged as promising alternatives by targeting MRONJ's complex pathophysiolo

Management of Myeloma Bone Lesions.

Multiple myeloma (MM) is a B-cell neoplasm characterized by clonal plasma-cell proliferation. The survival and prognosis of this condition have been significantly improved by treatment with active anti-MM drugs such as bortezomib or lenalidomide. Further, the discovery of novel agents has recently paved the way for new areas of investigation. However, MM, including myeloma-related bone diseases, remains fatal. Bone disease or bone destruction in MM is a consequence of skeletal involvement with bone pain, spinal cord compression, and bone fracture resulting from osteolytic lesions. These conseq

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… Osteocytes and the related microenvironment appear to be crucial in the development of MBD. … These interactions promote osteocyte apoptosis, resulting in increased myeloma growth and osteolytic bone destruction ( Figure 1 ) [ 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 ]. 2.1. …

Pathological Fractures in Rare Bone Diseases: Clinical Cases.

Rare bone diseases, though uncommon, present significant diagnostic and therapeutic challenges due to their clinical variability and overlapping symptoms with more prevalent conditions. This article describes a clinical case series of three patients with bone fragility fractures caused by rare bone diseases - primary hyperparathyroidism with brown tumor, Gorham-Stout disease, and alkaptonuria - treated at the Department of Orthopedic and Traumatology of Pisa University Hospital between 2018 and 2023. Each case highlights the diagnostic complexities, including inconclusive biopsies, nonspecific

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… Introduction Bone is a mineralized connective tissue composed of two components: cellular (osteoblasts, osteocytes, and osteoclasts) and extracellular (organic bone and mineral matrix). … Alteration of cellular function This first group includes diseases in which the primary problem is an alteration in the cellular function of the cells that build, remodel, or maintain bone: osteoblasts (which produce the bone matrix), osteoclasts (which resorb the bone matrix), and osteocytes (cells …

Amino acid metabolism in primary bone sarcomas.

Primary bone sarcomas, including osteosarcoma (OS) and Ewing sarcoma (ES), are aggressive tumors with peak incidence in childhood and adolescence. The intense standard treatment for these patients consists of combined surgery and/or radiation and maximal doses of chemotherapy; a regimen that has not seen improvement in decades. Like other tumor types, ES and OS are characterized by dysregulated cellular metabolism and a rewiring of metabolic pathways to support the biosynthetic demands of malignant growth. Not only are cancer cells characterized by Warburg metabolism, or aerobic glycolysis, bu

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… Osteoblasts and osteocytes originate from common precursor bone marrow mesenchymal stem cells ( 23 ). … Molecularly, research has shown that MYC-induced glutaminolysis occurs specifically in MYC-dependent OS cells, but not in osteocytes ( Figure 4 ) ( 92 ). …

Sclerotic prostate cancer bone metastasis: woven bone lesions with a twist.

Bone metastases are the most severe and prevalent consequences of prostate cancer (PC), affecting more than 80% of patients with advanced PC. PCBMs generate pain, pathological fractures, and paralysis. As modern therapies increase survival, more patients are suffering from these catastrophic consequences. Radiographically, PCBMs are predominantly osteosclerotic, but the mechanisms of abnormal bone formation and how this pathological increase in bone density is related to fractures are unclear. In this study, we conducted a comprehensive analysis on a cohort of 76 cadaveric PCBM specimens and 1

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… Higher lacunae density, abnormal lacunae morphology, and orientation characterize osteosclerotic bone in PCBM Lacunae house osteocytes, which are critical to bone modelling. … In bone, the mesenchymal cells are osteoblasts and osteocytes. Although they have been implicated in metastatic progression, 42 the precise mechanism(s) remain to be described. …

Application of Autologous Platelet-Rich Plasma on Tooth Extraction Site Prevents Occurence of Medication-Related Osteonecrosis of the Jaws in Rats.

This study evaluated the effects of local application of autologous platelet-rich plasma (PRP) on the tooth extraction site of rats presenting the main risk factors for medication-related osteonecrosis of the jaw (MRONJ). For seven weeks, senile rats were submitted to systemic treatment with vehicle (VEH and VEH-PRP) or 100 μg/Kg of zoledronate (ZOL and ZOL-PRP) every three days. After three weeks, the first lower molar was extracted. VEH-PRP and ZOL-PRP received PRP at the tooth extraction site. Euthanasia was performed at 28 days postoperatively. Clinical, histopathological, histometric and

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… Symbols: bt, bone tissue; black arrows, osteocytes; ct, connective tissue; ii, inflammatory infiltrate; nvb, non-vital bone; white arrows, empty lacunae or occupied by necrotic remains of osteocytes; † Statistically significant difference in relation to VEH; ‡ Statistically significant difference in … The NVBT consisted of regions where more than ten adjacent osteocyte lacunae were empty or containing osteocyte necrotic debris. The percentage of NFBT and NVBT was expressed as mean ± standard deviation. …

From Cells to Environment: Exploring the Interplay between Factors Shaping Bone Health and Disease.

The skeletal system is an extraordinary structure that serves multiple purposes within the body, including providing support, facilitating movement, and safeguarding vital organs. Moreover, it acts as a reservoir for essential minerals crucial for overall bodily function. The intricate interplay of bone cells plays a critical role in maintaining bone homeostasis, ensuring a delicate balance. However, various factors, both intrinsic and extrinsic, can disrupt this vital physiological process. These factors encompass genetics, aging, dietary and lifestyle choices, the gut microbiome, environment

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… Since osteocytes are terminally developed osteoblasts, it is hypothesized that they may also be impacted, but little research has been done in this area. … This mechanism revolves around osteocytes, primarily bone cells, which can detect and react to mechanical loading. Within this framework, the protein sclerostin, produced by osteocytes, plays a pivotal role by regulating bone formation. …

Innovative Biomaterials for the Treatment of Bone Cancer.

Bone cancer is a demanding challenge for contemporary medicine due to its high frequency of presentation and significant heterogeneity of malignant lesions developing within the bone. To date, available treatments are rarely curative and are primarily aimed at prolonging patients' survival and ameliorating their quality of life. Furthermore, both pharmacological and surgical therapies are aggravated by a consistent burden of adverse events and subsequent disability due to the loss of healthy bone structural and functional properties. Therefore, great research efforts are being made to develop

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… Through this vast network, osteocytes are able to sense mechanical and biological stimuli from the surrounding microenvironment and modulate both osteoblast and osteoclast activity [ 19 ]. … The amazing osteocyte J. Bone Miner. Res. 2011 26 229 238 10.1002/jbmr.320 21254230 PMC3179345 19. Paic F. Igwe J.C. Nori R. Kronenberg M.S. Franceschetti T. Harrington P. Kuo L. Shin D.G. Rowe D.W. Harris S.E. …

Bisphosphonate Treatment Ameliorates Chemotherapy-Induced Bone and Muscle Abnormalities in Young Mice.

Chemotherapy is frequently accompanied by several side effects, including nausea, diarrhea, anorexia and fatigue. Evidence from ours and other groups suggests that chemotherapy can also play a major role in causing not only cachexia, but also bone loss. This complicates prognosis and survival among cancer patients, affects quality of life, and can increase morbidity and mortality rates. Recent findings suggest that soluble factors released from resorbing bone directly contribute to loss of muscle mass and function secondary to metastatic cancer. However, it remains unknown whether similar mech

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… Another example is provided by osteocalcin, mainly produced by mature osteoblasts and osteocytes. … The osteocyte: an endocrine cell … and more. Endocr Rev. (2013) 34:658–90. 10.1210/er.2012-1026 75. Terpos E, Ntanasis-Stathopoulos I, Gavriatopoulou M, Dimopoulos MA. Pathogenesis of bone disease in multiple myeloma: from bench to bedside. …