Normal Bone Remodeling Research Articles (Page 1)

Diabetes mellitus significantly affects skeletal health, increasing the risk of osteoporosis and fractures in both type 1 and type 2 diabetes. In type 2 diabetes, this risk persists despite normal or elevated bone mineral density, indicating deficits in bone quality and microarchitecture. The pathophysiology involves chronic hyperglycemia, which promotes the accumulation of advanced glycation end-products that impair collagen structure, suppress osteoblast activity, and enhance bone resorption. Other contributing factors include insulin resistance, low-grade inflammation, altered adipokines, and diabetic complications, all of which disrupt normal bone remodeling. Standard diagnostic tools such as dual energy X-ray absorptiometry can underestimate fracture risk in diabetic patients, as they fail to capture qualitative changes in bone. Pharmacologic choices also influence skeletal outcomes. Thiazolidinediones are known to impair bone formation and increase fracture risk, while glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors show more neutral or favorable profiles. In conclusion, diabetes contributes to skeletal fragility through multifactorial mechanisms. Comprehensive management including individualized fracture risk assessment and selection of bone-friendly antidiabetic therapies is important to reduce osteoporosis and fracture risk in this vulnerable population.

Bone metastasis continues to be the greatest challenge in treating patients with prostate cancer despite ongoing research. In bone, prostate cancer tumors hijack normal bone remodeling processes to drive cancer progression. However, it is unclear how these interactions drive bone-metastatic prostate cancer growth in the bone environment. To understand the mechanisms associated with bone-metastatic prostate cancer regulation of mesenchymal stem cells (MSC), we previously identified that bone-metastatic prostate cancer induces MSC expression of the pro-inflammatory chemokine CXCL8 and its mouse functional homologue Cxcl1. To date, there has been little to no information about the role of CXCL1/8 in MSC biology and its impact in the tumor–bone environment. Using genetic deletion of Cxcl1, we discovered a novel role for Cxcl1/8 in regulating MSC osteoblast differentiation, such that targeted deletion of Cxcl1 enhanced MSC osteoblastogenesis. Despite the osteogenic nature of prostate cancer, co-injection of Cxcl1 knockout (KO) MSCs with bone-metastatic prostate cancer in bone significantly suppressed tumor growth compared with co-injection with scrambled control (non-targeting) MSCs, even in the presence of three times more prostate cancer to MSCs. Furthermore, bulk RNA sequencing revealed immune response pathways, both in Cxcl1-KO MSCs and bone-metastatic prostate cancer tumors containing Cxcl1-KO MSCs. In support of this, Cxcl1-KO MSCs reduced immature neutrophils in the bone environment, while increasing monocytes. These findings demonstrate the importance of MSC-derived Cxcl1 in the bone microenvironment and highlight the importance of Cxcl1 in bone-metastatic prostate cancer progression.Implications:MSC-derived Cxcl1 regulates prostate cancer progression in bone.

Osteoporosis is a metabolic bone disease primarily caused by a decreased bone formation and increased bone resorption. Osteoclasts are a special class of terminally differentiated cells that play an important role in normal bone remodeling and bone loss in osteoporosis as well as in a variety of osteolytic diseases. Osteoclasts can be differentiated from monocyte-macrophage cells of the hematopoietic system; they are the key cells in bone resorption. Osteoclast formation and differentiation are regulated by various cytokines and transcription factors. In this review, we summarize recent advances in research on the regulation of osteoclast differentiation and function by factors such as M-CSF, RANKL, AP-1, NFATC1, MITF, and PU.1. Understanding these cytokines and transcription factors can not only help identify targets for osteoclast differentiation but also aid in intervening in the treatment of osteoclast-related diseases.

Osteoporosis is a metabolic disease characterized by low bone density resulting from abnormal bone metabolism, caused by impaired osteogenesis and/or excessive bone resorption. The coordinated differentiation of osteoblasts (originating from mesenchymal stem cells) and osteoclasts (derived from hematopoietic progenitor cells) is necessary for maintaining normal bone remodeling and homeostasis. Metabolites have been confirmed to regulate cellular behavior through post-translational modifications (PTMs), including acetylation, lactylation, and succinylation. During osteoblast and osteoclast differentiation, progenitor cells undergo metabolic rewiring to meet the energy demands of these biological processes. Consequently, local metabolite profiles and intermediate metabolic products dynamically change during bone remodeling, influencing cell differentiation via PTMs. Given the regulatory role of PTMs in bone metabolism, this review systematically examines PTMs involved in osteoblast and osteoclast differentiation and explores potential avenues for addressing osteoporosis.

Diabetes mellitus (DM) is a chronic metabolic disorder that disrupts normal bone remodeling. This study aimed to investigate how the glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide (LIR) addresses bone metabolism imbalances induced by type-II diabetes. Type-II diabetic rat models were established through a single intraperitoneal injection of streptozotocin (STZ). Blood glucose levels were measured using a blood glucose meter, and insulin levels were assessed using an assay kit. Bone formation markers [alkaline phosphatase (ALP), osteocalcin (OCN), and procollagen I N-terminal propeptide (PINP)] and bone resorption markers [tartrate-resistant acid phosphatase (TRACP) and CTX-1] were monitored using assay kits. Bone marrow mesenchymal stem cells (BMSCs) were cultured in vitro under high-fat and high-glucose (HFHS) conditions to mimic diabetic bone metabolism dysregulation. Neutrophil extracellular traps (NETs) formation was examined through immunofluorescent staining and Western blot analysis. Liraglutide was found to reduce STZ-induced NETs formation, as indicated by decreased expression of cit-H3 by 36.90% - 53.57%, myeloperoxidase (MPO) by 55.81% - 65.12%, NE by 53.95% - 65.17%, and PAD4 by 46.81% - 63.83%, alongside increased Sirtuin-1 (SIRT1) expression in femur tissue (70.71% - 91.19%). In vitro, LIR enhanced osteogenesis and inhibited apoptosis, effects that were partially reversed by SIRT1 knockdown. Additionally, SIRT1 knockdown partially restored LIR-induced reductions in oxidative stress, inflammation, and NETs formation. LIR mitigates diabetes-induced bone metabolism imbalance by inhibiting NETs formation through SIRT1 mediation.

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) represents a serious health condition, impacting the lives of many patients worldwide. The condition challenges clinical care due to its complex etiology and limited therapeutic options. A thorough understanding of the pathophysiological and patient-related factors that promote disease development is essential. Recently, the oral microbiome has been implicated as a potential driver and modulating factor of BRONJ by several studies. Modern genomic sequencing methods have provided a wealth of data on the microbial composition of BRONJ lesions; however, the role of individual species in the process of disease development remains elusive. A comprehensive PubMed search was conducted to identify relevant studies on the microbiome of BRONJ patients using the terms "microbiome", "osteonecrosis of the jaws", and "bisphosphonates". Studies focusing on symptoms, epidemiology, pathophysiology, risk factors, and treatment options were included. The principal risk factors for BRONJ are tooth extraction, surgical procedures, and the administration of high doses of bisphosphonates. Importantly, the oral microbiome plays a significant role in the progression of the disease. Several studies have identified alterations of microbial composition in BRONJ lesions. However, there is no consensus regarding bacterial species that are associated with BRONJ across studies. The bacterial genera typically found include Actinomyces, Fusobacterium, and Streptococcus. It is postulated that these microbes contribute to the pathogenesis of BRONJ by promoting inflammation and disrupting normal bone remodeling processes. Current therapeutic approaches are disease-stage-specific and the necessity for more effective treatment strategies remains. This review examines the potential causes of and therapeutic approaches to BRONJ, highlighting the link between microbial colonization and BRONJ development. Future research should seek to more thoroughly investigate the interactions between bisphosphonates, the oral microbiome, and the immune system in order to develop targeted therapies.

Fibrous dysplasia (FD) is a common disorder of the skeletal system in which normal bone deposition and remodelling are disturbed and are replaced by anomalous fibrous tissue of varying stages. The age of presentation may vary depending on the genetic penetration and severity of the disease. Aneurysmal bone cyst (ABC) is a non-aggressive neoplastic pathology wherein there is the presence of blood-filled intramedullary cystic lesions and resultant aneurysm-like dilatation of the involved bone that may be a standalone true neoplasm or ABC-like changes associated with other lesions. Concurrence of FD with ABC-like changes is an uncommon entity with most of such cases involving the craniofacial location. To the best of our knowledge, only two cases of appendicular skeleton FD with ABC could be found in the literature, and neither of them is from the Indian subcontinent. Herein, we report one such case of appendicular FD with concomitant ABC-like changes presenting in the adolescent age group. Prompt and accurate diagnosis guides further surgical management and helps in avoiding inadvertent complications.

Osteostaticytes: A novel osteoclast subset couples bone resorption and bone formation

A traumatic bone cyst (TBC) is an uncommon asymptomatic benign lesion usually diagnosed on radiographic examination as a unilocular radiolucency in the posterior mandibular region. It is classified as a pseudocyst because of absent epithelial lining. The etiology remains unclear but is often a localized aberration in normal bone remodeling or metabolism associated with trauma. We report a TBC in a boy that appeared in the first year of orthodontic treatment below the mandibular right second molar and self-healed nearly 4 years later. The patient had no history of trauma. Surgery was discarded because of difficult access and risk of nerve damage; also, the mandibular body continuity was not jeopardized. Clinical examination and periodic radiographic and CBCT imaging were performed during orthodontic treatment (25 months) and the following retention (26 months). The findings suggest a course of observation of a slow developing TBC that does not compromise mandibular anatomic integrity.

For humans to explore and colonize the universe, both engineering and physiological obstacles must be successfully addressed. A major physiological problem is that humans lose bone rapidly in microgravity. Understanding the underlying mechanisms for this bone loss is crucial for designing strategies to ameliorate these effects. Because bone physiology is entangled with other organ systems, and bone loss is a component of human adaptation to microgravity, strategies to reduce bone loss must also account for potential effects on other systems. Here, we consider the receptors involved in normal bone remodeling and how this regulation is altered in low-gravity environments. We examine how single cells, tissues and organs, and humans as a whole are affected by low gravity, and the role of receptors that have been implicated in responses leading to bone loss. These include receptors linking cells to the extracellular matrix and to each other, alterations in the extracellular matrix associated with changes in gravity, and changes in fluid distribution and fluid behavior due to lack of gravity that may have effects on receptor-based signaling shared by bone and other regulatory systems. Inflammatory responses associated with the environment in space, which include microgravity and radiation, can also potentially trigger bone loss.

Acetaldehyde dehydrogenase 2 (ALDH2) is the second enzyme involved in the breakdown of acetaldehyde into acetic acid during the process of alcohol metabolism. Roughly 40% of East Asians carry one or two ALDH2*2 alleles, and the presence of ALDH2 genetic mutations in individuals may affect the bone remodeling cycle owing to accumulation of acetaldehyde in the body. In this study, we investigated the effects of ALDH2 mutations on bone remodeling. In this study, we examined the effects of ALDH2 polymorphisms on in vitro osteogensis using human induced pluripotent stem cells (hiPSCs). We differentiated wild-type (ALDH2*1/*1-) and ALDH2*1/*2-genotyped hiPSCs into osteoblasts (OBs) and confirmed their OB characteristics. Acetaldehyde was administered to confirm the impact caused by the mutation during OB differentiation. Calcium deposits formed during osteogenesis were significantly decreased in ALDH2*1/*2 OBs. The expression of osteogenic markers were also decreased in acetaldehyde-treated OBs differentiated from the ALDH2*1/*2 hiPSCs. Furthermore, the impact of ALDH2 polymorphism and acetaldehyde-induced stress on inflammatory factors such as 4-hydroxynonenal and tumor necrosis factor α was confirmed. Our findings suggest that individuals with ALDH2 deficiency may face challenges in acetaldehyde breakdown, rendering them susceptible to disturbances in normal bone remodeling therefore, caution should be exercised regarding alcohol consumption. In this proof-of-concept study, we were able to suggest these findings as a result of a disease-in-a-dish concept using hiPSCs derived from individuals bearing a certain mutation. This study also shows the potential of patient-derived hiPSCs for disease modeling with a specific condition.

Bone equilibria and disruptions

Abstract Multiple myeloma (MM) is an osteolytic plasma cell malignancy that, despite being responsive to therapies such as proteasome inhibitors, frequently relapses. Understanding the mechanism and the niches where resistant disease evolves remains of major clinical importance. Cancer cell intrinsic mechanisms and bone ecosystem factors are known contributors to the evolution of resistant MM but the exact contribution of each is difficult to define with current in vitro and in vivo models. Using a novel bmathematical model that incorporates key cellular species of the bone ecosystem that control normal bone remodeling and, in MM, yields a protective environment we studied how, under therapy, the bone ecosystem contributes to the evolutionary dynamics of resistant MM under control and proteasome inhibitor treatment. Our results show that Environmentally-Mediated Drug Resistance (EMDR) might not be sufficient to explain resistant disease. But our results highlight the importance of EMDR in facilitating the emergence of resistance, and more importantly facilitating the survival of tolerant cells, allowing the tumor multiple routes for resistant disease. Our results also provide evidence that intervention with therapies targetting the bone ecosystem would significantly improve the ability of treatment to increase the time to progression for patients with multiple myeloma and, potentially, other diseases where EMDR plays a role. Citation Format: David Basanta, Ryan Bishop, Anna Miller, Conor C. Lynch, Matthew Froid, Ariosto S. Silva, Kenneth H. Shain. The bone microenvironment's impact on the heterogeneity of resistance to proteasome inhibitors in multiple myeloma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Cancer Evolution and Data Science: The Next Frontier; 2023 Dec 3-6; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_2):Abstract nr B019.

Biomaterials are currently a unique class of materials that are essential to improving the standard of human life and extending it. In the assent of the appearance of biomaterials that contain non-toxic elements, in this study, we examine a system of Ti25Mo7Zr15TaxSi (x = 0, 0.5, 0.75, 1 wt.%) for future medical applications. The alloys were developed in a vacuum electric arc furnace and then studied from a structural, mechanical and in vivo assessment (on rabbits) perspective. The effect of the silicon addition was clearly seen in both the structural and the mechanical characteristics, standing out as beta alloys with a dendritic structure and lowering the mechanical properties as a result of the silicon addition. In experimental rabbits, the proliferation of mesenchymal stem cells was observed in the periosteum and peri-implant area, differentiating into osteoblasts and then into osteocytes. Osteoclasts were discovered within the cartilaginous islands that provide structural support to newly formed bone, playing a primary role in bone remodeling. The newly formed spongy tissue adhered to the fibrous capsule that surrounds the alloy, ensuring good osseointegration of metallic implants. The overexpression of Osteopontin, Metalloproteinase-2 (also known as gelatinase A), and Metallopeptidase-9 (also known as gelatinase B) underscores the processes of osteogenesis, bone mineralization, and normal bone remodeling.

Targeting proteostasis network in osteoporosis: Pathological mechanisms and therapeutic implications.

We previously reported that measles virus nucleocapsid protein (MVNP) expression in osteoclasts (OCLs) of patients with Paget disease (PD) or targeted to the OCL lineage in MVNP-transgenic mice (MVNP mice) increases IGF1 production in osteoclasts (OCL-IGF1) and leads to development of PD OCLs and pagetic bone lesions (PDLs). Conditional deletion of Igf1 in OCLs of MVNP mice fully blocked development of PDLs. In this study, we examined whether osteocytes (OCys), key regulators of normal bone remodeling, contribute to PD. OCys in PDLs of patients and of MVNP mice expressed less sclerostin, and had increased RANKL expression compared with OCys in bones from WT mice or normal patients. To test whether increased OCL-IGF1 is sufficient to induce PDLs and PD phenotypes, we generated TRAP-Igf1 (T-Igf1) transgenic mice to determine whether increased IGF1 expression in the absence of MVNP in OCLs is sufficient to induce PDLs and pagetic OCLs. We found that T-Igf1 mice at 16 months of age developed PD OCLs, PDLs, and OCys, with decreased sclerostin and increased RANKL, similar to MVNP mice. Thus, pagetic phenotypes could be induced by OCLs expressing increased IGF1. OCL-IGF1 in turn increased RANKL production in OCys to induce PD OCLs and PDLs.

Participant in the process of normal bone remodeling is vitamin D, which, in addition, has antiinflammatory (anti-cytokine), anti-proliferative and anti-tumor effects. Objective of the study is to assess the level of 25-hydroxyvitamin D3 concentration in blood serum before the start of treatment in patients with benign, primary malignant and metastatic bone tumors, taking into account polymorbidity. Materials and methods. The following patients were included in the study: 21 patients with benign pelvic bone tumors; 52 patients with malignant tumors of the bones of the pelvis and lower limbs; 52 patients with metastatic tumors of the bones of the pelvis and lower limbs. The control group consisted of 22 practically healthy volunteers without chronic diseases. The content of vitamin D was determined by the immunochemiluminescence method. The results. The content of vitamin D in blood serum in patients with benign bone tumors is in the range from 22.4 to 29.6 ng/ml, with primary malignant tumors — from 7.8 to 15.9 ng/ml, with metastatic ones — from 13.8 to 15.5 ng/ml. There are no statistically significant differences between the histotypes of primary malignant bone tumors (p > 0.05). Conclusions. Polymorbidity statistically significantly increases vitamin D deficiency in patients with osteogenic sarcoma and patients with metastatic bone tumors (p < 0.05). According to the national classification of vitamin D content, patients with benign bone tumors have a suboptimal level of vitamin D, while patients with primary malignant and metastatic bone tumors have vitamin D deficiency.

We analyzed pedicle bone from roe bucks that had died around antler casting or shortly before or during the rutting period. Pedicles obtained around antler casting were highly porous and showed signs of intense osteoclastic activity that had caused the formation of an abscission line. Following the detachment of the antler plus a portion of pedicle bone, osteoclastic activity in the pedicles continued for some time, and new bone was deposited onto the separation plane of the pedicle stump, leading to partial pedicle restoration. Pedicles obtained around the rutting period were compact structures. The newly formed, often very large secondary osteons, which had filled the resorption cavities, exhibited a lower mineral density than the persisting older bone. The middle zones of the lamellar infilling frequently showed hypomineralized lamellae and enlarged osteocyte lacunae. This indicates a deficiency in mineral elements during the formation of these zones that occurred along with peak antler mineralization. We suggest that growing antlers and compacting pedicles compete for mineral elements, with the rapidly growing antlers being the more effective sinks. The competition between the two simultaneously mineralizing structures is probably more severe in Capreolus capreolus than in other cervids. This is because roe bucks regrow their antlers during late autumn and winter, a period of limited food and associated mineral supply. The pedicle is a heavily remodeled bone structure with distinct seasonal variation in porosity. Pedicle remodeling differs in several aspects from the normal bone remodeling process in the mammalian skeleton.

Normal bone remodeling depends of a balance between bone forming cells, osteoblasts and bone resorbing cells, the osteoclasts. In chronic arthritides and some inflammatory and autoimmune diseases such as rheumatoid arthritis, there is a great constellation of cytokines produced by pannus that impair bone formation and stimulate bone resorption by inducing osteoclast differentiation and inhibiting osteoblast maturation. Patients with chronic inflammation have multiple causes that lead to low bone mineral density, osteoporosis and a high risk of fracture including circulating cytokines, impaired mobility, chronic administration of glucocorticoids, low vitamin D levels and post-menopausal status in women, among others. Biologic agents and other therapeutic measures to reach prompt remission might ameliorate these deleterious effects. In many cases, bone acting agents need to be added to conventional treatment to reduce the risk of fractures and to preserve articular integrity and independency for daily living activities. A limited number of studies related to fractures in chronic arthritides were published, and future investigation is needed to determine the risk of fractures and the protective effects of different treatments to reduce this risk.

As a highly dynamic organ, bone changes during throughout a person's life. This process is referred to as 'bone remodeling' and it involves two stages - a well-balanced osteoclastic bone resorption and an osteoblastic bone formation. Under normal physiological conditions bone remodeling is highly regulated that ensures tight coupling between bone formation and resorption, and its disruption results in a bone metabolic disorder, most commonly osteoporosis. Though osteoporosis is one of the most prevalent skeletal ailments that affect women and men aged over 40 of all races and ethnicities, currently there are few, if any safe and effective therapeutic interventions available. Developing state-of-the-art cellular systems for bone remodeling and osteoporosis can provide important insights into the cellular and molecular mechanisms involved in skeletal homeostasis and advise better therapies for patients. This review describes osteoblastogenesis and osteoclastogenesis as two vital processes for producing mature, active bone cells in the context of interactions between cells and the bone matrix. In addition, it considers current approaches in bone tissue engineering, pointing out cell sources, core factors and matrices used in scientific practice for modeling bone diseases and testing drugs. Finally, it focuses on the challenges that bone regenerative medicine is currently facing.