Wnt Pathway Extracellular Components and Their Essential Roles in Bone Homeostasis

The Wnt pathway is involved in several processes essential for bone development and homeostasis. For proper functioning, the Wnt pathway is tightly regulated by numerous extracellular elements that act by both activating and inhibiting the pathway at different moments. This review aims to describe, summarize and update the findings regarding the extracellular modulators of the Wnt pathway, including co-receptors, ligands and inhibitors, in relation to bone homeostasis, with an emphasis on the animal models generated, the diseases associated with each gene and the bone processes in which each member is involved. The precise knowledge of all these elements will help us to identify possible targets that can be used as a therapeutic target for the treatment of bone diseases such as osteoporosis.

Distinct Glucocorticoid Receptor Actions in Bone Homeostasis and Bone Diseases

Glucocorticoids (GCs) are steroid hormones that respond to stress and the circadian rhythm. Pharmacological GCs are widely used to treat autoimmune and chronic inflammatory diseases despite their adverse effects on bone after long-term therapy. GCs regulate bone homeostasis in a cell-type specific manner, affecting osteoblasts, osteoclasts, and osteocytes. Endogenous physiological and exogenous/excessive GCs act via nuclear receptors, mainly via the GC receptor (GR). Endogenous GCs have anabolic effects on bone mass regulation, while excessive or exogenous GCs can cause detrimental effects on bone. GC-induced osteoporosis (GIO) is a common adverse effect after GC therapy, which increases the risk of fractures. Exogenous GC treatment impairs osteoblastogenesis, survival of the osteoblasts/osteocytes and prolongs the longevity of osteoclasts. Under normal physiological conditions, endogenous GCs are regulated by the circadian rhythm and circadian genes display oscillatory rhythmicity in bone cells. However, exogenous GCs treatment disturbs the circadian rhythm. Recent evidence suggests that the disturbed circadian rhythm by continuous exogenous GCs treatment can in itself hamper bone integrity. GC signaling is also important for fracture healing and rheumatoid arthritis, where crosstalk among several cell types including macrophages and stromal cells is indispensable. This review summarizes the complexity of GC actions via GR in bone cells at cellular and molecular levels, including the effect on circadian rhythmicity, and outlines new therapeutic possibilities for the treatment of their adverse effects.

Marein prevented LPS-induced osteoclastogenesis by regulating the NF-κB pathway in vitro

Gram-negative bacterial infection causes many bone diseases such as osteolysis, osteomyelitis and septic arthritis. Lipopolysaccharide (LPS), a bacteria product, played an important role in this process. Drugs that inhibited LPS-induced osteoclastogenesis were urgently needed for the prevention of bone destruction in infective bone diseases. Marein, a major bioactive compound of Coreopsis.tinctoria, which possesses anti-oxidative, anti-inflammatory, anti-hypertensive, anti-hyperlipidemic and anti-diabetic effects. In this study, the effect of marein on RAW264.7 cells was measured by CCK-8 assay; TRAP staining was used to determine osteoclastogenesis; the levels of osteoclast-related genes and NF-κB-related proteins were analyzed by WB; the levels of pro-inflammatory cytokines were quantified by ELISA. Our results showed that marein inhibited LPS-induced osteoclast formation from osteoclast precursor RAW264.7 cells. The effect of marein was related to its inhibitory function on expressions of pro-inflammatory cytokines and osteoclast-related genes including RANK, TRAF6, MMP-9, CK and CAⅡ. Besides, marein treatment could inhibit LPS-induced activation of NF-κB signaling pathway in RAW264.7 cells. Meanwhile, inhibition of NF-κB signaling pathway decreased the formation of osteoclasts and expression of pro-inflammatory cytokines which were LPS-induced. Collectively, marein could prevent LPS-induced osteoclast formation in vitro by regulating NF-κB signaling pathway. These findings provided evidence that marein might be beneficial as a valuable choice for the prevention and treatment of bacteria-induced bone destruction disease, and gave new insights for understanding its possible mechanism.

The Emerging Role of MicroRNAs in Bone Diseases and Their Therapeutic Potential

MicroRNAs (miRNAs) are a class of small (20–24 nucleotides), highly conserved, non-coding RNA molecules whose main function is the post-transcriptional regulation of gene expression through sequence-specific manners, such as mRNA degradation or translational repression. Since these key regulatory molecules are implicated in several biological processes, their altered expression affects the preservation of cellular homeostasis and leads to the development of a wide range of pathologies. Over the last few years, relevant investigations have elucidated that miRNAs participate in different stages of bone growth and development. Moreover, the abnormal expression of these RNA molecules in bone cells and tissues has been significantly associated with the progression of numerous bone diseases, including osteoporosis, osteosarcoma, osteonecrosis and bone metastasis, among others. In fact, miRNAs regulate multiple pathological mechanisms, including altering either osteogenic or osteoblast differentiation, metastasis, osteosarcoma cell proliferation, and bone loss. Therefore, in this present review, aiming to impulse the research arena of the biological implications of miRNA transcriptome in bone diseases and to explore their potentiality as a theragnostic target, we summarize the recent findings associated with the clinical significance of miRNAs in these ailments.

Osteogenic Effects of Triterpene Saponin Soyasapogenol B on Differentiation, Mineralization, Autophagy, and Necroptosis

Background: Triterpenoid saponins are a diverse group of natural compounds in plants. A triterpene saponin, Soyasapogenol B (SoyB), from Arachis hypogaea (peanut) has various pharmacological properties. This study aimed to elucidate pharmacological properties and mechanisms of SoyB on bone-forming cells. Methods: Cell viability adhesion, and migration were analyzed using MTT assay, cell adhesion assay, and Boyden chamber assay. Osteogenic activity and osteogenicity were analyzed using alkaline phosphatase (ALP) staining and activity, and Alizarin Red S (ARS) staining. Cell signaling, protein expression, and autophagy were analyzed using Western blot analysis, immunofluorescence assay, and DAPGreen autophagy detection assay. Results and Conclusion: In the present study, SoyB (> 99.99% purity), triterpene saponin, was isolated from the fruit of A. hypogaea. At concentrations ranging from 1 to 20 mM, SoyB showed no cell proliferation effects, whereas 30 - 100 mM SoyB increased cell proliferation in MC3T3-E1 cells. Next, osteoblast differentiation was analyzed and found that SoyB enhanced ALP staining and activity and bone mineralization as evidence for early and late osteoblast differentiation. SoyB also induced RUNX2 expression in nucleus with the increased phosphorylation of Smad1/5/8 and JNK2 during osteoblast differentiation. In addition, SoyB-mediated osteoblast differentiation was not associated with autophagy and necroptosis. Furthermore, SoyB increased cell migration and adhesion with the upregulation of MMP13 levels during osteoblast differentiation. The findings of this study provide new evidence that SoyB possesses biological effects on osteogenic activity and osteogenicity in bone-forming cells, and suggest a potentially beneficial role for peanuts foods and drugs containing SoyB in the treatment and prevention of bone diseases.

Cellular Senescence in Bone

Senescence is an irreversible cell-cycle arrest process induced by environmental, genetic, and epigenetic factors. An accumulation of senescent cells in bone results in age-related disorders, and one of the common problems is osteoporosis. Deciphering the basic mechanisms contributing to the chronic ailments of aging may uncover new avenues for targeted treatment. This review focuses on the mechanisms and the most relevant research advancements in skeletal cellular senescence. To identify new options for the treatment or prevention of age-related chronic diseases, researchers have targeted hallmarks of aging, including telomere attrition, genomic instability, cellular senescence, and epigenetic alterations. First, this chapter provides an overview of the fundamentals of bone tissue, the causes of skeletal involution, and the role of cellular senescence in bone and bone diseases such as osteoporosis. Next, this review will discuss the utilization of pharmacological interventions in aging tissues and, more specifically, highlight the role of senescent cells to identify the most effective and safe strategies.

A Critical Review of the Design, Manufacture, and Evaluation of Bone Joint Replacements for Bone Repair

With the change of people’s living habits, bone trauma has become a common clinical disease. A large number of bone joint replacements is performed every year around the world. Bone joint replacement is a major approach for restoring the functionalities of human joints caused by bone traumas or some chronic bone diseases. However, the current bone joint replacement products still cannot meet the increasing demands and there is still room to increase the performance of the current products. The structural design of the implant is crucial because the performance of the implant relies heavily on its geometry and microarchitecture. Bionic design learning from the natural structure is widely used. With the progress of technology, machine learning can be used to optimize the structure of bone implants, which may become the focus of research in the future. In addition, the optimization of the microstructure of bone implants also has an important impact on its performance. The widely used design algorithm for the optimization of bone joint replacements is reviewed in the present study. Regarding the manufacturing of the implant, the emerging additive manufacturing technique provides more room for the design of complex microstructures. The additive manufacturing technique has enabled the production of bone joint replacements with more complex internal structures, which makes the design process more convenient. Numerical modeling plays an important role in the evaluation of the performance of an implant. For example, theoretical and numerical analysis can be carried out by establishing a musculoskeletal model to prepare for the practical use of bone implants. Besides, the in vitro and in vivo testing can provide mechanical properties of bone implants that are more in line with the implant recipient’s situation. In the present study, the progress of the design, manufacture, and evaluation of the orthopedic implant, especially the joint replacement, is critically reviewed.

Osteonecrosis of the jaw and antiresorptive agents in benign and malignant diseases: a critical review organized by ECTS

Context Antiresorptive therapy significantly reduces fracture risk in patients with benign bone disease and skeletal-related events (SREs) in patients with bone metastases. Osteonecrosis of the jaw (ONJ) is a rare, but severe condition, manifested as necrotic bone lesion(-s) of the jaws. ONJ has been linked to the use of potent antiresorptive agents, termed as Medication Related ONJ (MRONJ). Methods A working group of the European Calcified Tissue Society (ECTS) and two experts performed an updated detailed review of existing literature on MRONJ incidence, characteristics, and treatment applied in bone diseases with variable severity of skeletal insult, ranging from osteoporosis to prevention of cancer treatment-induced bone loss and SREs in cancer patients with bone metastases. We aimed to identify the differences in various aspects of MRONJ among these distinct patient categories and provide recommendations on how to mitigate the risk and optimally manage MRONJ in each one of them. Results The risk for MRONJ is much higher in patients with advanced malignancies compared to those with benign bone diseases, because of the higher doses and more frequent administration of antiresorptive agents in individuals with compromised general health, along with co-administration of other medications that predispose to MRONJ. The overall risk for MRONJ is considerably lower than the benefits in all categories of patients. Conclusions The risk for MRONJ largely depends on the underlying bone disease and the relevant antiresorptive regimen applied. Physicians and dentists should keep in mind that the benefits of antiresorptive therapy far outweigh the risk for MRONJ development.