Special Issue "Recent Advances in Skeletal Development and Diseases"

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: 31 May 2023 | Viewed by 7365

Special Issue Editor

Laboratory of Skeletal Biology, Department of Cell Biology, Van Andel Institute, Grand Rapids, MI 49503, USA
Interests: skeletal stem cell/progenitor maintenance and differentiation in the context of skeletal development, disease, and aging; protein sumoylation and epigenetic regulation
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The skeletal system is the framework for the body, providing protection for fragile internal organs, supporting locomotion, serving as a niche for hematopoiesis, and contributing to mineral metabolism. During embryogenesis, the skeletal system emerges from mesenchymal cells or neural crest cells and forms through a complex developmental process, which is finely orchestrated by interconnecting extracellular signaling networks that ultimately influence nuclear events. Many of the same mechanisms that are pivotal during skeletal development are also necessary for postnatal skeletal homeostasis, and their dysregulation is a main cause of skeletal disease. In this Special Issue, we invite manuscripts on recent advances in the mechanistic studies of skeletal development and diseases.

Dr. Tao Yang
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomolecules is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2300 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • signaling pathways
  • epigenetic regulation
  • stem cells and progenitors
  • environmental factors/stresses
  • cell-cell interaction/microenvironment

Published Papers (8 papers)

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Research

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Article
Effect of Hydrogen Oxide-Induced Oxidative Stress on Bone Formation in the Early Embryonic Development Stage of Chicken
Biomolecules 2023, 13(1), 154; https://doi.org/10.3390/biom13010154 - 12 Jan 2023
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Abstract
The current study aimed to monitor the impact of H2O2-induced oxidative stress on avian bone formation during the early stage of embryonic development. Fertilized Cobb broiler eggs were divided into five treatment groups and micro-injected with varying concentrations of [...] Read more.
The current study aimed to monitor the impact of H2O2-induced oxidative stress on avian bone formation during the early stage of embryonic development. Fertilized Cobb broiler eggs were divided into five treatment groups and micro-injected with varying concentrations of H2O2, i.e., control (PBS; 0 nM), 10 nM, 30 nM, 100 nM, and 300 nM, on embryonic day 3, with continued incubation thereafter. The treatment concentrations were selected based on the level of lipid peroxidation and the survival rate of embryo. Embryos were collected at 6 h, 24 h, 48 h, and 72 h post-injection. The mRNA expression levels of apoptotic markers, antioxidant enzymes, and early bone formation gene markers were measured. The results showed that the microinjection of H2O2 altered the expression pattern of antioxidant enzymes’ mRNA during early embryogenesis and decreased the expression of COL1A2 and COL2A1 at 6 h and 24 h post-injection. Decreased expression of BMP, BGLAP, and RUNX2 was observed 48 h post-injection. Additionally, a shorter embryo length was observed in the 100 nM and 300 nM H2O2 treatment groups 72 h post-injection. In conclusion, H2O2-induced oxidative stress suppressed the expression of bone formation gene markers, with chronic effects on avian embryonic development. Full article
(This article belongs to the Special Issue Recent Advances in Skeletal Development and Diseases)
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Article
Silencing miR-146a-5p Protects against Injury-Induced Osteoarthritis in Mice
Biomolecules 2023, 13(1), 123; https://doi.org/10.3390/biom13010123 - 07 Jan 2023
Viewed by 707
Abstract
Osteoarthritis (OA), the most prevalent joint disease and the leading cause of disability, remains an incurable disease largely because the etiology and pathogenesis underlying this degenerative process are poorly understood. Low-grade inflammation within joints is a well-established factor that disturbs joint homeostasis and [...] Read more.
Osteoarthritis (OA), the most prevalent joint disease and the leading cause of disability, remains an incurable disease largely because the etiology and pathogenesis underlying this degenerative process are poorly understood. Low-grade inflammation within joints is a well-established factor that disturbs joint homeostasis and leads to an imbalance between anabolic and catabolic processes in articular cartilage; however, the complexity of the network between inflammatory factors that often involves positive and negative feedback loops makes current anti-cytokine therapy ineffective. MicroRNAs (miRNAs) have emerged as key regulators to control inflammation, and aberrant miRNAs expression has recently been linked to OA pathophysiology. In the present study, we characterized transcriptomic profiles of miRNAs in primary murine articular chondrocytes in response to a proinflammatory cytokine, IL-1β, and identified miR-146a-5p as the most responsive miRNA to IL-1β. miR-146a-5p was also found to be upregulated in human OA cartilage. We further demonstrated that knockdown of miR-146a-5p antagonized IL-1β-mediated inflammatory responses and IL-1β-induced catabolism in vitro, and silencing of miR-146a in chondrocytes ameliorated articular cartilage destruction and reduced OA-evoked pain in an injury-induced murine OA model. Moreover, parallel RNA sequencing revealed that differentially expressed genes in response to IL-1β were enriched in pathways related to inflammatory processes, cartilage matrix homeostasis, and cell metabolism. Bioinformatic analyses of putative miR-146a-5p gene targets and following prediction of protein–protein interactions suggest a functional role of miR-146a-5p in mediating inflammatory processes and regulation of cartilage homeostasis. Our genetic and transcriptomic data define a crucial role of miR-146a-5p in OA pathogenesis and implicate modulation of miR-146a-5p in articular chondrocytes as a potential therapeutic strategy to alleviate OA. Full article
(This article belongs to the Special Issue Recent Advances in Skeletal Development and Diseases)
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Article
Morphometric Changes of Osteocyte Lacunar in Diabetic Pig Mandibular Cancellous Bone
Biomolecules 2023, 13(1), 49; https://doi.org/10.3390/biom13010049 - 27 Dec 2022
Viewed by 879
Abstract
Osteocytes play an important role in bone metabolism. The interactions of osteocytes with the surrounding microenvironment can alter cellular and lacunar morphological changes. However, objective quantification of osteocyte lacunae is challenging due to their deep location in the bone matrix. This project established [...] Read more.
Osteocytes play an important role in bone metabolism. The interactions of osteocytes with the surrounding microenvironment can alter cellular and lacunar morphological changes. However, objective quantification of osteocyte lacunae is challenging due to their deep location in the bone matrix. This project established a novel method for the analytical study of osteocytes/lacunae, which was then used to evaluate the osteocyte morphological changes in diabetic pig mandibular bone. Eight miniature pigs were sourced, and diabetes was randomly induced in four animals using streptozotocin (STZ) administration. The mandibular tissues were collected and processed. The jawbone density was evaluated with micro-CT. Osteocyte lacunae were effectively acquired and identified using backscattered electron scanning microscopy (BSE). A significantly decreased osteocyte lacunae size was found in the diabetic group. Using the acid etching method, it was demonstrated that the area of osteocyte and lacunae, and the pericellular areas were both significantly reduced in the diabetes group. In conclusion, a standard and relatively reliable method for analyzing osteocyte/lacunae morphological changes under compromised conditions has been successfully established. This method demonstrates that diabetes can significantly decrease osteocyte/lacunae size in a pig’s mandibular cancellous bone. Full article
(This article belongs to the Special Issue Recent Advances in Skeletal Development and Diseases)
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Article
Gabapentin Disrupts Binding of Perlecan to the α2δ1 Voltage Sensitive Calcium Channel Subunit and Impairs Skeletal Mechanosensation
Biomolecules 2022, 12(12), 1857; https://doi.org/10.3390/biom12121857 - 12 Dec 2022
Viewed by 787
Abstract
Our understanding of how osteocytes, the principal mechanosensors within bone, sense and perceive force remains unclear. Previous work identified “tethering elements” (TEs) spanning the pericellular space of osteocytes and transmitting mechanical information into biochemical signals. While we identified the heparan sulfate proteoglycan perlecan [...] Read more.
Our understanding of how osteocytes, the principal mechanosensors within bone, sense and perceive force remains unclear. Previous work identified “tethering elements” (TEs) spanning the pericellular space of osteocytes and transmitting mechanical information into biochemical signals. While we identified the heparan sulfate proteoglycan perlecan (PLN) as a component of these TEs, PLN must attach to the cell surface to induce biochemical responses. As voltage-sensitive calcium channels (VSCCs) are critical for bone mechanotransduction, we hypothesized that PLN binds the extracellular α2δ1 subunit of VSCCs to couple the bone matrix to the osteocyte membrane. Here, we showed co-localization of PLN and α2δ1 along osteocyte dendritic processes. Additionally, we quantified the molecular interactions between α2δ1 and PLN domains and demonstrated for the first time that α2δ1 strongly associates with PLN via its domain III. Furthermore, α2δ1 is the binding site for the commonly used pain drug, gabapentin (GBP), which is associated with adverse skeletal effects when used chronically. We found that GBP disrupts PLN::α2δ1 binding in vitro, and GBP treatment in vivo results in impaired bone mechanosensation. Our work identified a novel mechanosensory complex within osteocytes composed of PLN and α2δ1, necessary for bone force transmission and sensitive to the drug GBP. Full article
(This article belongs to the Special Issue Recent Advances in Skeletal Development and Diseases)
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Article
DAR 16-II Primes Endothelial Cells for Angiogenesis Improving Bone Ingrowth in 3D-Printed BCP Scaffolds and Regeneration of Critically Sized Bone Defects
Biomolecules 2022, 12(11), 1619; https://doi.org/10.3390/biom12111619 - 02 Nov 2022
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Abstract
Bone is a highly vascularized tissue and relies on the angiogenesis and response of cells in the immediate environmental niche at the defect site for regeneration. Hence, the ability to control angiogenesis and cellular responses during osteogenesis has important implications in tissue-engineered strategies. [...] Read more.
Bone is a highly vascularized tissue and relies on the angiogenesis and response of cells in the immediate environmental niche at the defect site for regeneration. Hence, the ability to control angiogenesis and cellular responses during osteogenesis has important implications in tissue-engineered strategies. Self-assembling ionic-complementary peptides have received much interest as they mimic the natural extracellular matrix. Three-dimensional (3D)-printed biphasic calcium phosphate (BCP) scaffolds coated with self-assembling DAR 16-II peptide provide a support template with the ability to recruit and enhance the adhesion of cells. In vitro studies demonstrated prompt the adhesion of both human umbilical vein endothelial cells (HUVEC) and human mesenchymal stem cells (hMSC), favoring endothelial cell activation toward an angiogenic phenotype. The SEM-EDS and protein micro bicinchoninic acid (BCA) assays demonstrated the efficacy of the coating. Whole proteomic analysis of DAR 16-II-treated HUVECs demonstrated the upregulation of proteins involved in cell adhesion (HABP2), migration (AMOTL1), cytoskeletal re-arrangement (SHC1, TMOD2), immuno-modulation (AMBP, MIF), and morphogenesis (COL4A1). In vivo studies using DAR-16-II-coated scaffolds provided an architectural template, promoting cell colonization, osteogenesis, and angiogenesis. In conclusion, DAR 16-II acts as a proactive angiogenic factor when adsorbed onto BCP scaffolds and provides a simple and effective functionalization step to facilitate the translation of tailored 3D-printed BCP scaffolds for clinical applications. Full article
(This article belongs to the Special Issue Recent Advances in Skeletal Development and Diseases)
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Review

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Review
Cystic Fibrosis Bone Disease: The Interplay between CFTR Dysfunction and Chronic Inflammation
Biomolecules 2023, 13(3), 425; https://doi.org/10.3390/biom13030425 - 24 Feb 2023
Viewed by 547
Abstract
Cystic fibrosis is a monogenic disease with a multisystemic phenotype, ranging from predisposition to chronic lung infection and inflammation to reduced bone mass. The exact mechanisms unbalancing the maintenance of an optimal bone mass in cystic fibrosis patients remain unknown. Multiple factors may [...] Read more.
Cystic fibrosis is a monogenic disease with a multisystemic phenotype, ranging from predisposition to chronic lung infection and inflammation to reduced bone mass. The exact mechanisms unbalancing the maintenance of an optimal bone mass in cystic fibrosis patients remain unknown. Multiple factors may contribute to severe bone mass reduction that, in turn, have devastating consequences in the patients’ quality of life and longevity. Here, we will review the existing evidence linking the CFTR dysfunction and cell-intrinsic bone defects. Additionally, we will also address how the proinflammatory environment due to CFTR dysfunction in immune cells and chronic infection impairs the maintenance of an adequate bone mass in CF patients. Full article
(This article belongs to the Special Issue Recent Advances in Skeletal Development and Diseases)
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Review
Pyroptosis in Periprosthetic Osteolysis
Biomolecules 2022, 12(12), 1733; https://doi.org/10.3390/biom12121733 - 23 Nov 2022
Cited by 1 | Viewed by 1024
Abstract
Periprosthetic osteolysis (PPO) along with aseptic loosening (AL) caused by wear particles after artificial joint replacement is the key factor in surgical failure and subsequent revision surgery, however, the precise molecular mechanism underlying PPO remains unclear. Aseptic inflammation triggered by metal particles, resulting [...] Read more.
Periprosthetic osteolysis (PPO) along with aseptic loosening (AL) caused by wear particles after artificial joint replacement is the key factor in surgical failure and subsequent revision surgery, however, the precise molecular mechanism underlying PPO remains unclear. Aseptic inflammation triggered by metal particles, resulting in the imbalance between bone formation by osteoblasts and bone resorption by osteoclasts may be the decisive factor. Pyroptosis is a new pro-inflammatory pattern of regulated cell death (RCD), mainly mediated by gasdermins (GSDMs) family, among which GSDMD is the best characterized. Recent evidence indicates that activation of NLRP3 inflammasomes and pyroptosis play a pivotal role in the pathological process of PPO. Here, we review the pathological process of PPO, the molecular mechanism of pyroptosis and the interventions to inhibit the inflammation and pyroptosis of different cells during the PPO. Conclusively, this review provides theoretical support for the search for new strategies and new targets for the treatment of PPO by inhibiting pyroptosis and inflammation. Full article
(This article belongs to the Special Issue Recent Advances in Skeletal Development and Diseases)
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Review
A Promising Candidate in Tendon Healing Events—PDGF-BB
Biomolecules 2022, 12(10), 1518; https://doi.org/10.3390/biom12101518 - 20 Oct 2022
Cited by 1 | Viewed by 1182
Abstract
Tendon injuries are one of the most common musculoskeletal disorders for which patients seek medical aid, reducing not only the quality of life of the patient but also imposing a significant economic burden on society. The administration of growth factors at the wound [...] Read more.
Tendon injuries are one of the most common musculoskeletal disorders for which patients seek medical aid, reducing not only the quality of life of the patient but also imposing a significant economic burden on society. The administration of growth factors at the wound site is a feasible solution for enhancing tendon healing. Platelet-derived growth factor-BB (PDGF-BB) has a well-defined safety profile compared to other growth factors and has been approved by the Food and Drug Administration (FDA). The purpose of this review is to summarize the role of PDGF-BB in tendon healing through a comprehensive review of the published literature. Experimental studies suggest that PDGF-BB has a positive effect on tendon healing by enhancing inflammatory responses, speeding up angiogenesis, stimulating tendon cell proliferation, increasing collagen synthesis and increasing the biomechanics of the repaired tendon. PDGF-BB is regarded as a promising candidate in tendon healing. However, in order to realize its full potential, we still need to carefully consider and study key issues such as dose and application time in the future, so as to explore further applications of PDGF-BB in the tendon healing process. Full article
(This article belongs to the Special Issue Recent Advances in Skeletal Development and Diseases)
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Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

Title: Early Ablation of Chemokine Receptor-2 in Mouse Osteoblasts Decreases Cartilage Matrix Damage and Subchondral Bone Sclerosis during Injury-Induced Osteoarthritis
Authors: Huseyin Ozkan; Helen Wilcockson; Esra Mucahit; Layla Musawwir; Lara Longobardi
Affiliation: Division of Rheumatology, Allergy and Immunology and the Thurston Arthritis Research Center, University of North Carolina-Chapel Hill, NC, USA

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