Osteoporosis is a metabolic bone disorder that over time results in bone loss and raises the risk of fracture. The condition is frequently silent and only becomes apparent when fractures develop. Osteoporosis is treated with pharmacotherapy as well as non-pharmacological therapies such as mineral supplements, lifestyle changes, and exercise routines. Herbal medicine is frequently used in clinical procedures because of its low risk of adverse effects and cost-effective therapeutic results. In the current review, we have used a thorough strategy to identify some known medicinal plants with anti-osteoporosis capabilities, their origin, active ingredients, and pharmacological information. Furthermore, several signaling pathways, such as the apoptotic pathway, transcription factors, the Wnt/-catenin signaling pathway, and others, are regulated by bioactive components and help to improve bone homeostasis. This review will provide a better understanding of the anti-osteoporotic effects of bioactive components and the concomitant modulations of signaling pathways.

Endoplasmic reticulum (ER) stress and its adaptive mechanism, the unfolded protein response (UPR), are triggered by the accumulation of unfolded and misfolded proteins. During osteoclastogenesis, a large number of active proteins are synthesized. When an imbalance in the protein folding process occurs, it causes osteoclasts to trigger the UPR. This close association has led to the role of the UPR in osteoclastogenesis being increasingly explored. In recent years, several studies have reported the role of ER stress and UPR in osteoclastogenesis and bone resorption. Here, we reviewed the relevant literature and discussed the UPR signaling cascade response, osteoclastogenesis-related signaling pathways, and the role of UPR in osteoclastogenesis and bone resorption in detail. It was found that the UPR signal (PERK, CHOP, and IRE1-XBP1) promoted the expression of the receptor activator of the nuclear factor-kappa B ligand (RANKL) in osteoblasts and indirectly enhanced osteoclastogenesis. IRE1 promoted osteoclastogenesis via promoting NF-κB, MAPK signaling, or the release of pro-inflammatory factors (IL-6, IL-1β, and TNFα). CREBH promoted osteoclast differentiation by promoting NFATc1 expression. The PERK signaling pathway also promoted osteoclastogenesis through NF-κB and MAPK signaling pathways, autophagy, and RANKL secretion from osteoblasts. However, salubrinal (an inhibitor of eIF2α dephosphorylation that upregulated p-eIF2α expression) directly inhibited osteoclastogenesis by suppressing NFATc1 expression and indirectly promoted osteoclastogenesis by promoting RANKL secretion from osteoblasts. Therefore, the specific effects and mechanisms of p-PERK and its downstream signaling on osteoclastogenesis still need further experiments to confirm. In addition, the exact role of ATF6 and BiP in osteoclastogenesis also required further exploration. In conclusion, our detailed and systematic review provides some references for the next step to fully elucidate the relationship between UPR and osteoclastogenesis, intending to provide new insights for the treatment of diseases caused by osteoclast over-differentiation, such as osteoporosis.

Osteoclastogenesis is an ongoing rigorous course that includes osteoclast precursors fusion and bone resorption executed by degradative enzymes. Osteoclastogenesis is controlled by endogenous signaling and/or regulators or affected by exogenous conditions and can also be controlled both internally and externally. More evidence indicates that autophagy, inflammation, and immunity are closely related to osteoclastogenesis and involve multiple intracellular organelles (e.g., lysosomes and autophagosomes) and certain inflammatory or immunological factors. Based on the literature on osteoclastogenesis induced by different regulatory aspects, emerging basic cross-studies have reported the emerging disquisitive orientation for osteoclast differentiation and function. In this review, we summarize the partial potential therapeutic targets for osteoclast differentiation and function, including the signaling pathways and various cellular processes.

OBJECTIVE: In this review, we focus on the recent progress of circular ribonucleic acids (circRNAs)-related molecular mechanisms in the processes of osteogenesis and osteoclastogenesis, and explore their roles in the development of bone-remodeling disorders.
BACKGROUND: The well-coupled bone-formation and bone-resorption processes are vital in bone remodeling. Once the balance is disrupted, bone-remodeling disorders (e.g., osteoporosis and osteopetrosis) occur, severely affecting patients\' quality of life. CircRNAs, the newly discovered members of the non-coding RNA family, have been reported to act as key checkpoints of various signaling pathways that influence osteoblasts and osteoclasts functions, thus regulating the physiological and pathological processes of bone homeostasis.
METHODS: Three English and three Chinese databases [i.e., PubMed, Embase, MEDLINE (via Ovid), Chinese Biomedical Literature, China National Knowledge Infrastructure, and VIP databases] were searched to June 2021 without language restrictions. Studies exploring the roles of circRNAs in key bone remodeling mediators, such as Smad-dependent bone morphogenetic protein (BMP)/transforming growth factor beta (TGF-β), Wnts, runt-related transcription factor (RUNX), forkhead boxes (FOXs), colony-stimulating factor 1 (CSF-1), receptor activator of nuclear factor kappa B ligand (RANKL)/osteoprotegerin (OPG), and circRNA-related bone-remodeling disorders, were included.
CONCLUSIONS: Many circRNAs have been shown to promote osteogenesis and facilitate osteoclast differentiation via diverse mechanisms, and thus modulate the process of bone homeostasis. The imbalance or impairment of these two parts causes diseases, such as osteoporosis, and osteonecrosis of the femoral head, which are also closely correlated to the aberrant presence of circRNAs. Current evidence provides us with promising diagnosis and treatment methods for some bone homeostasis disorders.

Chronic inflammatory diseases are debilitating, affect patients\' quality of life, and are a significant financial burden on health care. Inflammation is regulated by pro-inflammatory cytokines and chemokines that are expressed by immune and non-immune cells, and their expression is highly controlled, both spatially and temporally. Their dysregulation is a hallmark of chronic inflammatory and autoimmune diseases. Significant evidence supports that monoamine oxidase (MAO) inhibitor drugs have anti-inflammatory effects. MAO inhibitors are principally prescribed for the management of a variety of central nervous system (CNS)-associated diseases such as depression, Alzheimer\'s, and Parkinson\'s; however, they also have anti-inflammatory effects in the CNS and a variety of non-CNS tissues. To bolster support for their development as anti-inflammatories, it is critical to elucidate their mechanism(s) of action. MAO inhibitors decrease the generation of end products such as hydrogen peroxide, aldehyde, and ammonium. They also inhibit biogenic amine degradation, and this increases cellular and pericellular catecholamines in a variety of immune and some non-immune cells. This decrease in end product metabolites and increase in catecholamines can play a significant role in the anti-inflammatory effects of MAO inhibitors. This review examines MAO inhibitor effects on inflammation in a variety of in vitro and in vivo CNS and non-CNS disease models, as well as their anti-inflammatory mechanism(s) of action.

Alveolar bone remodeling in orthodontic tooth movement (OTM) is a highly regulated process that coordinates bone resorption by osteoclasts and new bone formation by osteoblasts. Mechanisms involved in OTM include mechano-sensing, sterile inflammation-mediated osteoclastogenesis on the compression side and tensile force-induced osteogenesis on the tension side. Several intracellular signaling pathways and mechanosensors including the cilia and ion channels transduce mechanical force into biochemical signals that stimulate formation of osteoclasts or osteoblasts. To date, many studies were performed in vitro or using human gingival crevicular fluid samples. Thus, the use of transgenic animals is very helpful in examining a cause and effect relationship. Key cell types that participate in mediating the response to OTM include periodontal ligament fibroblasts, mesenchymal stem cells, osteoblasts, osteocytes, and osteoclasts. Intercellular signals that stimulate cellular processes needed for orthodontic tooth movement include receptor activator of nuclear factor-κB ligand (RANKL), tumor necrosis factor-α (TNF-α), dickkopf Wnt signaling pathway inhibitor 1 (DKK1), sclerostin, transforming growth factor beta (TGF-β), and bone morphogenetic proteins (BMPs). In this review, we critically summarize the current OTM studies using transgenic animal models in order to provide mechanistic insight into the cellular events and the molecular regulation of OTM.

BACKGROUND: Osteoporosis results from excessive bone resorption and reduced bone formation, triggered by sex hormone deficiency, oxidative stress and inflammation. Tanshinones are a class of lipophilic phenanthrene compounds found in the roots of Salvia miltiorrhiza with antioxidant and anti-inflammatory activities, which contribute to its anti-osteoporosis effects. This systematic review aims to provide an overview of the skeletal beneficial effects of tanshinones.
METHODS: A systematic literature search was conducted in January 2021 using Pubmed, Scopus and Web of Science from the inception of these databases. Original studies reporting the effects of tanshinones on bone through cell cultures, animal models and human clinical trials were considered.
RESULTS: The literature search found 158 unique articles on this topic, but only 20 articles met the inclusion criteria and were included in this review. The available evidence showed that tanshinones promoted osteoblastogenesis and bone formation while reducing osteoclastogenesis and bone resorption.
CONCLUSIONS: Tanshinones modulates bone remodelling by inhibiting osteoclastogenesis and osteoblast apoptosis and stimulating osteoblastogenesis. Therefore, it might complement existing strategies to prevent bone loss.

Pyogenic spondylodiscitis can cause severe osteolytic and destructive lesions in the spine. Elderly or immunocompromised individuals are particularly susceptible to infectious diseases; specifically, infections in the spine can impair the ability of the spine to support the trunk, causing patients to be bedridden, which can also severely affect the physical condition of patients. Although treatments for osteoporosis have been well studied, treatments for bone loss secondary to infection remain to be elucidated because they have pathological manifestations that are similar to but distinct from those of osteoporosis. Recently, we encountered a patient with severely osteolytic pyogenic spondylodiscitis who was treated with romosozumab and exhibited enhanced bone formation. Romosozumab stimulated canonical Wnt/β-catenin signaling, causing robust bone formation and the inhibition of bone resorption, which exceeded the bone loss secondary to infection. Bone loss due to infections involves the suppression of osteoblastogenesis by osteoblast apoptosis, which is induced by the nuclear factor-κB and mitogen-activated protein kinase pathways, and osteoclastogenesis with the receptor activator of the nuclear factor-κB ligand-receptor combination and subsequent activation of the nuclear factor of activated T cells cytoplasmic 1 and c-Fos. In this study, we review and discuss the molecular mechanisms of bone loss secondary to infection and analyze the efficacy of the medications for osteoporosis, focusing on romosozumab, teriparatide, denosumab, and bisphosphonates, in treating this pathological condition.

BACKGROUND: Members of the botanical families Apiaceae/Umbelliferae, Asteraceae, Fabaceae/Leguminosae, and Thymelaeaceae are rich in coumarins and have traditionally been used as ethnomedicines in many regions including Europe, Asia, and South America. Coumarins are a class of secondary metabolites that are widely present in plants, fungi, and bacteria and exhibit several pharmacological, biochemical, and therapeutic effects. Recently, many plants rich in coumarins and their derivatives were found to affect bone metabolism.
OBJECTIVE: To review scientific literature describing the mechanisms of action of coumarins in osteoclastogenesis and bone resorption.
METHODS: For this systematic review, the PubMed, Scopus, and Periodical Capes databases and portals were searched. We included in vitro research articles published between 2010 and 2020 that evaluated coumarins using osteoclastogenic markers.
RESULTS: Coumarins have been reported to downregulate RANKL-RANK signaling and various downstream signaling pathways required for osteoclast development, such as NF-κB, MAPK, Akt, and Ca2+ signaling, as well as pathways downstream of the nuclear factor of activated T-cells (NFATc1), including tartrate-resistant acid phosphatase (TRAP), cathepsin K (CTSK), and matrix metalloproteinase 9 (MMP-9).
CONCLUSIONS: Coumarins primarily inhibit osteoclast differentiation and activation by modulating different intracellular signaling pathways; therefore, they could serve as potential candidates for controlled randomized clinical trials aimed at improving human bone health.

To identify epigenetic and transcriptional factors controlling osteoclastogenesis (OCG), that have been shown to play a role in the pathogenesis of skeletal diseases.
A systematic review was conducted in accordance with the PRISMA guidelines. The PubMed and EMBASE databases were searched up to 30th April 2020; references of included articles and pertinent review articles were also screened to identify eligible studies. Studies were included if they described epigenetic and/or transcriptional regulation of OCG in a specific skeletal disorder, and quantified alterations in OCG by any well-described experimental method. Risk of bias was assessed by a previously described modification of the CAMARADES tool.
The combined searches yielded 2265 records. Out of these, 24 studies investigating 12 different skeletal disorders were included in the review. Osteoporosis, followed by osteopetrosis, was the most commonly evaluated disorder. A total of 22 different epigenetic and transcriptional regulators of OCG were identified; key epigenetic regulators included DNA methylation, histone methylation, histone acetylation, miRNAs and lncRNAs. In majority of the disorders, dysregulated OCG was noted to occur at the stage of formation of committed osteoclast from preosteoclast. Dysregulation the stage of formation of the preosteoclast from late monocyte was noted in rheumatoid arthritis and fracture, whereas dysregulation at stage of formation of late monocyte from early monocyte was noted in osteopetrosis and spondyloarthritis. Quality assessment revealed a high risk of bias in domains pertaining to randomization, allocation concealment, blinding of outcome assessors and determination of sample size.
A variety of epigenetic and transcriptional factors can result in dysregulated osteoclastogenesis in different skeletal disorders. Dysregulation can occur at any stage; however, the formation of committed osteoclasts from preosteoclasts is the most common target. Although the published literature on this subject seems promising, the overall strength of evidence is limited by the small number of studies evaluating individual skeletal disorders, and also by deficiencies in key aspects of study design.