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Rheumatoid arthritis (RA) is characterized by inflammation and destruction of bone and cartilage in affected joints. Autoimmune responses lead to increased osteoclastic bone resorption and impaired osteoblastic bone formation, the imbalance of which underlies bone loss in RA, which includes bone erosion, periarticular bone loss and systemic osteoporosis. The crucial role of osteoclasts in bone erosion has been demonstrated in basic studies as well as by the clinical efficacy of antibodies targeting RANKL, an important mediator of osteoclastogenesis. Synovial fibroblasts contribute to joint damage by stimulating both pro-inflammatory and tissue-destructive pathways. New technologies, such as single-cell RNA sequencing, have revealed the heterogeneity of synovial fibroblasts and of immune cells including T cells and macrophages. To understand the mechanisms of bone damage in RA, it is important to clarify how the immune system promotes the tissue-destructive properties of synovial fibroblasts and influences bone cells. The interaction between immune cells and fibroblasts underlies the imbalance between regulatory T cells and T helper 17 cells, which in turn exacerbates not only inflammation but also bone destruction, mainly by promoting RANKL expression on synovial fibroblasts. An improved understanding of the immune mechanisms underlying joint damage and the interplay between the immune system, synovial fibroblasts and bone will contribute to the identification of novel therapeutic targets in RA.In this Review, the authors provide an overview of the mechanisms contributing to joint damage in rheumatoid arthritis, particularly the interactions among immune cells, fibroblasts and bone, and discuss how this knowledge could inform the development of novel therapies.

In terrestrial vertebrates, bone tissue constitutes the ‘osteoimmune’ system, which functions as a locomotor organ and a mineral reservoir as well as a primary lymphoid organ where haematopoietic stem cells are maintained. Bone and mineral metabolism is maintained by the balanced action of bone cells such as osteoclasts, osteoblasts and osteocytes, yet subverted by aberrant and/or prolonged immune responses under pathological conditions. However, osteoimmune interactions are not restricted to the unidirectional effect of the immune system on bone metabolism. In recent years, we have witnessed the discovery of effects of bone cells on immune regulation, including the function of osteoprogenitor cells in haematopoietic stem cell regulation and osteoblast-mediated suppression of haematopoietic malignancies. Moreover, the dynamic reciprocal interactions between bone and malignancies in remote organs have attracted attention, extending the horizon of osteoimmunology. Here, we discuss emerging concepts in the osteoimmune dialogue in health and disease.It is well known that immune cells can have profound effects on bone cells, but this interaction is not unidirectional. In this review, Tsukasaki and Takayanagi explore the reciprocal dialogue between bone cells and immune cells during health and disease.

Bone has a remarkable endogenous regenerative capacity that enables scarless healing and restoration of its prior mechanical function, even under challenging conditions such as advanced age and metabolic or immunological degenerative diseases. However — despite much progress — a high number of bone injuries still heal with unsatisfactory outcomes. The mechanisms leading to impaired healing are heterogeneous, and involve exuberant and non-resolving immune reactions or overstrained mechanical conditions that affect the delicate regulation of the early initiation of scar-free healing. Every healing process begins phylogenetically with an inflammatory reaction, but its spatial and temporal intensity must be tightly controlled. Dysregulation of this inflammatory cascade directly affects the subsequent healing phases and hinders the healing progression. This Review discusses the complex processes underlying bone regeneration, focusing on the early healing phase and its highly dynamic environment, where vibrant changes in cellular and tissue composition alter the mechanical environment and thus affect the signalling pathways that orchestrate the healing process. Essential to scar-free healing is the interplay of various dynamic cascades that control timely resolution of local inflammation and tissue self-organization, while also providing sufficient local stability to initiate endogenous restoration. Various immunotherapy and mechanobiology-based therapy options are under investigation for promoting bone regeneration.Bone regeneration is a dynamic and tightly regulated process, but various mechanisms can disrupt this process and cause healing impairment. This Review discusses the complex processes that occur during the early phases that might be targeted to prevent bone healing disorders.

Intervertebral disc (IVD) degeneration is a common finding on spine imaging that increases in prevalence with age. IVD degeneration is a frequent cause of low back pain, which is a leading cause of disability. The process of IVD degeneration consists of gradual structural change accompanied by severe alterations in metabolic homeostasis. IVD degeneration, like osteoarthritis, is a common comorbidity in patients with obesity and type 2 diabetes mellitus, two metabolic syndrome pathological conditions in which adipokines are important promoters of low-grade inflammation, extracellular matrix degradation and fibrosis. Impairment in white adipose tissue function, due to the abnormal fat accumulation in obesity, is characterized by increased production of specific pro-inflammatory proteins such as adipokines by white adipose tissue and of cytokines such as TNF by immune cells of the stromal compartment. Investigations into the immunometabolic alterations in obesity and type 2 diabetes mellitus and their interconnections with IVD degeneration provide insights into how adipokines might affect the pathogenesis of IVD degeneration and impair IVD function and repair. Toll-like receptor-mediated signalling has also been implicated as a promoter of the inflammatory response in the metabolic alterations associated with IVD and is thus thought to have a role in IVD degeneration. Pathological starvation, obesity and adipokine dysregulation can result in immunometabolic alterations, which could be targeted for the development of new therapeutics.In this Review, the authors discuss the immunometabolic alterations involved in the pathogenesis of intervertebral disc degeneration, including the role of adipokines in impaired metabolism in intervertebral disc cells, and discuss opportunities for future research and development of new therapies.

Low back pain is a leading cause of disability worldwide. Intervertebral disc (IVD) degeneration is often associated with low back pain but is sometimes asymptomatic. IVD calcification is an often overlooked disc phenotype that might have considerable clinical impact. IVD calcification is not a rare finding in ageing or in degenerative and scoliotic spinal conditions, but is often ignored and under-reported. IVD calcification may lead to stiffer IVDs and altered segmental biomechanics, more severe IVD degeneration, inflammation and low back pain. Calcification is not restricted to the IVD but is also observed in the degeneration of other cartilaginous tissues, such as joint cartilage, and is involved in the tissue inflammatory process. Furthermore, IVD calcification may also affect the vertebral endplate, leading to Modic changes (non-neoplastic subchondral vertebral bone marrow lesions) and the generation of pain. Such effects in the spine might develop in similar ways to the development of subchondral marrow lesions of the knee, which are associated with osteoarthritis-related pain. We propose that IVD calcification is a phenotypic biomarker of clinically relevant disc degeneration and endplate changes. As IVD calcification has implications for the management and prognosis of degenerative spinal changes and could affect targeted therapeutics and regenerative approaches for the spine, awareness of IVD calcification should be raised in the spine community.Intervertebral disc calcification is an often overlooked phenotype that can have considerable clinical consequences. In this article, the authors aim to raise awareness of intervertebral disc calcification and discuss its implications for the management and prognosis of degenerative spinal changes.

Dual-energy X-ray absorptiometry (DXA) is underutilized to measure bone mineral density (BMD) and evaluate fracture risk. We present an automated tool to identify fractures, predict BMD, and evaluate fracture risk using plain radiographs. The tool performance is evaluated on 5164 and 18175 patients with pelvis/lumbar spine radiographs and Hologic DXA. The model is well calibrated with minimal bias in the hip (slope = 0.982, calibration-in-the-large = −0.003) and the lumbar spine BMD (slope = 0.978, calibration-in-the-large = 0.003). The area under the precision-recall curve and accuracy are 0.89 and 91.7% for hip osteoporosis, 0.89 and 86.2% for spine osteoporosis, 0.83 and 95.0% for high 10-year major fracture risk, and 0.96 and 90.0% for high hip fracture risk. The tool classifies 5206 (84.8%) patients with 95% positive or negative predictive value for osteoporosis, compared to 3008 DXA conducted at the same study period. This automated tool may help identify high-risk patients for osteoporosis. Dual-energy X-ray absorptiometry and the Fracture Risk Assessment Tool are recommended tools for osteoporotic fracture risk evaluation, but are underutilized. Here, the authors present an opportunistic tool to identify fractures, predict bone mineral density and evaluate fracture risk using plain pelvis and lumbar spine radiographs.

Key Points Osteoarthritis (OA) is a whole-joint disease in which all of the components of the joint are affected The articular cartilage, subchondral bone, and calcified cartilage form an osteochondral biocomposite that is uniquely adapted to transferring loads during weight bearing and joint motion Marked alterations in the composition, functional properties, and structure of the osteochondral tissues occur during the evolution of OA Alteration in the composition or structure of any of the individual components of the osteochondral unit can initiate OA pathology in the joint The differential capacity of bone and cartilage to adapt to the effects of local mechanical and environmental influences has an important role in the development of OA Crosstalk between chondrocytes and bone cells contributes to OA pathogenesis To develop rational therapies for OA, it is essential to have diagnostic tools to define the state of the components of the osteochondral unit In this Review, the authors summarize the changes that occur in the biocomposite formed by articular cartilage and bone during the evolution of osteoarthritis (OA). They also discuss how an improved understanding of these changes could be exploited to develop new therapies for patients with OA. In diarthrodial joints, the articular cartilage, calcified cartilage, and subchondral cortical and trabecular bone form a biocomposite — referred to as the osteochondral unit — that is uniquely adapted to the transfer of load. During the evolution of the osteoarthritic process the compositions, functional properties, and structures of these tissues undergo marked alterations. Although pathological processes might selectively target a single joint tissue, ultimately all of the components of the osteochondral unit will be affected because of their intimate association, and thus the biological and physical crosstalk among them is of great importance. The development of targeted therapies against the osteoarthritic processes in cartilage or bone will, therefore, require an understanding of the state of these joint tissues at the time of the intervention. Importantly, these interventions will not be successful unless they are applied at the early stages of disease before considerable structural and functional alterations occur in the osteochondral unit. This Review describes the changes that occur in bone and cartilage during the osteoarthritic process, and highlights strategies for how this knowledge could be applied to develop new therapeutic interventions for osteoarthritis.

Denosumab, a human monoclonal antibody against receptor activator of nuclear factor-κB ligand (RANKL), is a potent inhibitor of osteoclast differentiation and activity. As the first biologic drug used to treat osteoporosis, denosumab has shown potent anti-resorptive properties and anti-fracture efficacy. The effects of this drug are also unique compared with the effects of bisphosphonates: namely, long-term treatment with this drug results in a continuous gain of bone mineral density, whereas withdrawal of the drug results in a transient overshoot in bone turnover and rapid bone loss. Although the mechanisms for these specific effects remain incompletely understood, emerging experimental and clinical data have started to highlight potential biological and pharmacological mechanisms by which denosumab might affect osteoclasts, as well as osteoblasts, and cause both sustained bone gain and bone loss upon treatment cessation. This Perspective discusses those potential mechanisms and the future studies and clinical implications that might ensue from these findings.Long-term treatment with the anti-resorptive drug denosumab results in a continuous gain in bone mineral density, whereas denosumab withdrawal results in a transient overshoot in bone turnover, with rapid bone loss. This Perspective explores the potential mechanisms underlying these effects.

Osteoimmunology encompasses all aspects of the cross-regulation of bone and the immune system, including various cell types, signalling pathways, cytokines and chemokines, under both homeostatic and pathogenic conditions. A number of key areas are of increasing interest and relevance to osteoimmunology researchers. Although rheumatoid arthritis has long been recognized as one of the most common autoimmune diseases to affect bone integrity, researchers have focused increased attention on understanding how molecular triggers and innate signalling pathways (such as Toll-like receptors and purinergic signalling pathways) related to pathogenic and/or commensal microbiota are relevant to bone biology and rheumatic diseases. Additionally, although most discussions relating to osteoimmune regulation of homeostasis and disease have focused on the effects of adaptive immune responses on bone, evidence exists of the regulation of immune cells by bone cells, a concept that is consistent with the established role of the bone marrow in the development and homeostasis of the immune system. The active regulation of immune cells by bone cells is an interesting emerging component of investigations that seek to understand how to control immune-associated diseases of the bone and joints.

Pelvic radiograph (PXR) is essential for detecting proximal femur and pelvis injuries in trauma patients, which is also the key component for trauma survey. None of the currently available algorithms can accurately detect all kinds of trauma-related radiographic findings on PXRs. Here, we show a universal algorithm can detect most types of trauma-related radiographic findings on PXRs. We develop a multiscale deep learning algorithm called PelviXNet trained with 5204 PXRs with weakly supervised point annotation. PelviXNet yields an area under the receiver operating characteristic curve (AUROC) of 0.973 (95% CI, 0.960–0.983) and an area under the precision-recall curve (AUPRC) of 0.963 (95% CI, 0.948–0.974) in the clinical population test set of 1888 PXRs. The accuracy, sensitivity, and specificity at the cutoff value are 0.924 (95% CI, 0.912–0.936), 0.908 (95% CI, 0.885–0.908), and 0.932 (95% CI, 0.919–0.946), respectively. PelviXNet demonstrates comparable performance with radiologists and orthopedics in detecting pelvic and hip fractures. Pelvic radiographs (PXRs) are essential for detecting proximal femur and pelvis injuries in trauma patients, but none of the currently available algorithms can detect all kinds of trauma-related radiographic findings. Here, the authors develop a multiscale deep learning algorithm trained with weakly supervised point annotation.