Editorial

4 pages, 190 KiB

Open AccessEditorial

by Riko Nishimura

Int. J. Mol. Sci. 2023, 24(6), 5264; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24065264 - 09 Mar 2023

Cited by 1 | Viewed by 996

Recent technical and conceptual advances in molecular and cellular biology have dramatically advanced bone and cartilage biology [...] Full article

(This article belongs to the Special Issue Bone and Cartilage Biology)

Research

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18 pages, 4303 KiB

Open AccessArticle

Association between an Increased Serum CCL5 Level and Pathophysiology of Degenerative Joint Disease in the Temporomandibular Joint in Females

by Haruhisa Watanabe, Takashi Iori, Ji-Won Lee, Takashi S. Kajii, Aya Takakura, Ryoko Takao-Kawabata, Yoshimasa Kitagawa, Yutaka Maruoka and Tadahiro Iimura

Int. J. Mol. Sci. 2023, 24(3), 2775; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24032775 - 01 Feb 2023

Cited by 2 | Viewed by 1778

Abstract

Degenerative joint disease of the temporomandibular joints (DJD-TMJ) clinically manifests with symptoms such as orofacial pain, joint sounds and limited jaw movements. Our research group previously reported the functional necessity of a chemokine-chemokine receptor axis of CCL5-CCR5 in osteoclasts. Accumulated studies reported that [...] Read more.

Degenerative joint disease of the temporomandibular joints (DJD-TMJ) clinically manifests with symptoms such as orofacial pain, joint sounds and limited jaw movements. Our research group previously reported the functional necessity of a chemokine-chemokine receptor axis of CCL5-CCR5 in osteoclasts. Accumulated studies reported that this axis was involved in the pathogenesis of bone and joint destructive diseases, suggesting CCL5 as a potent biomarker. This study investigated whether or not the serum level of CCL5 can be a biomarker of DJD-TMJ and concomitantly analyzed changes in the serum and urine levels of bone markers to see whether or not changes in the rate of bone metabolism were predisposing. We enrolled 17 female subjects with diagnosed DJD-TMJ and sexually and age-matched 17 controls. The serum CCL5 level in DJD-TMJ subjects was significantly higher than that in the control subjects. Multivariate analyses indicated an association between an augmented CCL5 level and the rate of bone metabolism, especially in relatively young DJD-TMJ subjects without other systemic symptoms. A principal component analysis of serum markers and our pharmacological experiment using a postmenopausal model of ovariectomized rats suggested that an augmented serum CCL5 level specifically reflected DJD-TMJ and that covert changes in the rate of bone metabolism predisposed individuals to DJD-TMJ. Full article

(This article belongs to the Special Issue Bone and Cartilage Biology)

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27 pages, 17196 KiB

Open AccessArticle

Different Requirements of CBFB and RUNX2 in Skeletal Development among Calvaria, Limbs, Vertebrae and Ribs

by Qing Jiang, Xin Qin, Kenichi Nagano, Hisato Komori, Yuki Matsuo, Ichiro Taniuchi, Kosei Ito and Toshihisa Komori

Int. J. Mol. Sci. 2022, 23(21), 13299; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232113299 - 31 Oct 2022

Cited by 3 | Viewed by 1387

Abstract

RUNX proteins, such as RUNX2, regulate the proliferation and differentiation of chondrocytes and osteoblasts. Haploinsufficiency of RUNX2 causes cleidocranial dysplasia, but a detailed analysis of Runx2^+/− mice has not been reported. Furthermore, CBFB is required for the stability and DNA binding of [...] Read more.

RUNX proteins, such as RUNX2, regulate the proliferation and differentiation of chondrocytes and osteoblasts. Haploinsufficiency of RUNX2 causes cleidocranial dysplasia, but a detailed analysis of Runx2^+/− mice has not been reported. Furthermore, CBFB is required for the stability and DNA binding of RUNX family proteins. CBFB has two isoforms, and CBFB2 plays a major role in skeletal development. The calvaria, femurs, vertebrae and ribs in Cbfb2^−/− mice were analyzed after birth, and compared with those in Runx2^+/− mice. Calvarial development was impaired in Runx2^+/− mice but mildly delayed in Cbfb2^−/− mice. In femurs, the cortical bone but not trabecular bone was reduced in Cbfb2^−/− mice, whereas both the trabecular and cortical bone were reduced in Runx2^+/− mice. The trabecular bone in vertebrae increased in Cbfb2^−/− mice but not in Runx2^+/− mice. Rib development was impaired in Cbfb2^−/− mice but not in Runx2^+/− mice. These differences were likely caused by differences in the indispensability of CBFB and RUNX2, the balance of bone formation and resorption, or the number and maturation stage of osteoblasts. Thus, different amounts of CBFB and RUNX2 were required among the bone tissues for proper bone development and maintenance. Full article

(This article belongs to the Special Issue Bone and Cartilage Biology)

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10 pages, 3179 KiB

Open AccessArticle

Cranial Base Synchondrosis Lacks PTHrP-Expressing Column-Forming Chondrocytes

by Shawn A. Hallett, Annabelle Zhou, Curtis Herzog, Ariel Arbiv, Wanida Ono and Noriaki Ono

Int. J. Mol. Sci. 2022, 23(14), 7873; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23147873 - 17 Jul 2022

Cited by 4 | Viewed by 1799

Abstract

The cranial base contains a special type of growth plate termed the synchondrosis, which functions as the growth center of the skull. The synchondrosis is composed of bidirectional opposite-facing layers of resting, proliferating, and hypertrophic chondrocytes, and lacks the secondary ossification center. In [...] Read more.

The cranial base contains a special type of growth plate termed the synchondrosis, which functions as the growth center of the skull. The synchondrosis is composed of bidirectional opposite-facing layers of resting, proliferating, and hypertrophic chondrocytes, and lacks the secondary ossification center. In long bones, the resting zone of the epiphyseal growth plate houses a population of parathyroid hormone-related protein (PTHrP)-expressing chondrocytes that contribute to the formation of columnar chondrocytes. Whether PTHrP⁺ chondrocytes in the synchondrosis possess similar functions remains undefined. Using Pthrp-mCherry knock-in mice, we found that PTHrP⁺ chondrocytes predominantly occupied the lateral wedge-shaped area of the synchondrosis, unlike those in the femoral growth plate that reside in the resting zone within the epiphysis. In vivo cell-lineage analyses using a tamoxifen-inducible Pthrp-creER line revealed that PTHrP⁺ chondrocytes failed to establish columnar chondrocytes in the synchondrosis. Therefore, PTHrP⁺ chondrocytes in the synchondrosis do not possess column-forming capabilities, unlike those in the resting zone of the long bone growth plate. These findings support the importance of the secondary ossification center within the long bone epiphysis in establishing the stem cell niche for PTHrP⁺ chondrocytes, the absence of which may explain the lack of column-forming capabilities of PTHrP⁺ chondrocytes in the cranial base synchondrosis. Full article

(This article belongs to the Special Issue Bone and Cartilage Biology)

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36 pages, 12090 KiB

Open AccessArticle

Single-Cell RNA-Seq Analysis of Cells from Degenerating and Non-Degenerating Intervertebral Discs from the Same Individual Reveals New Biomarkers for Intervertebral Disc Degeneration

by Hosni Cherif, Matthew Mannarino, Alain Sarabia Pacis, Jiannis Ragoussis, Oded Rabau, Jean A. Ouellet and Lisbet Haglund

Int. J. Mol. Sci. 2022, 23(7), 3993; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23073993 - 03 Apr 2022

Cited by 38 | Viewed by 7883

Abstract

In this study, we used single-cell transcriptomic analysis to identify new specific biomarkers for nucleus pulposus (NP) and inner annulus fibrosis (iAF) cells, and to define cell populations within non-degenerating (nD) and degenerating (D) human intervertebral discs (IVD) of the same individual. Cluster [...] Read more.

In this study, we used single-cell transcriptomic analysis to identify new specific biomarkers for nucleus pulposus (NP) and inner annulus fibrosis (iAF) cells, and to define cell populations within non-degenerating (nD) and degenerating (D) human intervertebral discs (IVD) of the same individual. Cluster analysis based on differential gene expression delineated 14 cell clusters. Gene expression profiles at single-cell resolution revealed the potential functional differences linked to degeneration, and among NP and iAF subpopulations. GO and KEGG analyses discovered molecular functions, biological processes, and transcription factors linked to cell type and degeneration state. We propose two lists of biomarkers, one as specific cell type, including C2orf40, MGP, MSMP, CD44, EIF1, LGALS1, RGCC, EPYC, HILPDA, ACAN, MT1F, CHI3L1, ID1, ID3 and TMED2. The second list proposes predictive IVD degeneration genes, including MT1G, SPP1, HMGA1, FN1, FBXO2, SPARC, VIM, CTGF, MGST1, TAF1D, CAPS, SPTSSB, S100A1, CHI3L2, PLA2G2A, TNRSF11B, FGFBP2, MGP, SLPI, DCN, MT-ND2, MTCYB, ADIRF, FRZB, CLEC3A, UPP1, S100A2, PRG4, COL2A1, SOD2 and MT2A. Protein and mRNA expression of MGST1, vimentin, SOD2 and SYF2 (p29) genes validated our scRNA-seq findings. Our data provide new insights into disc cells phenotypes and biomarkers of IVD degeneration that could improve diagnostic and therapeutic options. Full article

(This article belongs to the Special Issue Bone and Cartilage Biology)

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23 pages, 11841 KiB

Open AccessArticle

Sp7 Transgenic Mice with a Markedly Impaired Lacunocanalicular Network Induced Sost and Reduced Bone Mass by Unloading

by Takeshi Moriishi, Takuro Ito, Ryo Fukuyama, Xin Qin, Hisato Komori, Hitomi Kaneko, Yuki Matsuo, Noriaki Yoshida and Toshihisa Komori

Int. J. Mol. Sci. 2022, 23(6), 3173; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23063173 - 15 Mar 2022

Cited by 6 | Viewed by 2219

Abstract

The relationship of lacunocanalicular network structure and mechanoresponse has not been well studied. The lacunocanalicular structures differed in the compression and tension sides, in the regions, and in genders in wild-type femoral cortical bone. The overexpression of Sp7 in osteoblasts resulted in thin [...] Read more.

The relationship of lacunocanalicular network structure and mechanoresponse has not been well studied. The lacunocanalicular structures differed in the compression and tension sides, in the regions, and in genders in wild-type femoral cortical bone. The overexpression of Sp7 in osteoblasts resulted in thin and porous cortical bone with increased osteoclasts and apoptotic osteocytes, and the number of canaliculi was half of that in the wild-type mice, leading to a markedly impaired lacunocanalicular network. To investigate the response to unloading, we performed tail suspension. Unloading reduced trabecular and cortical bone in the Sp7 transgenic mice due to reduced bone formation. Sost-positive osteocytes increased by unloading on the compression side, but not on the tension side of cortical bone in the wild-type femurs. However, these differential responses were lost in the Sp7 transgenic femurs. Serum Sost increased in the Sp7 transgenic mice, but not in the wild-type mice. Unloading reduced the Col1a1 and Bglap/Bglap2 expression in the Sp7 transgenic mice but not the wild-type mice. Thus, Sp7 transgenic mice with the impaired lacunocanalicular network induced Sost expression by unloading but lost the differential regulation in the compression and tension sides, and the mice failed to restore bone formation during unloading, implicating the relationship of lacunocanalicular network structure and the regulation of bone formation in mechanoresponse. Full article

(This article belongs to the Special Issue Bone and Cartilage Biology)

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17 pages, 3534 KiB

Open AccessArticle

Lipocalin 2 Influences Bone and Muscle Phenotype in the MDX Mouse Model of Duchenne Muscular Dystrophy

by Marco Ponzetti, Argia Ucci, Antonio Maurizi, Luca Giacchi, Anna Teti and Nadia Rucci

Int. J. Mol. Sci. 2022, 23(2), 958; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23020958 - 16 Jan 2022

Cited by 13 | Viewed by 2745

Abstract

Lipocalin 2 (Lcn2) is an adipokine involved in bone and energy metabolism. Its serum levels correlate with bone mechanical unloading and inflammation, two conditions representing hallmarks of Duchenne Muscular Dystrophy (DMD). Therefore, we investigated the role of Lcn2 in bone loss induced by [...] Read more.

Lipocalin 2 (Lcn2) is an adipokine involved in bone and energy metabolism. Its serum levels correlate with bone mechanical unloading and inflammation, two conditions representing hallmarks of Duchenne Muscular Dystrophy (DMD). Therefore, we investigated the role of Lcn2 in bone loss induced by muscle failure in the MDX mouse model of DMD. We found increased Lcn2 serum levels in MDX mice at 1, 3, 6, and 12 months of age. Consistently, Lcn2 mRNA was higher in MDX versus WT muscles. Immunohistochemistry showed Lcn2 expression in mononuclear cells between muscle fibres and in muscle fibres, thus confirming the gene expression results. We then ablated Lcn2 in MDX mice, breeding them with Lcn2^−/− mice (MDXxLcn2^−/−), resulting in a higher percentage of trabecular volume/total tissue volume compared to MDX mice, likely due to reduced bone resorption. Moreover, MDXxLcn2^−/− mice presented with higher grip strength, increased intact muscle fibres, and reduced serum creatine kinase levels compared to MDX. Consistently, blocking Lcn2 by treating 2-month-old MDX mice with an anti-Lcn2 monoclonal antibody (Lcn2Ab) increased trabecular volume, while reducing osteoclast surface/bone surface compared to MDX mice treated with irrelevant IgG. Grip force was also increased, and diaphragm fibrosis was reduced by the Lcn2Ab. These results suggest that Lcn2 could be a possible therapeutic target to treat DMD-induced bone loss. Full article

(This article belongs to the Special Issue Bone and Cartilage Biology)

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15 pages, 3731 KiB

Open AccessArticle

ER Stress in ERp57 Knockout Knee Joint Chondrocytes Induces Osteoarthritic Cartilage Degradation and Osteophyte Formation

by Yvonne Rellmann, Elco Eidhof, Uwe Hansen, Lutz Fleischhauer, Jonas Vogel, Hauke Clausen-Schaumann, Attila Aszodi and Rita Dreier

Int. J. Mol. Sci. 2022, 23(1), 182; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23010182 - 24 Dec 2021

Cited by 8 | Viewed by 3160

Abstract

Ageing or obesity are risk factors for protein aggregation in the endoplasmic reticulum (ER) of chondrocytes. This condition is called ER stress and leads to induction of the unfolded protein response (UPR), which, depending on the stress level, restores normal cell function or [...] Read more.

Ageing or obesity are risk factors for protein aggregation in the endoplasmic reticulum (ER) of chondrocytes. This condition is called ER stress and leads to induction of the unfolded protein response (UPR), which, depending on the stress level, restores normal cell function or initiates apoptotic cell death. Here the role of ER stress in knee osteoarthritis (OA) was evaluated. It was first tested in vitro and in vivo whether a knockout (KO) of the protein disulfide isomerase ERp57 in chondrocytes induces sufficient ER stress for such analyses. ER stress in ERp57 KO chondrocytes was confirmed by immunofluorescence, immunohistochemistry, and transmission electron microscopy. Knee joints of wildtype (WT) and cartilage-specific ERp57 KO mice (ERp57 cKO) were analyzed by indentation-type atomic force microscopy (IT-AFM), toluidine blue, and immunofluorescence/-histochemical staining. Apoptotic cell death was investigated by a TUNEL assay. Additionally, OA was induced via forced exercise on a treadmill. ER stress in chondrocytes resulted in a reduced compressive stiffness of knee cartilage. With ER stress, 18-month-old mice developed osteoarthritic cartilage degeneration with osteophyte formation in knee joints. These degenerative changes were preceded by apoptotic death in articular chondrocytes. Young mice were not susceptible to OA, even when subjected to forced exercise. This study demonstrates that ER stress induces the development of age-related knee osteoarthritis owing to a decreased protective function of the UPR in chondrocytes with increasing age, while apoptosis increases. Therefore, inhibition of ER stress appears to be an attractive therapeutic target for OA. Full article

(This article belongs to the Special Issue Bone and Cartilage Biology)

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Review

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18 pages, 877 KiB

Open AccessReview

Targeting Inflammation and Regeneration: Scaffolds, Extracellular Vesicles, and Nanotechnologies as Cell-Free Dual-Target Therapeutic Strategies

by Maria Peshkova, Nastasia Kosheleva, Anastasia Shpichka, Stefka Radenska-Lopovok, Dmitry Telyshev, Alexey Lychagin, Fangzhou Li, Peter Timashev and Xing-Jie Liang

Int. J. Mol. Sci. 2022, 23(22), 13796; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232213796 - 09 Nov 2022

Cited by 5 | Viewed by 1905

Abstract

Osteoarthritis (OA) affects over 250 million people worldwide and despite various existing treatment strategies still has no cure. It is a multifactorial disease characterized by cartilage loss and low-grade synovial inflammation. Focusing on these two targets together could be the key to developing [...] Read more.

Osteoarthritis (OA) affects over 250 million people worldwide and despite various existing treatment strategies still has no cure. It is a multifactorial disease characterized by cartilage loss and low-grade synovial inflammation. Focusing on these two targets together could be the key to developing currently missing disease-modifying OA drugs (DMOADs). This review aims to discuss the latest cell-free techniques applied in cartilage tissue regeneration, since they can provide a more controllable approach to inflammation management than the cell-based ones. Scaffolds, extracellular vesicles, and nanocarriers can be used to suppress inflammation, but they can also act as immunomodulatory agents. This is consistent with the latest tissue engineering paradigm, postulating a moderate, controllable inflammatory reaction to be beneficial for tissue remodeling and successful regeneration. Full article

(This article belongs to the Special Issue Bone and Cartilage Biology)

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15 pages, 3086 KiB

Open AccessReview

Matrix Vesicle-Mediated Mineralization and Osteocytic Regulation of Bone Mineralization

by Tomoka Hasegawa, Hiromi Hongo, Tomomaya Yamamoto, Miki Abe, Hirona Yoshino, Mai Haraguchi-Kitakamae, Hotaka Ishizu, Tomohiro Shimizu, Norimasa Iwasaki and Norio Amizuka

Int. J. Mol. Sci. 2022, 23(17), 9941; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23179941 - 01 Sep 2022

Cited by 26 | Viewed by 3199

Abstract

Bone mineralization entails two mineralization phases: primary and secondary mineralization. Primary mineralization is achieved when matrix vesicles are secreted by osteoblasts, and thereafter, bone mineral density gradually increases during secondary mineralization. Nearby extracellular phosphate ions (PO₄³⁻) flow into the vesicles [...] Read more.

Bone mineralization entails two mineralization phases: primary and secondary mineralization. Primary mineralization is achieved when matrix vesicles are secreted by osteoblasts, and thereafter, bone mineral density gradually increases during secondary mineralization. Nearby extracellular phosphate ions (PO₄³⁻) flow into the vesicles via membrane transporters and enzymes located on the vesicles’ membranes, while calcium ions (Ca²⁺), abundant in the tissue fluid, are also transported into the vesicles. The accumulation of Ca²⁺ and PO₄³⁻ in the matrix vesicles induces crystal nucleation and growth. The calcium phosphate crystals grow radially within the vesicle, penetrate the vesicle’s membrane, and continue to grow outside the vesicle, ultimately forming mineralized nodules. The mineralized nodules then attach to collagen fibrils, mineralizing them from the contact sites (i.e., collagen mineralization). Afterward, the bone mineral density gradually increases during the secondary mineralization process. The mechanisms of this phenomenon remain unclear, but osteocytes may play a key role; it is assumed that osteocytes enable the transport of Ca²⁺ and PO₄³⁻ through the canaliculi of the osteocyte network, as well as regulate the mineralization of the surrounding bone matrix via the Phex/SIBLINGs axis. Thus, bone mineralization is biologically regulated by osteoblasts and osteocytes. Full article

(This article belongs to the Special Issue Bone and Cartilage Biology)

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14 pages, 4808 KiB

Open AccessReview

Fibroblast Growth Factors and Cellular Communication Network Factors: Intimate Interplay by the Founding Members in Cartilage

by Satoshi Kubota, Eriko Aoyama, Masaharu Takigawa and Takashi Nishida

Int. J. Mol. Sci. 2022, 23(15), 8592; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23158592 - 02 Aug 2022

Cited by 5 | Viewed by 2611

Abstract

Fibroblast growth factors (FGFs) constitute a large family of signaling molecules that act in an autocrine/paracrine, endocrine, or intracrine manner, whereas the cellular communication network factors (CCN) family is composed of six members that manipulate extracellular signaling networks. FGFs and CCNs are structurally [...] Read more.

Fibroblast growth factors (FGFs) constitute a large family of signaling molecules that act in an autocrine/paracrine, endocrine, or intracrine manner, whereas the cellular communication network factors (CCN) family is composed of six members that manipulate extracellular signaling networks. FGFs and CCNs are structurally and functionally distinct, except for the common characteristics as matricellular proteins. Both play significant roles in the development of a variety of tissues and organs, including the skeletal system. In vertebrates, most of the skeletal parts are formed and grow through a process designated endochondral ossification, in which chondrocytes play the central role. The growth plate cartilage is the place where endochondral ossification occurs, and articular cartilage is left to support the locomotive function of joints. Several FGFs, including FGF-2, one of the founding members of this family, and all of the CCNs represented by CCN2, which is required for proper skeletal development, can be found therein. Research over a decade has revealed direct binding of CCN2 to FGFs and FGF receptors (FGFRs), which occasionally affect the biological outcome via FGF signaling. Moreover, a recent study uncovered an integrated regulation of FGF and CCN genes by FGF signaling. In this review, after a brief introduction of these two families, molecular and genetic interactions between CCN and FGF family members in cartilage, and their biological effects, are summarized. The molecular interplay represents the mutual involvement of the other in their molecular functions, leading to collaboration between CCN2 and FGFs during skeletal development. Full article

(This article belongs to the Special Issue Bone and Cartilage Biology)

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12 pages, 1400 KiB

Open AccessReview

Critical Roles of NF-κB Signaling Molecules in Bone Metabolism Revealed by Genetic Mutations in Osteopetrosis

by Eijiro Jimi and Takenobu Katagiri

Int. J. Mol. Sci. 2022, 23(14), 7995; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23147995 - 20 Jul 2022

Cited by 19 | Viewed by 2481

Abstract

The nuclear factor-κB (NF-κB) transcription factor family consists of five related proteins, RelA (p65), c-Rel, RelB, p50/p105 (NF-κB1), and p52/p100 (NF-κB2). These proteins are important not only for inflammation and the immune response but also for bone metabolism. Activation of NF-κB occurs via [...] Read more.

The nuclear factor-κB (NF-κB) transcription factor family consists of five related proteins, RelA (p65), c-Rel, RelB, p50/p105 (NF-κB1), and p52/p100 (NF-κB2). These proteins are important not only for inflammation and the immune response but also for bone metabolism. Activation of NF-κB occurs via the classic and alternative pathways. Inflammatory cytokines, such as tumor necrosis factor (TNF)-α and interleukin (IL)-1β, activate the former, and cytokines involved in lymph node formation, such as receptor activator of NF-κB ligand (RANKL) and CD40L, activate the latter. p50 and p52 double-knockout mice revealed severe osteopetrosis due to the total lack of osteoclasts, which are specialized cells for bone resorption. This finding suggests that the activation of NF-κB is required for osteoclast differentiation. The NF-κB signaling pathway is controlled by various regulators, including NF-κB essential modulator (NEMO), which is encoded by the IKBKG gene. In recent years, mutant forms of the IKBKG gene have been reported as causative genes of osteopetrosis, lymphedema, hypohidrotic ectodermal dysplasia, and immunodeficiency (OL-EDA-ID). In addition, a mutation in the RELA gene, encoding RelA, has been reported for the first time in newborns with high neonatal bone mass. Osteopetrosis is characterized by a diffuse increase in bone mass, ranging from a lethal form observed in newborns to an asymptomatic form that appears in adulthood. This review describes the genetic mutations in NF-κB signaling molecules that have been identified in patients with osteopetrosis. Full article

(This article belongs to the Special Issue Bone and Cartilage Biology)

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19 pages, 1265 KiB

Open AccessReview

Cranial Base Synchondrosis: Chondrocytes at the Hub

by Shawn A. Hallett, Wanida Ono, Renny T. Franceschi and Noriaki Ono

Int. J. Mol. Sci. 2022, 23(14), 7817; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23147817 - 15 Jul 2022

Cited by 9 | Viewed by 2635

Abstract

The cranial base is formed by endochondral ossification and functions as a driver of anteroposterior cranial elongation and overall craniofacial growth. The cranial base contains the synchondroses that are composed of opposite-facing layers of resting, proliferating and hypertrophic chondrocytes with unique developmental origins, [...] Read more.

The cranial base is formed by endochondral ossification and functions as a driver of anteroposterior cranial elongation and overall craniofacial growth. The cranial base contains the synchondroses that are composed of opposite-facing layers of resting, proliferating and hypertrophic chondrocytes with unique developmental origins, both in the neural crest and mesoderm. In humans, premature ossification of the synchondroses causes midfacial hypoplasia, which commonly presents in patients with syndromic craniosynostoses and skeletal Class III malocclusion. Major signaling pathways and transcription factors that regulate the long bone growth plate—PTHrP–Ihh, FGF, Wnt, BMP signaling and Runx2—are also involved in the cranial base synchondrosis. Here, we provide an updated overview of the cranial base synchondrosis and the cell population within, as well as its molecular regulation, and further discuss future research opportunities to understand the unique function of this craniofacial skeletal structure. Full article

(This article belongs to the Special Issue Bone and Cartilage Biology)

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10 pages, 626 KiB

Open AccessReview

Whole Aspect of Runx2 Functions in Skeletal Development

by Toshihisa Komori

Int. J. Mol. Sci. 2022, 23(10), 5776; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23105776 - 21 May 2022

Cited by 54 | Viewed by 5081

Abstract

Runt-related transcription factor 2 (Runx2) is a fundamental transcription factor for bone development. In endochondral ossification, Runx2 induces chondrocyte maturation, enhances chondrocyte proliferation through Indian hedgehog (Ihh) induction, and induces the expression of vascular endothelial growth factor A (Vegfa), secreted phosphoprotein 1 (Spp1), [...] Read more.

Runt-related transcription factor 2 (Runx2) is a fundamental transcription factor for bone development. In endochondral ossification, Runx2 induces chondrocyte maturation, enhances chondrocyte proliferation through Indian hedgehog (Ihh) induction, and induces the expression of vascular endothelial growth factor A (Vegfa), secreted phosphoprotein 1 (Spp1), integrin-binding sialoprotein (Ibsp), and matrix metallopeptidase 13 (Mmp13) in the terminal hypertrophic chondrocytes. Runx2 inhibits the apoptosis of the terminal hypertrophic chondrocytes and induces their transdifferentiation into osteoblasts and osteoblast progenitors. The transdifferentiation is required for trabecular bone formation during embryonic and newborn stages but is dispensable for acquiring normal bone mass in young and adult mice. Runx2 enhances the proliferation of osteoblast progenitors and induces their commitment to osteoblast lineage cells through the direct regulation of the expressions of a hedgehog, fibroblast growth factor (Fgf), Wnt, and parathyroid hormone-like hormone (Pthlh) signaling pathway genes and distal-less homeobox 5 (Dlx5), which all regulate Runx2 expression and/or protein activity. Runx2, Sp7, and Wnt signaling further induce osteoblast differentiation. In immature osteoblasts, Runx2 regulates the expression of bone matrix protein genes, including Col1a1, Col1a2, Spp1, Ibsp, and bone gamma carboxyglutamate protein (Bglap)/Bglap2, and induces osteoblast maturation. Osteocalcin (Bglap/Bglap2) is required for the alignment of apatite crystals parallel to the collagen fibers; however, it does not physiologically work as a hormone that regulates glucose metabolism, testosterone synthesis, or muscle mass. Thus, Runx2 exerts multiple functions essential for skeletal development. Full article

(This article belongs to the Special Issue Bone and Cartilage Biology)

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12 pages, 848 KiB

Open AccessReview

Sp7 Action in the Skeleton: Its Mode of Action, Functions, and Relevance to Skeletal Diseases

by Hironori Hojo and Shinsuke Ohba

Int. J. Mol. Sci. 2022, 23(10), 5647; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23105647 - 18 May 2022

Cited by 16 | Viewed by 2560

Abstract

Osteoblast differentiation is a tightly regulated process in which key transcription factors (TFs) and their target genes constitute gene regulatory networks (GRNs) under the control of osteogenic signaling pathways. Among these TFs, Sp7 works as an osteoblast determinant critical for osteoblast differentiation. Following [...] Read more.

Osteoblast differentiation is a tightly regulated process in which key transcription factors (TFs) and their target genes constitute gene regulatory networks (GRNs) under the control of osteogenic signaling pathways. Among these TFs, Sp7 works as an osteoblast determinant critical for osteoblast differentiation. Following the identification of Sp7 and a large number of its functional studies, recent genome-scale analyses have made a major contribution to the identification of a “non-canonical” mode of Sp7 action as well as “canonical” ones. The analyses have not only confirmed known Sp7 targets but have also uncovered its additional targets and upstream factors. In addition, biochemical analyses have demonstrated that Sp7 actions are regulated by chemical modifications and protein–protein interaction with other transcriptional regulators. Sp7 is also involved in chondrocyte differentiation and osteocyte biology as well as postnatal bone metabolism. The critical role of SP7 in the skeleton is supported by its relevance to human skeletal diseases. This review aims to overview the Sp7 actions in skeletal development and maintenance, particularly focusing on recent advances in our understanding of how Sp7 functions in the skeleton under physiological and pathological conditions. Full article

(This article belongs to the Special Issue Bone and Cartilage Biology)

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19 pages, 1017 KiB

Open AccessReview

Osteoimmunology in Periodontitis: Local Proteins and Compounds to Alleviate Periodontitis

by Kridtapat Sirisereephap, Tomoki Maekawa, Hikaru Tamura, Takumi Hiyoshi, Hisanori Domon, Toshihito Isono, Yutaka Terao, Takeyasu Maeda and Koichi Tabeta

Int. J. Mol. Sci. 2022, 23(10), 5540; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23105540 - 16 May 2022

Cited by 18 | Viewed by 5017

Abstract

Periodontitis is one of the most common oral diseases resulting in gingival inflammation and tooth loss. Growing evidence indicates that it results from dysbiosis of the oral microbiome, which interferes with the host immune system, leading to bone destruction. Immune cells activate periodontal [...] Read more.

Periodontitis is one of the most common oral diseases resulting in gingival inflammation and tooth loss. Growing evidence indicates that it results from dysbiosis of the oral microbiome, which interferes with the host immune system, leading to bone destruction. Immune cells activate periodontal ligament cells to express the receptor activator of nuclear factor kappa-B (NF-κB) ligand (RANKL) and promote osteoclast activity. Osteocytes have active roles in periodontitis progression in the bone matrix. Local proteins are involved in bone regeneration through functional immunological plasticity. Here, we discuss the current knowledge of cellular and molecular mechanisms in periodontitis, the roles of local proteins, and promising synthetic compounds generating a periodontal regeneration effect. It is anticipated that this may lead to a better perception of periodontitis pathophysiology. Full article

(This article belongs to the Special Issue Bone and Cartilage Biology)

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13 pages, 827 KiB

Open AccessReview

Tyrosine Kinase Src Is a Regulatory Factor of Bone Homeostasis

by Takuma Matsubara, Kazuma Yasuda, Kana Mizuta, Hiroka Kawaue and Shoichiro Kokabu

Int. J. Mol. Sci. 2022, 23(10), 5508; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23105508 - 14 May 2022

Cited by 13 | Viewed by 2259

Abstract

Osteoclasts, which resorb the bone, and osteoblasts, which form the bone, are the key cells regulating bone homeostasis. Osteoporosis and other metabolic bone diseases occur when osteoclast-mediated bone resorption is increased and bone formation by osteoblasts is decreased. Analyses of tyrosine kinase Src-knockout [...] Read more.

Osteoclasts, which resorb the bone, and osteoblasts, which form the bone, are the key cells regulating bone homeostasis. Osteoporosis and other metabolic bone diseases occur when osteoclast-mediated bone resorption is increased and bone formation by osteoblasts is decreased. Analyses of tyrosine kinase Src-knockout mice revealed that Src is essential for bone resorption by osteoclasts and suppresses bone formation by osteoblasts. Src-knockout mice exhibit osteopetrosis. Therefore, Src is a potential target for osteoporosis therapy. However, Src is ubiquitously expressed in many tissues and is involved in various biological processes, such as cell proliferation, growth, and migration. Thus, it is challenging to develop effective osteoporosis therapies targeting Src. To solve this problem, it is necessary to understand the molecular mechanism of Src function in the bone. Src expression and catalytic activity are maintained at high levels in osteoclasts. The high activity of Src is essential for the attachment of osteoclasts to the bone matrix and to resorb the bone by regulating actin-related molecules. Src also inhibits the activity of Runx2, a master regulator of osteoblast differentiation, suppressing bone formation in osteoblasts. In this paper, we introduce the molecular mechanisms of Src in osteoclasts and osteoblasts to explore its potential for bone metabolic disease therapy. Full article

(This article belongs to the Special Issue Bone and Cartilage Biology)

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18 pages, 986 KiB

Open AccessReview

Activation and Function of NLRP3 Inflammasome in Bone and Joint-Related Diseases

by Tomohiko Murakami, Yuri Nakaminami, Yoshifumi Takahata, Kenji Hata and Riko Nishimura

Int. J. Mol. Sci. 2022, 23(10), 5365; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23105365 - 11 May 2022

Cited by 30 | Viewed by 4240

Abstract

Inflammation is a pivotal response to a variety of stimuli, and inflammatory molecules such as cytokines have central roles in the pathogenesis of various diseases, including bone and joint diseases. Proinflammatory cytokines are mainly produced by immune cells and mediate inflammatory and innate [...] Read more.

Inflammation is a pivotal response to a variety of stimuli, and inflammatory molecules such as cytokines have central roles in the pathogenesis of various diseases, including bone and joint diseases. Proinflammatory cytokines are mainly produced by immune cells and mediate inflammatory and innate immune responses. Additionally, proinflammatory cytokines accelerate bone resorption and cartilage destruction, resulting in the destruction of bone and joint tissues. Thus, proinflammatory cytokines are involved in regulating the pathogenesis of bone and joint diseases. Interleukin (IL)-1 is a representative inflammatory cytokine that strongly promotes bone and cartilage destruction, and elucidating the regulation of IL-1 will advance our understanding of the onset and progression of bone and joint diseases. IL-1 has two isoforms, IL-1α and IL-1β. Both isoforms signal through the same IL-1 receptor type 1, but the activation mechanisms are completely different. In particular, IL-1β is tightly regulated by protein complexes termed inflammasomes. Recent research using innovative technologies has led to a series of discoveries about inflammasomes. This review highlights the current understanding of the activation and function of the NLRP3 (NOD-like receptor family, pyrin domain-containing 3) inflammasome in bone and joint diseases. Full article

(This article belongs to the Special Issue Bone and Cartilage Biology)

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15 pages, 705 KiB

Open AccessReview

Positive and Negative Regulators of Sclerostin Expression

by Rina Iwamoto, Masanori Koide, Nobuyuki Udagawa and Yasuhiro Kobayashi

Int. J. Mol. Sci. 2022, 23(9), 4895; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23094895 - 28 Apr 2022

Cited by 7 | Viewed by 2556

Abstract

Sclerostin is secreted from osteocytes, binds to the Wnt co-receptor Lrp5/6, and affects the interaction between Wnt ligands and Lrp5/6, which inhibits Wnt/β-catenin signals and suppresses bone formation. Sclerostin plays an important role in the preservation of bone mass by functioning as a [...] Read more.

Sclerostin is secreted from osteocytes, binds to the Wnt co-receptor Lrp5/6, and affects the interaction between Wnt ligands and Lrp5/6, which inhibits Wnt/β-catenin signals and suppresses bone formation. Sclerostin plays an important role in the preservation of bone mass by functioning as a negative regulator of bone formation. A sclerostin deficiency causes sclerosteosis, which is characterized by an excess bone mass with enhanced bone formation in humans and mice. The expression of sclerostin is positively and negatively regulated by many factors, which also govern bone metabolism. Positive and negative regulators of sclerostin expression and their effects are introduced and discussed herein based on recent and previous findings, including our research. Full article

(This article belongs to the Special Issue Bone and Cartilage Biology)

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22 pages, 917 KiB

Open AccessReview

Osteoarthritis Pain

by Huan Yu, Tianwen Huang, William Weijia Lu, Liping Tong and Di Chen

Int. J. Mol. Sci. 2022, 23(9), 4642; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23094642 - 22 Apr 2022

Cited by 45 | Viewed by 8994

Abstract

Joint pain is the hallmark symptom of osteoarthritis (OA) and the main reason for patients to seek medical assistance. OA pain greatly contributes to functional limitations of joints and reduced quality of life. Although several pain-relieving medications are available for OA treatment, the [...] Read more.

Joint pain is the hallmark symptom of osteoarthritis (OA) and the main reason for patients to seek medical assistance. OA pain greatly contributes to functional limitations of joints and reduced quality of life. Although several pain-relieving medications are available for OA treatment, the current intervention strategy for OA pain cannot provide satisfactory pain relief, and the chronic use of the drugs for pain management is often associated with significant side effects and toxicities. These observations suggest that the mechanisms of OA-related pain remain undefined. The current review mainly focuses on the characteristics and mechanisms of OA pain. We evaluate pathways associated with OA pain, such as nerve growth factor (NGF)/tropomyosin receptor kinase A (TrkA), calcitonin gene-related peptide (CGRP), C–C motif chemokine ligands 2 (CCL2)/chemokine receptor 2 (CCR2) and tumor necrosis factor alpha (TNF-α), interleukin-1beta (IL-1β), the NOD-like receptor (NLR) family, pyrin domain-containing protein 3 (NLRP3) inflammasome, and the Wnt/β-catenin signaling pathway. In addition, animal models currently used for OA pain studies and emerging preclinical studies are discussed. Understanding the multifactorial components contributing to OA pain could provide novel insights into the development of more specific and effective drugs for OA pain management. Full article

(This article belongs to the Special Issue Bone and Cartilage Biology)

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16 pages, 9491 KiB

Open AccessReview

Autotaxin/Lysophosphatidic Acid Axis: From Bone Biology to Bone Disorders

by Candide Alioli, Léa Demesmay, Olivier Peyruchaud and Irma Machuca-Gayet

Int. J. Mol. Sci. 2022, 23(7), 3427; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23073427 - 22 Mar 2022

Cited by 5 | Viewed by 2322

Abstract

Lysophosphatidic acid (LPA) is a natural bioactive phospholipid with pleiotropic activities affecting multiple tissues, including bone. LPA exerts its biological functions by binding to G-protein coupled LPA receptors (LPA_1-6) to stimulate cell migration, proliferation, and survival. It is largely produced by [...] Read more.

Lysophosphatidic acid (LPA) is a natural bioactive phospholipid with pleiotropic activities affecting multiple tissues, including bone. LPA exerts its biological functions by binding to G-protein coupled LPA receptors (LPA_1-6) to stimulate cell migration, proliferation, and survival. It is largely produced by autotaxin (ATX), a secreted enzyme with lysophospholipase D activity that converts lysophosphatidylcholine (LPC) into active LPA. Beyond its enzymatic activity, ATX serves as a docking molecule facilitating the efficient delivery of LPA to its specific cell surface receptors. Thus, LPA effects are the result of local production by ATX in a given tissue or cell type. As a consequence, the ATX/LPA axis should be considered as an entity to better understand their roles in physiology and pathophysiology and to propose novel therapeutic strategies. Herein, we provide not only an extensive overview of the relevance of the ATX/LPA axis in bone cell commitment and differentiation, skeletal development, and bone disorders, but also discuss new working hypotheses emerging from the interplay of ATX/LPA with well-established signaling pathways regulating bone mass. Full article

(This article belongs to the Special Issue Bone and Cartilage Biology)

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20 pages, 1599 KiB

Open AccessReview

Main and Minor Types of Collagens in the Articular Cartilage: The Role of Collagens in Repair Tissue Evaluation in Chondral Defects

by Lourdes Alcaide-Ruggiero, Verónica Molina-Hernández, María M. Granados and Juan M. Domínguez

Int. J. Mol. Sci. 2021, 22(24), 13329; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222413329 - 11 Dec 2021

Cited by 30 | Viewed by 5378

Abstract

Several collagen subtypes have been identified in hyaline articular cartilage. The main and most abundant collagens are type II, IX and XI collagens. The minor and less abundant collagens are type III, IV, V, VI, X, XII, XIV, XVI, XXII, and XXVII collagens. [...] Read more.

Several collagen subtypes have been identified in hyaline articular cartilage. The main and most abundant collagens are type II, IX and XI collagens. The minor and less abundant collagens are type III, IV, V, VI, X, XII, XIV, XVI, XXII, and XXVII collagens. All these collagens have been found to play a key role in healthy cartilage, regardless of whether they are more or less abundant. Additionally, an exhaustive evaluation of collagen fibrils in a repaired cartilage tissue after a chondral lesion is necessary to determine the quality of the repaired tissue and even whether or not this repaired tissue is considered hyaline cartilage. Therefore, this review aims to describe in depth all the collagen types found in the normal articular cartilage structure, and based on this, establish the parameters that allow one to consider a repaired cartilage tissue as a hyaline cartilage. Full article

(This article belongs to the Special Issue Bone and Cartilage Biology)

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