Osteoimmunology and Bone Biology

Topic Information

Dear Colleagues,

Traditionally, osteoimmunology investigated the molecular mechanisms underlying bone destruction associated with inflammatory diseases and focused primarily on the role of osteoclasts in bone homeostasis. In recent years, it has become increasingly clear that other pathologic conditions and genetic deficiencies in immunomodulatory molecules also elicit skeletal phenotypes. The advent of OMIC approaches has also revealed that the immune and bone systems share many molecules, including cytokines, chemokines, transcription factors, and signaling molecules and that bone cells reciprocally regulate immune cells and hematopoiesis. Here, we invite the submission of new studies that explore the role of immune cells and immune-cell-derived factors that control, regulate, or influence the function of osteoblasts, osteoclasts, and osteocytes. Similarly, we seek studies where defects in molecules expressed primarily in skeletal cells, or alleles associated with skeletal phenotypes, reciprocally affect the development, persistence, or behavior of immune cells in the bone marrow, or systemically.

Dr. Gabriela Loots
Dr. Jennifer O. Manilay
Topic Editors

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Participating Journals

Journal Name	Impact Factor	CiteScore	Launched Year	First Decision (median)	APC
Biology biology	4.2	4.0	2012	18.7 Days	CHF 2700	Submit
Biomedicines biomedicines	4.7	3.7	2013	15.4 Days	CHF 2600	Submit
Biomolecules biomolecules	5.5	8.3	2011	16.9 Days	CHF 2700	Submit
Cells cells	6.0	9.0	2012	16.6 Days	CHF 2700	Submit
International Journal of Molecular Sciences ijms	5.6	7.8	2000	16.3 Days	CHF 2900	Submit

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Published Papers (9 papers)

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Open AccessArticle

The Expression and Secretion Profile of TRAP5 Isoforms in Gaucher Disease

by Margarita M. Ivanova, Julia Dao, Neala Loynab, Sohailla Noor, Neil Kasaci, Andrew Friedman and Ozlem Goker-Alpan

Cells 2024, 13(8), 716; https://doi.org/10.3390/cells13080716 - 20 Apr 2024

Viewed by 209

Abstract

Background: Gaucher disease (GD) is caused by glucocerebrosidase (GCase) enzyme deficiency, leading to glycosylceramide (Gb-1) and glucosylsphingosine (Lyso-Gb-1) accumulation. The pathological hallmark for GD is an accumulation of large macrophages called Gaucher cells (GCs) in the liver, spleen, and bone marrow, which are [...] Read more.

Background: Gaucher disease (GD) is caused by glucocerebrosidase (GCase) enzyme deficiency, leading to glycosylceramide (Gb-1) and glucosylsphingosine (Lyso-Gb-1) accumulation. The pathological hallmark for GD is an accumulation of large macrophages called Gaucher cells (GCs) in the liver, spleen, and bone marrow, which are associated with chronic organ enlargement, bone manifestations, and inflammation. Tartrate-resistant acid phosphatase type 5 (TRAP5 protein, ACP5 gene) has long been a nonspecific biomarker of macrophage/GCs activation; however, the discovery of two isoforms of TRAP5 has expanded its significance. The discovery of TRAP5′s two isoforms revealed that it is more than just a biomarker of macrophage activity. While TRAP5a is highly expressed in macrophages, TRAP5b is secreted by osteoclasts. Recently, we have shown that the elevation of TRAP5b in plasma is associated with osteoporosis in GD. However, the role of TRAP isoforms in GD and how the accumulation of Gb-1 and Lyso-Gb-1 affects TRAP expression is unknown. Methods: 39 patients with GD were categorized into cohorts based on bone mineral density (BMD). TRAP5a and TRAP5b plasma levels were quantified by ELISA. ACP5 mRNA was estimated using RT-PCR. Results: An increase in TRAP5b was associated with reduced BMD and correlated with Lyso-Gb-1 and immune activator chemokine ligand 18 (CCL18). In contrast, the elevation of TRAP5a correlated with chitotriosidase activity in GD. Lyso-Gb-1 and plasma seemed to influence the expression of ACP5 in macrophages. Conclusions: As an early indicator of BMD alteration, measurement of circulating TRAP5b is a valuable tool for assessing osteopenia–osteoporosis in GD, while TRAP5a serves as a biomarker of macrophage activation in GD. Understanding the distinct expression pattern of TRAP5 isoforms offers valuable insight into both bone disease and the broader implications for immune system activation in GD. Full article

(This article belongs to the Topic Osteoimmunology and Bone Biology)

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19 pages, 4533 KiB  

Open AccessArticle

Loss of Function of the Retinoblastoma Gene Affects Gap Junctional Intercellular Communication and Cell Fate in Osteoblasts

by Elisha Pendleton, Anthony Ketner, Phil Ransick, Doug Ardekani, Thomas Bodenstine and Nalini Chandar

Biology 2024, 13(1), 39; https://doi.org/10.3390/biology13010039 - 11 Jan 2024

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Abstract

Loss of function of the Retinoblastoma gene (RB1) due to mutations is commonly seen in human osteosarcomas. One of the Rb1 gene functions is to facilitate cell fate from mesenchymal stem cells to osteoblasts and prevent adipocyte differentiations. In this study, we demonstrate [...] Read more.

Loss of function of the Retinoblastoma gene (RB1) due to mutations is commonly seen in human osteosarcomas. One of the Rb1 gene functions is to facilitate cell fate from mesenchymal stem cells to osteoblasts and prevent adipocyte differentiations. In this study, we demonstrate that a stable reduction of Rb1 expression (RbKD) in murine osteoblasts causes them to express higher levels of PPAR-ɣ and other adipocyte-specific transcription factors while retaining high expression of osteoblast-specific transcription factors, Runx2/Cbfa1 and SP7/Osterix. Inhibition of gap junctional intercellular communication (GJIC) in osteoblasts is another mechanism that causes osteoblasts to transdifferentiate to adipocytes. We found that preosteoblasts exposed to osteoblast differentiating media (DP media) increased GJIC. RbKD cells showed reduced GJIC along with a reduction in expression of Cx43, the protein that mediates GJIC. Other membrane associated adhesion protein Cadherin 11 (Cad11) was also decreased. Since PPAR-ɣ is increased with Rb1 loss, we wondered if the reduction of this transcription factor would reverse the changes observed. Reduction of PPAR-ɣ in control osteoblasts slightly increased bone-specific expression and reduced adipocytic expression as expected along with an increase in Cad11 and Cx43 expression. GJIC remained high and was unaffected by a reduction in PPAR-ɣ in control cells. Knockdown of PPAR-ɣ in RbKD cells reduced adipocyte gene expression, while osteoblast-specific expression showed improvement. Cx43, Cad11 and GJIC remained unaffected by PPAR-ɣ reduction. Our observations suggest that increased PPAR-ɣ that happens with Rb1 loss only affects osteoblast-adipocyte-specific gene expression but does not completely reverse Cx43 gene expression or GJIC. Therefore, these effects may represent independent events triggered by Rb1loss and/or the differentiation process. Full article

(This article belongs to the Topic Osteoimmunology and Bone Biology)

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16 pages, 3194 KiB  

Open AccessArticle

The Cysteine Protease Legumain Is Upregulated by Vitamin D and Is a Regulator of Vitamin D Metabolism in Mice

by Karl Martin Forbord, Meshail Okla, Ngoc Nguyen Lunde, Tatjana Bosnjak-Olsen, Guro Arnekleiv, Daniel Hesselson, Harald Thidemann Johansen, Jonathan C. Y. Tang, Moustapha Kassem, Rigmor Solberg and Abbas Jafari

Cells 2024, 13(1), 36; https://doi.org/10.3390/cells13010036 - 22 Dec 2023

Cited by 1 | Viewed by 1091

Abstract

Legumain is a lysosomal cysteine protease that has been implicated in an increasing amount of physiological and pathophysiological processes. However, the upstream mechanisms regulating the expression and function of legumain are not well understood. Here, we provide in vitro and in vivo data [...] Read more.

Legumain is a lysosomal cysteine protease that has been implicated in an increasing amount of physiological and pathophysiological processes. However, the upstream mechanisms regulating the expression and function of legumain are not well understood. Here, we provide in vitro and in vivo data showing that vitamin D₃ (VD₃) enhances legumain expression and function. In turn, legumain alters VD₃ bioavailability, possibly through proteolytic cleavage of vitamin D binding protein (VDBP). Active VD₃ (1,25(OH)₂D₃) increased legumain expression, activity, and secretion in osteogenic cultures of human bone marrow stromal cells. Upregulation of legumain was also observed in vivo, evidenced by increased legumain mRNA in the liver and spleen, as well as increased legumain activity in kidneys from wild-type mice treated with 25(OH)D₃ (50 µg/kg, subcutaneously) for 8 days compared to a control. In addition, the serum level of legumain was also increased. We further showed that active legumain cleaved purified VDBP (55 kDa) in vitro, forming a 45 kDa fragment. In vivo, no VDBP cleavage was found in kidneys or liver from legumain-deficient mice (Lgmn^−/−), whereas VDBP was cleaved in wild-type control mice (Lgmn^+/+). Finally, legumain deficiency resulted in increased plasma levels of 25(OH)D₃ and total VD₃ and altered expression of key renal enzymes involved in VD₃ metabolism (CYP24A1 and CYP27B1). In conclusion, a regulatory interplay between VD₃ and legumain is suggested. Full article

(This article belongs to the Topic Osteoimmunology and Bone Biology)

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34 pages, 1972 KiB  

Open AccessReview

Osteoimmunology of Spondyloarthritis

by Angelo Fassio, Fabiola Atzeni, Maurizio Rossini, Valeria D’Amico, Francesco Cantatore, Maria Sole Chimenti, Chiara Crotti, Bruno Frediani, Andrea Giusti, Giusy Peluso, Guido Rovera, Palma Scolieri, Vincenzo Raimondo, Davide Gatti and on behalf of the Study Group on Osteoporosis and Skeletal Metabolic Diseases of the Italian Society of Rheumatology

Int. J. Mol. Sci. 2023, 24(19), 14924; https://doi.org/10.3390/ijms241914924 - 05 Oct 2023

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Abstract

The mechanisms underlying the development of bone damage in the context of spondyloarthritis (SpA) are not completely understood. To date, a considerable amount of evidence indicates that several developmental pathways are crucially involved in osteoimmunology. The present review explores the biological mechanisms underlying [...] Read more.

The mechanisms underlying the development of bone damage in the context of spondyloarthritis (SpA) are not completely understood. To date, a considerable amount of evidence indicates that several developmental pathways are crucially involved in osteoimmunology. The present review explores the biological mechanisms underlying the relationship between inflammatory dysregulation, structural progression, and osteoporosis in this diverse family of conditions. We summarize the current knowledge of bone biology and balance and the foundations of bone regulation, including bone morphogenetic protein, the Wnt pathway, and Hedgehog signaling, as well as the role of cytokines in the development of bone damage in SpA. Other areas surveyed include the pathobiology of bone damage and systemic bone loss (osteoporosis) in SpA and the effects of pharmacological treatment on focal bone damage. Lastly, we present data relative to a survey of bone metabolic assessment in SpA from Italian bone specialist rheumatology centers. The results confirm that most of the attention to bone health is given to postmenopausal subjects and that the aspect of metabolic bone health may still be underrepresented. In our opinion, it may be the time for a call to action to increase the interest in and focus on the diagnosis and management of SpA. Full article

(This article belongs to the Topic Osteoimmunology and Bone Biology)

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15 pages, 1622 KiB  

Open AccessArticle

The Mechanism of Interleukin 33-Induced Stimulation of Interleukin 6 in MLO-Y4 Cells

by Sae Noguchi, Ryota Yamasaki, Yoshie Nagai-Yoshioka, Tsuyoshi Sato, Kayoko Kuroishi, Kaori Gunjigake, Wataru Ariyoshi and Tatsuo Kawamoto

Int. J. Mol. Sci. 2023, 24(19), 14842; https://doi.org/10.3390/ijms241914842 - 02 Oct 2023

Cited by 1 | Viewed by 948

Abstract

The differentiation and function of osteocytes are controlled by surrounding cells and mechanical stress; however, the detailed mechanisms are unknown. Recent findings suggest that IL-33 is highly expressed in periodontal tissues in orthodontic tooth movement. The present study aimed to elucidate the effect [...] Read more.

The differentiation and function of osteocytes are controlled by surrounding cells and mechanical stress; however, the detailed mechanisms are unknown. Recent findings suggest that IL-33 is highly expressed in periodontal tissues in orthodontic tooth movement. The present study aimed to elucidate the effect of IL-33 on the expression of regulatory factors for bone remodeling and their molecular mechanisms in the osteocyte-like cell line MLO-Y4. MLO-Y4 cells were treated with IL-33, and the activation of intracellular signaling molecules and transcriptional factors was determined using Western blot analysis and chromatin immunoprecipitation assay. IL-33 treatment enhanced the expression of IL-6 in MLO-Y4 cells, which was suppressed by the knockdown of the IL-33 receptor ST2L. Additionally, IL-33 treatment induced activation of NF-κB, JNK/AP-1, and p38 MAPK signaling pathways in MLO-Y4 cells. Moreover, pretreatment with specific inhibitors of NF-κB, p38 MAPK, and JNK/AP-1 attenuated the IL-33-induced expression of IL-6. Furthermore, chromatin immunoprecipitation indicated that IL-33 increased c-Jun recruitment to the IL-6 promoter. Overall, these results suggest that IL-33 induces IL-6 expression and regulates osteocyte function via activation of the NF-κB, JNK/AP-1, and p38 MAPK pathways through interaction with ST2L receptors on the plasma membrane. Full article

(This article belongs to the Topic Osteoimmunology and Bone Biology)

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15 pages, 4928 KiB  

Open AccessArticle

An Integrative Study on the Inhibition of Bone Loss via Osteo-F Based on Network Pharmacology, Experimental Verification, and Clinical Trials in Postmenopausal Women

by Mi Hye Kim, Minkyung Bok, Hyunjung Lim and Woong Mo Yang

Cells 2023, 12(15), 1992; https://doi.org/10.3390/cells12151992 - 03 Aug 2023

Cited by 1 | Viewed by 1069

Abstract

The inhibition of bone loss remains a challenge for postmenopausal women, considering the fact that only three anabolic treatments for osteoporosis have been approved by the FDA. This study aimed to investigate the osteogenic capacities of Osteo-F, a newly developed herbal formula, upon [...] Read more.

The inhibition of bone loss remains a challenge for postmenopausal women, considering the fact that only three anabolic treatments for osteoporosis have been approved by the FDA. This study aimed to investigate the osteogenic capacities of Osteo-F, a newly developed herbal formula, upon integrating network analysis and pre-clinical studies into clinical trials. The network pharmacology analysis showed that a potential mechanism of Osteo-F is closely related to osteoblast differentiation. Consistent with the predicted mechanism, Osteo-F treatment significantly enhanced bone matrix formation and mineralization with collagen expression in osteoblasts. Simultaneously, secreted bone-forming molecules were upregulated by Osteo-F. After the administration of Osteo-F to osteoporotic mice, the femoral BMD and osteocalcin in the serum and bone tissues were significantly improved. Subsequently, a randomized, double-blinded, placebo-controlled clinical trial showed that 253 mg of Osteo-F supplementation for 24 weeks resulted in significant improvements in the Z-score and serum osteocalcin levels of postmenopausal women compared to the placebo, thus indicating bone anabolic efficacy. In the current study, the bone anabolic effect of Osteo-F was determined by activating the differentiation and mineralization of osteoblasts through integrating experiments based on network analysis into clinical trials, with synchronized, reliable evidence, demonstrating that Osteo-F is a novel bone anabolic treatment in postmenopausal women. Full article

(This article belongs to the Topic Osteoimmunology and Bone Biology)

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13 pages, 1205 KiB  

Open AccessArticle

In Rats, Whole and Refined Grains Decrease Bone Mineral Density and Content through Modulating Osteoprotegerin and Receptor Activator of Nuclear Factor Kappa B

by Hussein Sakr, Zenat Khired and Marzieh Moghadas

Biomedicines 2023, 11(6), 1686; https://doi.org/10.3390/biomedicines11061686 - 10 Jun 2023

Cited by 1 | Viewed by 1451

Abstract

Wheat is a staple grain in most parts of the world and is also frequently used in livestock feed. The current study looked at the impact of a wheat grain diet on bone turnover markers. Thirty male rats (n = 10) were [...] Read more.

Wheat is a staple grain in most parts of the world and is also frequently used in livestock feed. The current study looked at the impact of a wheat grain diet on bone turnover markers. Thirty male rats (n = 10) were separated into three groups of ten. The rats in Group 1 were fed a chow diet, while the rats in Group 2 were provided whole grains. The rats in Group 3 were fed refined grains. Each rat’s bone mineral content (BMC) and bone mineral density (BMD) were measured after 12 weeks in the tibia of the right hind limb. We also looked at the amounts of bone turnover indicators in the blood. TRAP-5b (Tartrate-resistant acid Phosphatase 5b), NTx (N-telopeptide of type I collagen), DPD (deoxypyridinoline), alkaline phosphatase (ALP), and osteocalcin (OC), as well as the levels of Receptor Activator of Nuclear Factor Kappa B (RANK) and osteoprotegerin (OPG). Rats fed whole and refined grains showed lower BMC and BMD (p < 0.05) than the control group rats. The grain diet resulted in lower OPG, OC, and ALP levels than the chow-fed rats, as well as significantly higher (p < 0.05) levels of RANK, DPD, TRAB 5b, and NTx. In a rat model, an exclusive whole or refined grain diet lowered bone turnover and mass. Full article

(This article belongs to the Topic Osteoimmunology and Bone Biology)

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22 pages, 4494 KiB  

Open AccessArticle

Anatomical, Histological, and Morphometrical Investigations of the Auditory Ossicles in Chlorocebus aethiops sabaeus from Saint Kitts Island

by Cristian Olimpiu Martonos, Alexandru Ion Gudea, Ioana A. Ratiu, Florin Gheorghe Stan, Pompei Bolfă, William Brady Little and Cristian Constantin Dezdrobitu

Biology 2023, 12(4), 631; https://doi.org/10.3390/biology12040631 - 21 Apr 2023

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Abstract

Otological studies rely on a lot of data drawn from animal studies. A lot of pathological or evolutionary questions may find answers in studies on primates, providing insights into the morphological, pathological, and physiological aspects of systematic biological studies. Our study on auditory [...] Read more.

Otological studies rely on a lot of data drawn from animal studies. A lot of pathological or evolutionary questions may find answers in studies on primates, providing insights into the morphological, pathological, and physiological aspects of systematic biological studies. Our study on auditory ossicles moves from a pure morphological (macroscopic and microscopic) investigation of auditory ossicles to the morphometrical evaluation of several individuals as well as to some interpretative data regarding some functional aspects drawn from these investigations. Particularities from this perspective blend with metric data and point toward comparative elements that might also serve as an important reference in further morphologic and comparative studies. Full article

(This article belongs to the Topic Osteoimmunology and Bone Biology)

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29 pages, 2505 KiB  

Open AccessReview

Osteopontin: A Bone-Derived Protein Involved in Rheumatoid Arthritis and Osteoarthritis Immunopathology

by Beatriz Teresita Martín-Márquez, Flavio Sandoval-García, Fernanda Isadora Corona-Meraz, Erika Aurora Martínez-García, Pedro Ernesto Sánchez-Hernández, Mario Salazar-Páramo, Ana Lilia Fletes-Rayas, Daniel González-Inostroz and Monica Vazquez-Del Mercado

Biomolecules 2023, 13(3), 502; https://doi.org/10.3390/biom13030502 - 09 Mar 2023

Cited by 5 | Viewed by 3068

Abstract

Osteopontin (OPN) is a bone-derived phosphoglycoprotein related to physiological and pathological mechanisms that nowadays has gained relevance due to its role in the immune system response to chronic degenerative diseases, including rheumatoid arthritis (RA) and osteoarthritis (OA). OPN is an extracellular matrix (ECM) [...] Read more.

Osteopontin (OPN) is a bone-derived phosphoglycoprotein related to physiological and pathological mechanisms that nowadays has gained relevance due to its role in the immune system response to chronic degenerative diseases, including rheumatoid arthritis (RA) and osteoarthritis (OA). OPN is an extracellular matrix (ECM) glycoprotein that plays a critical role in bone remodeling. Therefore, it is an effector molecule that promotes joint and cartilage destruction observed in clinical studies, in vitro assays, and animal models of RA and OA. Since OPN undergoes multiple modifications, including posttranslational changes, proteolytic cleavage, and binding to a wide range of receptors, the mechanisms by which it produces its effects, in some cases, remain unclear. Although there is strong evidence that OPN contributes significantly to the immunopathology of RA and OA when considering it as a common denominator molecule, some experimental trial results argue for its protective role in rheumatic diseases. Elucidating in detail OPN involvement in bone and cartilage degeneration is of interest to the field of rheumatology. This review aims to provide evidence of the OPN’s multifaceted role in promoting joint and cartilage destruction and propose it as a common denominator of AR and OA immunopathology. Full article

(This article belongs to the Topic Osteoimmunology and Bone Biology)

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