Bone Research

Journal Information
ISSN / EISSN : 2095-4700 / 2095-6231
Current Publisher: Springer Science and Business Media LLC (10.1038)
Former Publisher: International Journal of Oral Science, West China School of Stomatology (10.4248)
Total articles ≅ 273
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Latest articles in this journal

Nikolai Jaschke, Wolfgang Sipos, , Tilman D. Rachner,
Bone Research, Volume 9, pp 1-10; doi:10.1038/s41413-021-00149-x

The regulation of whole-body homeostasis by the skeleton is mediated by its capacity to secrete endocrine signaling molecules. Although bone-derived hormones confer several adaptive benefits, their physiological functions also involve trade-offs, thus eventually contributing to disease. In this manuscript, we discuss the origins and functions of two of the best-studied skeletal mediators, fibroblast growth factor 23 and osteocalcin, in an evolutionary context. Moreover, we provide a theoretical framework seeking to explain the broad involvement of these two hormones in amniote physiology as well as their potential to fuel the development and progression of diseases. Vice versa, we outline which perturbations might be amenable to manipulation of these systems and discuss limitations and ongoing challenges in skeletal endocrine research. Finally, we summarize unresolved questions and potential future studies in this thriving field.
Sun-Ju Yi, You-Jee Jang, Hye-Jung Kim, Kyubin Lee, Hyerim Lee, Yeojin Kim, Junil Kim, Seon Young Hwang, Jin Sook Song, Hitoshi Okada, et al.
Published: 25 May 2021
Bone Research, Volume 9, pp 1-13; doi:10.1038/s41413-021-00145-1

Bone undergoes a constant and continuous remodeling process that is tightly regulated by the coordinated and sequential actions of bone-resorbing osteoclasts and bone-forming osteoblasts. Recent studies have shown that histone demethylases are implicated in osteoblastogenesis; however, little is known about the role of histone demethylases in osteoclast formation. Here, we identified KDM4B as an epigenetic regulator of osteoclast differentiation. Knockdown of KDM4B significantly blocked the formation of tartrate-resistant acid phosphatase-positive multinucleated cells. Mice with myeloid-specific conditional knockout of KDM4B showed an osteopetrotic phenotype due to osteoclast deficiency. Biochemical analysis revealed that KDM4B physically and functionally associates with CCAR1 and MED1 in a complex. Using genome-wide chromatin immunoprecipitation (ChIP)-sequencing, we revealed that the KDM4B–CCAR1–MED1 complex is localized to the promoters of several osteoclast-related genes upon receptor activator of NF-κB ligand stimulation. We demonstrated that the KDM4B–CCAR1–MED1 signaling axis induces changes in chromatin structure (euchromatinization) near the promoters of osteoclast-related genes through H3K9 demethylation, leading to NF-κB p65 recruitment via a direct interaction between KDM4B and p65. Finally, small molecule inhibition of KDM4B activity impeded bone loss in an ovariectomized mouse model. Taken together, our findings establish KDM4B as a critical regulator of osteoclastogenesis, providing a potential therapeutic target for osteoporosis.
Yao Fan, Rongrong Zha, Tomohiko Sano, Xinyu Zhao, Shengzhi Liu, Mark D. Woollam, Di Wu, Xun Sun, Kexin Li, Motoki Egi, et al.
Published: 24 May 2021
Bone Research, Volume 9, pp 1-10; doi:10.1038/s41413-021-00144-2

Mechanical loading to the bone is known to be beneficial for bone homeostasis and for suppressing tumor-induced osteolysis in the loaded bone. However, whether loading to a weight-bearing hind limb can inhibit distant tumor growth in the brain is unknown. We examined the possibility of bone-to-brain mechanotransduction using a mouse model of a brain tumor by focusing on the response to Lrp5-mediated Wnt signaling and dopamine in tumor cells. The results revealed that loading the tibia with elevated levels of tyrosine hydroxylase, a rate-limiting enzyme in dopamine synthesis, markedly reduced the progression of the brain tumors. The simultaneous application of fluphenazine (FP), an antipsychotic dopamine modulator, enhanced tumor suppression. Dopamine and FP exerted antitumor effects through the dopamine receptors DRD1 and DRD2, respectively. Notably, dopamine downregulated Lrp5 via DRD1 in tumor cells. A cytokine array analysis revealed that the reduction in CCN4 was critical for loading-driven, dopamine-mediated tumor suppression. The silencing of Lrp5 reduced CCN4, and the administration of CCN4 elevated oncogenic genes such as MMP9, Runx2, and Snail. In summary, this study demonstrates that mechanical loading regulates dopaminergic signaling and remotely suppresses brain tumors by inhibiting the Lrp5-CCN4 axis via DRD1, indicating the possibility of developing an adjuvant bone-mediated loading therapy.
Ruoyu Zhou, Qiaoyue Guo, Ye Xiao, Qi Guo, Yan Huang, Changjun Li,
Bone Research, Volume 9, pp 1-19; doi:10.1038/s41413-021-00142-4

S Bone mainly functions as a supportive framework for the whole body and is the major regulator of calcium homeostasis and hematopoietic function. Recently, an increasing number of studies have characterized the significance of bone as an endocrine organ, suggesting that bone-derived factors regulate local bone metabolism and metabolic functions. In addition, these factors can regulate global energy homeostasis by altering insulin sensitivity, feeding behavior, and adipocyte commitment. These findings may provide a new pathological mechanism for related metabolic diseases or be used in the diagnosis, treatment, and prevention of metabolic diseases such as osteoporosis, obesity, and diabetes mellitus. In this review, we summarize the regulatory effect of bone and bone-derived factors on energy metabolism and discuss directions for future research.
Navatha Shree Polavaram, Samikshan Dutta, Ridwan Islam, Arup K. Bag, Sohini Roy, David Poitz, Jeffrey Karnes, Lorenz C. Hofbauer, Manish Kohli, Brian A. Costello, et al.
Published: 14 May 2021
Bone Research, Volume 9, pp 1-16; doi:10.1038/s41413-021-00136-2

Understanding the role of neuropilin 2 (NRP2) in prostate cancer cells as well as in the bone microenvironment is pivotal in the development of an effective targeted therapy for the treatment of prostate cancer bone metastasis. We observed a significant upregulation of NRP2 in prostate cancer cells metastasized to bone. Here, we report that targeting NRP2 in cancer cells can enhance taxane-based chemotherapy with a better therapeutic outcome in bone metastasis, implicating NRP2 as a promising therapeutic target. Since, osteoclasts present in the tumor microenvironment express NRP2, we have investigated the potential effect of targeting NRP2 in osteoclasts. Our results revealed NRP2 negatively regulates osteoclast differentiation and function in the presence of prostate cancer cells that promotes mixed bone lesions. Our study further delineated the molecular mechanisms by which NRP2 regulates osteoclast function. Interestingly, depletion of NRP2 in osteoclasts in vivo showed a decrease in the overall prostate tumor burden in the bone. These results therefore indicate that targeting NRP2 in prostate cancer cells as well as in the osteoclastic compartment can be beneficial in the treatment of prostate cancer bone metastasis.
Xiaowei Zhu, Weiyang Bai,
Bone Research, Volume 9, pp 1-19; doi:10.1038/s41413-021-00143-3

Osteoporosis is a common skeletal disease, affecting ~200 million people around the world. As a complex disease, osteoporosis is influenced by many factors, including diet (e.g. calcium and protein intake), physical activity, endocrine status, coexisting diseases and genetic factors. In this review, we first summarize the discovery from genome-wide association studies (GWASs) in the bone field in the last 12 years. To date, GWASs and meta-analyses have discovered hundreds of loci that are associated with bone mineral density (BMD), osteoporosis, and osteoporotic fractures. However, the GWAS approach has sometimes been criticized because of the small effect size of the discovered variants and the mystery of missing heritability, these two questions could be partially explained by the newly raised conceptual models, such as omnigenic model and natural selection. Finally, we introduce the clinical use of GWAS findings in the bone field, such as the identification of causal clinical risk factors, the development of drug targets and disease prediction. Despite the fruitful GWAS discoveries in the bone field, most of these GWAS participants were of European descent, and more genetic studies should be carried out in other ethnic populations to benefit disease prediction in the corresponding population.
Hanan Aljohani, , Sunipa Majumdar, Deepa Srinivasan, Linda Senbanjo,
Bone Research, Volume 9, pp 1-10; doi:10.1038/s41413-020-00135-9

L-plastin (LPL) was identified as a potential regulator of the actin-bundling process involved in forming nascent sealing zones (NSZs), which are precursor zones for mature sealing zones. TAT-fused cell-penetrating small molecular weight LPL peptide (TAT- MARGSVSDEE, denoted as an inhibitory LPL peptide) attenuated the formation of NSZs and impaired bone resorption in vitro in osteoclasts. Also, the genetic deletion of LPL in mice demonstrated decreased eroded perimeters and increased trabecular bone density. In the present study, we hypothesized that targeting LPL with the inhibitory LPL peptide in vivo could reduce osteoclast function and increase bone density in a mice model of low bone mass. We injected aging C57BL/6 female mice (36 weeks old) subcutaneously with the inhibitory and scrambled peptides of LPL for 14 weeks. Micro-CT and histomorphometry analyses demonstrated an increase in trabecular bone density of femoral and tibial bones with no change in cortical thickness in mice injected with the inhibitory LPL peptide. A reduction in the serum levels of CTX-1 peptide suggests that the increase in bone density is associated with a decrease in osteoclast function. No changes in bone formation rate and mineral apposition rate, and the serum levels of P1NP indicate that the inhibitory LPL peptide does not affect osteoblast function. Our study shows that the inhibitory LPL peptide can block osteoclast function without impairing the function of osteoblasts. LPL peptide could be developed as a prospective therapeutic agent to treat osteoporosis.
Ming Chen, Yi Li, Xiang Huang, Ya Gu, Shang Li, , ,
Bone Research, Volume 9, pp 1-20; doi:10.1038/s41413-021-00138-0

Angiogenesis and osteogenesis are coupled. However, the cellular and molecular regulation of these processes remains to be further investigated. Both tissues have recently been recognized as endocrine organs, which has stimulated research interest in the screening and functional identification of novel paracrine factors from both tissues. This review aims to elaborate on the novelty and significance of endocrine regulatory loops between bone and the vasculature. In addition, research progress related to the bone vasculature, vessel-related skeletal diseases, pathological conditions, and angiogenesis-targeted therapeutic strategies are also summarized. With respect to future perspectives, new techniques such as single-cell sequencing, which can be used to show the cellular diversity and plasticity of both tissues, are facilitating progress in this field. Moreover, extracellular vesicle-mediated nuclear acid communication deserves further investigation. In conclusion, a deeper understanding of the cellular and molecular regulation of angiogenesis and osteogenesis coupling may offer an opportunity to identify new therapeutic targets.
Yan Hu, Xiao Chen, Sicheng Wang, ,
Bone Research, Volume 9, pp 1-13; doi:10.1038/s41413-021-00147-z

Osteoarthritis comprises several joint disorders characterized by articular cartilage degeneration and persistent pain, causing disability and economic burden. The incidence of osteoarthritis is rapidly increasing worldwide due to aging and obesity trends. Basic and clinical research on osteoarthritis has been carried out for decades, but many questions remain unanswered. The exact role of subchondral bone during the initiation and progression osteoarthritis remains unclear. Accumulating evidence shows that subchondral bone lesions, including bone marrow edema and angiogenesis, develop earlier than cartilage degeneration. Clinical interventions targeting subchondral bone have shown therapeutic potential, while others targeting cartilage have yielded disappointing results. Abnormal subchondral bone remodeling, angiogenesis and sensory nerve innervation contribute directly or indirectly to cartilage destruction and pain. This review is about bone-cartilage crosstalk, the subchondral microenvironment and the critical role of both in osteoarthritis progression. It also provides an update on the pathogenesis of and interventions for osteoarthritis and future research targeting subchondral bone.
Tao Yu, Jianguo Zhang, Wei Zhu, , Yun Bai, Bin Feng, Qianyu Zhuang, Chang Han, Shengru Wang, Qimiao Hu, et al.
Bone Research, Volume 9, pp 1-12; doi:10.1038/s41413-021-00140-6

Ankylosing spondylitis (AS) is chronic inflammatory arthritis with a progressive fusion of axial joints. Anti-inflammatory treatments such as anti-TNF-α antibody therapy suppress inflammation but do not effectively halt the progression of spine fusion in AS patients. Here we report that the autoimmune inflammation of AS generates a microenvironment that promotes chondrogenesis in spine ligaments as the process of spine fusion. Chondrocyte differentiation was observed in the ligaments of patients with early-stage AS, and cartilage formation was followed by calcification. Moreover, a large number of giant osteoclasts were found in the inflammatory environment of ligaments and on bony surfaces of calcified cartilage. Resorption activity by these giant osteoclasts generated marrow with high levels of active TGF-β, which induced new bone formation in the ligaments. Notably, no Osterix+ osteoprogenitors were found in osteoclast resorption areas, indicating uncoupled bone resorption and formation. Even at the late and maturation stages, the uncoupled osteoclast resorption in bony interspinous ligament activates TGF-β to induce the progression of ossification in AS patients. Osteoclast resorption of calcified cartilage-initiated ossification in the progression of AS is a similar pathologic process of acquired heterotopic ossification (HO). Our finding of cartilage formation in the ligaments of AS patients revealed that the pathogenesis of spinal fusion is a process of HO and explained why anti-inflammatory treatments do not slow ankylosing once there is new bone formation in spinal soft tissues. Thus, inhibition of HO formation, such as osteoclast activity, cartilage formation, or TGF-β activity could be a potential therapy for AS.
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