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Current Osteoporosis Reports Aug 2023This article gives a brief overview of the most recent developments in osteosarcoma treatment, including targeting of signaling pathways, immune checkpoint inhibitors,... (Review)
Review
PURPOSE OF REVIEW
This article gives a brief overview of the most recent developments in osteosarcoma treatment, including targeting of signaling pathways, immune checkpoint inhibitors, drug delivery strategies as single or combined approaches, and the identification of new therapeutic targets to face this highly heterogeneous disease.
RECENT FINDINGS
Osteosarcoma is one of the most common primary malignant bone tumors in children and young adults, with a high risk of bone and lung metastases and a 5-year survival rate around 70% in the absence of metastases and 30% if metastases are detected at the time of diagnosis. Despite the novel advances in neoadjuvant chemotherapy, the effective treatment for osteosarcoma has not improved in the last 4 decades. The emergence of immunotherapy has transformed the paradigm of treatment, focusing therapeutic strategies on the potential of immune checkpoint inhibitors. However, the most recent clinical trials show a slight improvement over the conventional polychemotherapy scheme. The tumor microenvironment plays a crucial role in the pathogenesis of osteosarcoma by controlling the tumor growth, the metastatic process and the drug resistance and paved the way of new therapeutic options that must be validated by accurate pre-clinical studies and clinical trials.
Topics: Child; Young Adult; Humans; Immune Checkpoint Inhibitors; Osteosarcoma; Lung Neoplasms; Bone and Bones; Bone Neoplasms; Tumor Microenvironment
PubMed: 37329384
DOI: 10.1007/s11914-023-00803-9 -
International Journal of Molecular... Sep 2023Osteoporosis is a major public health concern affecting millions of people worldwide and resulting in significant economic costs. The condition is characterized by... (Review)
Review
Osteoporosis is a major public health concern affecting millions of people worldwide and resulting in significant economic costs. The condition is characterized by changes in bone homeostasis, which lead to reduced bone mass, impaired bone quality, and an increased risk of fractures. The pathophysiology of osteoporosis is complex and multifactorial, involving imbalances in hormones, cytokines, and growth factors. Understanding the cellular and molecular mechanisms underlying osteoporosis is essential for appropriate diagnosis and management of the condition. This paper provides a comprehensive review of the normal cellular and molecular mechanisms of bone homeostasis, followed by an in-depth discussion of the proposed pathophysiology of osteoporosis through the osteoimmunological, gut microbiome, and cellular senescence models. Furthermore, the diagnostic tools used to assess osteoporosis, including bone mineral density measurements, biochemical markers of bone turnover, and diagnostic imaging modalities, are also discussed. Finally, both the current pharmacological and non-pharmacological treatment algorithms and management options for osteoporosis, including an exploration of the management of osteoporotic fragility fractures, are highlighted. This review reveals the need for further research to fully elucidate the molecular mechanisms underlying the condition and to develop more effective therapeutic strategies.
Topics: Humans; Pathology, Molecular; Osteoporosis; Osteoporotic Fractures; Bone Density; Bone and Bones
PubMed: 37834025
DOI: 10.3390/ijms241914583 -
Cell Proliferation Dec 2023Osteoarthritis is a progressive and heterogeneous joint disease with complex pathogenesis. The various phenotypes associated with each patient suggest that better... (Review)
Review
Osteoarthritis is a progressive and heterogeneous joint disease with complex pathogenesis. The various phenotypes associated with each patient suggest that better subgrouping of tissues associated with genotypes in different phases of osteoarthritis may provide new insights into the onset and progression of the disease. Recently, single-cell RNA sequencing was used to describe osteoarthritis pathogenesis on a high-resolution view surpassing traditional technologies. Herein, this review summarizes the microstructural changes in articular cartilage, meniscus, synovium and subchondral bone that are mainly due to crosstalk amongst chondrocytes, osteoblasts, fibroblasts and endothelial cells during osteoarthritis progression. Next, we focus on the promising targets discovered by single-cell RNA sequencing and its potential applications in target drugs and tissue engineering. Additionally, the limited amount of research on the evaluation of bone-related biomaterials is reviewed. Based on the pre-clinical findings, we elaborate on the potential clinical values of single-cell RNA sequencing for the therapeutic strategies of osteoarthritis. Finally, a perspective on the future development of patient-centred medicine for osteoarthritis therapy combining other single-cell multi-omics technologies is discussed. This review will provide new insights into osteoarthritis pathogenesis on a cellular level and the field of applications of single-cell RNA sequencing in personalized therapeutics for osteoarthritis in the future.
Topics: Humans; Endothelial Cells; Osteoarthritis; Cartilage, Articular; Bone and Bones; Chondrocytes; Sequence Analysis, RNA
PubMed: 37317049
DOI: 10.1111/cpr.13517 -
Aging Cell Jun 2023As we age, our bones undergo a process of loss, often accompanied by muscle weakness and reduced physical activity. This is exacerbated by decreased responsiveness to...
As we age, our bones undergo a process of loss, often accompanied by muscle weakness and reduced physical activity. This is exacerbated by decreased responsiveness to mechanical stimulation in aged skeleton, leading to the hypothesis that decreased mechanical stimulation plays an important role in age-related bone loss. Piezo1, a mechanosensitive ion channel, is critical for bone homeostasis and mechanotransduction. Here, we observed a decrease in Piezo1 expression with age in both murine and human cortical bone. Furthermore, loss of Piezo1 in osteoblasts and osteocytes resulted in an increase in age-associated cortical bone loss compared to control mice. The loss of cortical bone was due to an expansion of the endosteal perimeter resulting from increased endocortical resorption. In addition, expression of Tnfrsf11b, encoding anti-osteoclastogenic protein OPG, decreases with Piezo1 in vitro and in vivo in bone cells, suggesting that Piezo1 suppresses osteoclast formation by promoting Tnfrsf11b expression. Our results highlight the importance of Piezo1-mediated mechanical signaling in protecting against age-associated cortical bone loss by inhibiting bone resorption in mice.
Topics: Aged; Animals; Humans; Mice; Bone and Bones; Bone Diseases, Metabolic; Cortical Bone; Ion Channels; Mechanotransduction, Cellular; Osteoblasts; Osteoclasts
PubMed: 37147884
DOI: 10.1111/acel.13846 -
Osteoarthritis and Cartilage Feb 2024Great progress continues to be made in our understanding of the multiple facets of osteoarthritis (OA) biology. Here, we review the major advances in this field and... (Review)
Review
Great progress continues to be made in our understanding of the multiple facets of osteoarthritis (OA) biology. Here, we review the major advances in this field and progress towards therapy development over the past year, highlighting a selection of relevant published literature from a PubMed search covering the year from the end of April 2022 to the end of April 2023. The selected articles have been arranged in themes. These include 1) molecular regulation of articular cartilage and implications for OA, 2) mechanisms of subchondral bone remodelling, 3) role of synovium and inflammation, 4) role of age-related changes including cartilage matrix stiffening, cellular senescence, mitochondrial dysfunction, metabolic dysfunction, and impaired autophagy, and 5) peripheral mechanisms of OA pain. Progress in the understanding of the cellular and molecular mechanisms responsible for the multiple aspects of OA biology is unravelling novel therapeutic targets for disease modification.
Topics: Humans; Osteoarthritis; Inflammation; Cartilage, Articular; Bone and Bones; Biology
PubMed: 37944663
DOI: 10.1016/j.joca.2023.11.002 -
Bone Research Oct 2023Despite the diverse roles of tripartite motif (Trim)-containing proteins in the regulation of autophagy, the innate immune response, and cell differentiation, their...
Despite the diverse roles of tripartite motif (Trim)-containing proteins in the regulation of autophagy, the innate immune response, and cell differentiation, their roles in skeletal diseases are largely unknown. We recently demonstrated that Trim21 plays a crucial role in regulating osteoblast (OB) differentiation in osteosarcoma. However, how Trim21 contributes to skeletal degenerative disorders, including osteoporosis, remains unknown. First, human and mouse bone specimens were evaluated, and the results showed that Trim21 expression was significantly elevated in bone tissues obtained from osteoporosis patients. Next, we found that global knockout of the Trim21 gene (KO, Trim21) resulted in higher bone mass compared to that of the control littermates. We further demonstrated that loss of Trim21 promoted bone formation by enhancing the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) and elevating the activity of OBs; moreover, Trim21 depletion suppressed osteoclast (OC) formation of RAW264.7 cells. In addition, the differentiation of OCs from bone marrow-derived macrophages (BMMs) isolated from Trim21 and Ctsk-cre; Trim21 mice was largely compromised compared to that of the littermate control mice. Mechanistically, YAP1/β-catenin signaling was identified and demonstrated to be required for the Trim21-mediated osteogenic differentiation of BMSCs. More importantly, the loss of Trim21 prevented ovariectomy (OVX)- and lipopolysaccharide (LPS)-induced bone loss in vivo by orchestrating the coupling of OBs and OCs through YAP1 signaling. Our current study demonstrated that Trim21 is crucial for regulating OB-mediated bone formation and OC-mediated bone resorption, thereby providing a basis for exploring Trim21 as a novel dual-targeting approach for treating osteoporosis and pathological bone loss.
Topics: Animals; Female; Humans; Mice; beta Catenin; Bone and Bones; Cell Differentiation; Osteogenesis; Osteoporosis
PubMed: 37884520
DOI: 10.1038/s41413-023-00296-3 -
Advanced Science (Weinheim,... Jun 2023Bone undergoes constant remodeling by osteoclast bone resorption coupled with osteoblast bone formation at the bone surface. A third major cell type in the bone is...
Bone undergoes constant remodeling by osteoclast bone resorption coupled with osteoblast bone formation at the bone surface. A third major cell type in the bone is osteocytes, which are embedded in the matrix, are well-connected to the lacunar network, and are believed to act as mechanical sensors. Here, it is reported that sympathetic innervation directly regulates lacunar osteocyte-mediated bone resorption inside cortical bone. It is found that sympathetic activity is elevated in different mouse models of bone loss, including lactation, ovariectomy, and glucocorticoid treatment. Further, during lactation elevated sympathetic outflow induces netrin-1 expression by osteocytes to further promote sympathetic nerve sprouting in the cortical bone endosteum in a feed-forward loop. Depletion of tyrosine hydroxylase-positive (TH ) sympathetic nerves ameliorated osteocyte-mediated perilacunar bone resorption in lactating mice. Moreover, norepinephrine activates β-adrenergic receptor 2 (Adrb2) signaling to promote secretion of extracellular vesicles (EVs) containing bone-degrading enzymes for perilacunar bone resorption and inhibit osteoblast differentiation. Importantly, osteocyte-specific deletion of Adrb2 or treatment with a β-blocker results in lower bone resorption in lactating mice. Together, these findings show that the sympathetic nervous system promotes osteocyte-driven bone loss during lactation, likely as an adaptive response to the increased energy and mineral demands of the nursing mother.
Topics: Female; Animals; Mice; Osteocytes; Lactation; Bone and Bones; Cortical Bone; Bone Resorption; Bone Diseases, Metabolic
PubMed: 37186379
DOI: 10.1002/advs.202207602 -
Calcified Tissue International Jul 2023Senescence is a complex cell state characterized by stable cell cycle arrest and a unique secretory pattern known as the senescence-associated secretory phenotype... (Review)
Review
Senescence is a complex cell state characterized by stable cell cycle arrest and a unique secretory pattern known as the senescence-associated secretory phenotype (SASP). The SASP factors, which are heterogeneous and tissue specific, normally include chemokines, cytokines, growth factors, adhesion molecules, and lipid components that can lead to multiple age-associated disorders by eliciting local and systemic consequences. The skeleton is a highly dynamic organ that changes constantly in shape and composition. Senescent cells in bone and bone marrow produce diverse SASP factors that induce alterations of the skeleton through paracrine effects. Herein, we refer to bone cell-associated SASP as "bone-SASP." In this review, we describe current knowledge of cellular senescence and SASP, focusing on the role of senescent cells in mediating bone pathologies during natural aging and premature aging syndromes. We also summarize the role of cellular senescence and the bone-SASP in glucocorticoids-induced bone damage. In addition, we discuss the role of bone-SASP in the development of osteoarthritis, highlighting the mechanisms by which bone-SASP drives subchondral bone changes in metabolic syndrome-associated osteoarthritis.
Topics: Cellular Senescence; Bone and Bones; Osteocytes; Cytokines; Phenotype
PubMed: 37256358
DOI: 10.1007/s00223-023-01100-4 -
Bone Research Apr 2024The interoception maintains proper physiological conditions and metabolic homeostasis by releasing regulatory signals after perceving changes in the internal state of... (Review)
Review
The interoception maintains proper physiological conditions and metabolic homeostasis by releasing regulatory signals after perceving changes in the internal state of the organism. Among its various forms, skeletal interoception specifically regulates the metabolic homeostasis of bones. Osteoarthritis (OA) is a complex joint disorder involving cartilage, subchondral bone, and synovium. The subchondral bone undergoes continuous remodeling to adapt to dynamic joint loads. Recent findings highlight that skeletal interoception mediated by aberrant mechanical loads contributes to pathological remodeling of the subchondral bone, resulting in subchondral bone sclerosis in OA. The skeletal interoception is also a potential mechanism for chronic synovial inflammation in OA. In this review, we offer a general overview of interoception, specifically skeletal interoception, subchondral bone microenviroment and the aberrant subchondral remedeling. We also discuss the role of skeletal interoception in abnormal subchondral bone remodeling and synovial inflammation in OA, as well as the potential prospects and challenges in exploring novel OA therapies that target skeletal interoception.
Topics: Humans; Interoception; Osteoarthritis; Bone and Bones; Cartilage; Inflammation
PubMed: 38561376
DOI: 10.1038/s41413-024-00328-6 -
Frontiers in Endocrinology 2023The skeleton is an organ of dual functionality; on the one hand, it provides protection and structural competence. On the other hand, it participates extensively in... (Review)
Review
The skeleton is an organ of dual functionality; on the one hand, it provides protection and structural competence. On the other hand, it participates extensively in coordinating homeostasis globally given that it is a mineral and hormonal reservoir. Bone is the only tissue in the body that goes through strategically consistent bouts of bone resorption to ensure its integrity and organismal survival in a temporally and spatially coordinated process, known as bone remodeling. Bone remodeling is directly enacted by three skeletal cell types, osteoclasts, osteoblasts, and osteocytes; these cells represent the acting force in a basic multicellular unit and ensure bone health maintenance. The osteocyte is an excellent mechanosensory cell and has been positioned as the choreographer of bone remodeling. It is, therefore, not surprising that a holistic grasp of the osteocyte entity in the bone is warranted. This review discusses osteocytogenesis and associated molecular and morphological changes and describes the osteocytic lacunocanalicular network (LCN) and its organization. We highlight new knowledge obtained from transcriptomic analyses of osteocytes and discuss the regulatory role of osteocytes in promoting osteoclastogenesis with an emphasis on the case of osteoclastogenesis in anosteocytic bones. We arrive at the conclusion that osteocytes exhibit several redundant means through which osteoclast formation can be initiated. However, whether osteocytes are true "orchestrators of bone remodeling" cannot be verified from the animal models used to study osteocyte biology . Results from studying osteocyte biology using current animal models should come with the caveat that these models are not osteocyte-specific, and conclusions from these studies should be interpreted cautiously.
Topics: Animals; Osteogenesis; Osteoclasts; Bone and Bones; Bone Resorption; Osteocytes
PubMed: 37293482
DOI: 10.3389/fendo.2023.1121727