Biomaterials Effect on the Bone Microenvironment E-Book
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This book presents a systematic exposition from all aspects of biomaterials regulated microenvironment in bone regeneration. Its potential challenges and future development direction are also prospected for professionals.
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Veröffentlichungsjahr: 2022
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Table of Contents
Cover
Title Page
Copyright
Preface
1 Bone Microenvironment
1.1 Introduction
1.2 Bone Microenvironment and Diseases
1.3 Biomaterials and Bone Microenvironment
References
2 Materiobiological Effects Regulate the Bone Microenvironment
2.1 Bioactive Components Influence the Bone Microenvironment
2.2 Physicochemical Property Influence the Bone Microenvironment
References
3 Design and Application of Biomaterials to Regulate Microenvironment for Bone Regeneration
3.1 Natural Biomaterials for Bone Microenvironment Regulation
3.2 Synthetic Biomaterials for Bone Microenvironment Regulation
References
4 Fabrication Technologies of Biomaterials
4.1 Fabrication Technologies of Biomaterials
4.2 Fabrication Technologies of Hydrogels
4.3 Fabrication Technologies of Other Biomaterials
References
5 Mechanisms for Biomaterials Reconstruct Microenvironment in Bone Regeneration
5.1 Mechanical Support Effect
5.2 Redox Effect
5.3 Pro‐angiogenesis Effect
5.4 Inflammatory Immune Effect
5.5 Anti‐Aging Effect
References
6 Biomaterials Regulating Bone Microenvironment in Clinical Application
6.1 Introduction
6.2 Autogenous Bone Remodeling
6.3 Allogeneic Bone Regeneration
6.4 Clinical Effect of Biomaterials
6.5 Clinical Challenges and Opportunities
References
7 Conclusions and Perspectives
7.1 Bone Microenvironment Under Physiological and Pathological Conditions
7.2 Biological Effects Under Modulation of Materials
7.3 Design and Application of Biomaterials in Bone Regeneration
7.4 Fabrication Technologies
7.5 Microenvironment Under Biomaterial Regulation
7.6 Biomaterials in Clinical Experience
Index
End User License Agreement
List of Tables
Chapter 1
Table 1.1 Application of biomaterials in bone marrow hematopoietic system....
Table 1.2 Summary of biomaterials that do not affect the immune system in t...
Chapter 2
Table 2.1 Cytokines involved in the bone healing process.
Table 2.2 Ions involved in the bone healing process and their functions....
Table 2.3 Common biomaterials for bone tissue engineering.
List of Illustrations
Chapter 1
Figure 1.1 Classification of BMSCs.
Figure 1.2 The differentiation spectrum of human HSCs.
Figure 1.3 Bone microenvironment and diseases.
Figure 1.4 Effects of physical and chemical properties of biomaterials on bo...
Chapter 2
Figure 2.1 The biphasic role of ROS on bone healing. ROS can recruit stem ce...
Figure 2.2 Schematic diagram of bone marrow microenvironment.
Figure 2.3 A spatiotemporal relationship of various growth factors during th...
Figure 2.4 The crosstalk of cytokines for the bone healing process.
Figure 2.5 Metal ions play critical roles in cell fates in bone microenviron...
Figure 2.6 The materobiological relationship of bone biomaterials, in which ...
Figure 2.7 Hierarchical structure of bone tissue with various dimensions....
Chapter 3
Figure 3.1 (a) Scanning electron microscopy ([SEM], left) and second harmoni...
Figure 3.2 SEM images of (a) gelatin/PCL mat, (b) gelatin/PCL/HA mat and (c)...
Figure 3.3 (a) XPS Ca 2p spectra and Von Kossa staining (insert) of transgen...
Figure 3.4 SEM images of (a) pure SF scaffolds and (b) SF scaffolds immobili...
Figure 3.5 Alginate chemical structures with different conformational blocks...
Figure 3.6 (a) Schematic illustration of the reaction route for the preparat...
Figure 3.7 Schematic illustration of the secretion and regulation of EVs for...
Figure 3.8 Ti implants regulate immune microenvironment through multiple pat...
Figure 3.9 Schematic diagram of the inherent chemical and topographical prop...
Figure 3.10 (A) Macro‐porous scaffolds developed from CaSiO
3
nanofibers for ...
Figure 3.11 (A) Multilevel rice leaf surfaces with anisotropic sliding behav...
Figure 3.12 (A) 3D‐printed polylactic acid scaffolds promote bone‐like matri...
Figure 3.13 Schematic diagram of ZnSr‐Col‐HA composite promoting bone regene...
Chapter 4
Figure 4.1 Schematic of a typical electrospinning system [2].
Figure 4.2 Preparation procedure for 3D‐printed biomimetic scaffolds.
Figure 4.3 Future prospects for enabling technologies in 3D printing for reg...
Figure 4.4 Approach for synthesis of highly porous fibrous scaffolds.
Figure 4.5 Scaffold preparation using the ice porogen.
Figure 4.6
(
a) Schematic diagram of the role of smart hydrogels. (b) injectab...
Figure 4.7 Different biomimetic hydrogels prepared by various crosslinked co...
Figure 4.8 (a) Molecular structural formula of 4cPEG and mPEG‐COOH. (b) Sche...
Figure 4.9 A GelMA hydrogel with black phosphorus nanosheets (BPNs) enclosed...
Figure 4.10 The preparation process of the Col‐HA hydrogel in cartilage rege...
Figure 4.11 Pressure‐driven fusion of amorphous particles into integrated mo...
Figure 4.12 Mesoporous silk‐bioactive glass nanocomposites as drug‐eluting m...
Figure 4.13 Schematic illustration of metal peroxide paradigms and underlyin...
Figure 4.14 Schematic illustration of GO as an interface phase to combine PE...
Figure 4.15 Schematic illustration of the process to fabricate tHA/PCL compo...
Figure 4.16 Schematic illustration of implant surface modified by nano‐CeO
2
...
Chapter 5
Figure 5.1 Interactions between the cell and matrix: (a) Matrix mechanical c...
Figure 5.2 (a) The curvature‐sensing protein FBP17 can sense the cell membra...
Figure 5.3 ROS influence bone cells. The left panel represents the physiolog...
Figure 5.4 Illustration of the molecular signaling pathways of polyphenols c...
Figure 5.5 Action mechanism of the ROS‐responsive biomaterial. (a) The drug,...
Figure 5.6 Gene silencing mechanisms of siRNA and miRNA. siRNA: dsRNA is pro...
Figure 5.7 Illustration of classification for various forms of vascularized ...
Figure 5.8 Illustration of release rate of VEGF from fibrin gel matrices is ...
Figure 5.9 (a) Three stages following tissue injury: the early proinflammato...
Figure 5.10 (a) Schematic illustration of the programmed surface that enhanc...
Figure 5.11 (a) Schematic illustration of osteoinductive and immunomodulator...
Chapter 6
Figure 6.1 Examples of applications of biomaterials.
Guide
Cover
Table of Contents
Title Page
Copyright
Preface
Begin Reading
Index
End User License Agreement
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Biomaterials Effect on the Bone Microenvironment
Fabrication, Regeneration, and Clinical Applications
Edited by Jiacan Su, Xiao Chen, and Yingying Jing
Editors
Prof. Jiacan SuShanghai UniversityInstitute of Translational Medicine200444 ShanghaiChina
Prof. Xiao ChenShanghai Changhai HospitalDepartment of OrthopedicsNo. 168, Changhai Road200433 ShanghaiChina
Prof. Yingying JingShanghai UniversityInstitute of Translational Medicine200444 ShanghaiChina
Cover Image: © Marko Aliaksandr/Shutterstock
All books published by WILEY‐VCH are carefully produced. Nevertheless, authors, editors, and publisher do not warrant the information contained in these books, including this book, to be free of errors. Readers are advised to keep in mind that statements, data, illustrations, procedural details or other items may inadvertently be inaccurate.
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© 2023 Wiley‐VCH GmbH, Boschstraße 12, 69469 Weinheim, Germany
All rights reserved (including those of translation into other languages). No part of this book may be reproduced in any form – by photoprinting, microfilm, or any other means – nor transmitted or translated into a machine language without written permission from the publishers. Registered names, trademarks, etc. used in this book, even when not specifically marked as such, are not to be considered unprotected by law.
Print ISBN:978‐3‐527‐35043‐8ePDF ISBN:978‐3‐527‐83780‐9ePub ISBN:978‐3‐527‐83781‐6oBook ISBN:978‐3‐527‐83782‐3
Preface
The bone microenvironment is a three‐dimensional environment composed of adjacent blood sinusoids, body fluids, trabecular bone, and bone‐related cells. Understanding the interaction between biomaterials and the bone microenvironment is vital for the development of bone biomaterials. Based on the biological effects of materials in the bone microenvironment, in‐depth exploration of the mechanism of how biomaterials regulate the bone microenvironment and promote bone regeneration will provide a great theoretical guidance and technical support for the design of new biomaterials and the treatment of bone‐related diseases. At present, although various biomaterials, such as bioceramic materials, biofunctional nanomaterials, and multifunctional hydrogel materials, have been widely reported, biomaterials with clinical translation prospects should be an important direction for the research and development of bone biomaterials in the future. Our team have many years of research experience in bone biomaterials and bone biomechanisms. Based on the mechanism, materials, and clinical research, we creatively proposed the concept of bone‐targeted biomaterials and a “three‐in‐one” bone repair strategy, which is expected to provide new insights into biomaterials and their clinical applications.
In this book, we summarized the latest knowledge on the bone microenvironment, the design strategies, applications, and mechanisms of biomaterials that regulating the bone microenvironment, the methods for manufacturing biomaterials, and their clinical translation. The first chapter focused on the role of bone microenvironment and its associated biomaterials in modulating bone diseases and reviewed the biomaterials used to regulate the bone microenvironment. The second chapter introduced the relationship between biological factors of various materials and physiological functions in the bone microenvironment. The third chapter introduced the application of the third generation of biomaterials, which would regenerate the bone to regulate the bone microenvironment. The fourth chapter underlined a variety of emerging biological material manufacturing technologies. The fifth chapter highlighted the mechanisms of novel biomaterials modulating the microenvironment for bone regeneration and discussed how to apply this therapeutic strategy to bone tissue engineering in the future. The last chapter provided key points about the process of bone remodeling and regeneration. We hope this book will provide new insights into the clinical application of biomaterials via regulating the bone microenvironment.
This book is a perfect crystallization of the basic and clinical experience of our group over the past few decades. Although we spared no efforts to make this book, inevitable mistakes and omissions still exist. We welcome all readers to comment and share their viewpoints with us.
Jiacan SuIn ShanghaiJune 2022
1Bone Microenvironment
Yingying Jing1 and Xiao Chen2
1Shanghai University, Institute of Translational Medicine, No. 333, Nan Chen Road, Shanghai, 200444, China
2Changhai Hospital, Department of Orthopedics, Shanghai, No. 168, Chang Hai Road, 200438, China
1.1 Introduction
1.1.1 Cell Types
There are many types of cells in bone microenvironment [1], including genuine bone cells (osteoblasts, osteocytes, osteoclasts, and their precursors), cells of the hematopoietic and immune systems, stromal cells, adipocytes, fibroblasts, and endothelial cells and so on [2]. A growing body of evidence, with the development of techniques such as single‐cell sequencing, proposes a fluidity in the ability of bone marrow (BM) stem cells to differentiate toward distinct lineages [3]. In this section, the main cells in the bone microenvironment are presented below with origins, functions, and identifications.
1.1.1.1 Genuine Bone Cells
1.1.1.1.1 Bone Mesenchymal Stem Cells
As defined by the International Society for Cellular Therapy (ISCT), mesenchymal stem cells (MSCs) are capable of adhering to plastic and capable of differentiating toward adipogenic, osteogenic, and chondrogenic pathways and other specific phenotypes [4]. In the bone marrow, the percentage of MSCs is very low in terms of numbers, only 0.01% [5], but these cells play an important role, especially CAR cells (CXCL12‐rich reticulocytes), CD146+ cells, and Nestin+ cells [6]. CAR cells are a subtype dispersed within the bone marrow that regulates the cell cycle and hematopoietic stem cell (HSC) self‐renewal through high expression of CXCL12 and SCF [7, 8]. CD146+ cells are a subtype predominantly found in the human vascular ecology that interacts with s and endothelial cells through the expression of Tie‐2 and CXCR4 [9]. Nestin+ cells are associated with the nerves of the sympathetic nervous system (SNS) [6, 10] in the perivascular area of bone marrow [11]. It supports the homing role of HSCs and also regulates homeostasis of HSCs by maintaining high expression of various genes such as CXCL12, SCF, and Ang1 [11]. Besides, skeletal stem cells (SSCs) have been identified as a lineage‐restricted subset of bone marrow mesenchymal stem cells (BMSCs) with self‐renewal and osteochondral properties [6, 12]. They are able to differentiate into osteo‐lineage cells, bone, cartilage, and stroma [13, 14] (Figure 1.1).
Figure 1.1 Classification of BMSCs.
Source: Adapted from Gao et al. [15].
1.1.1.1.2 Osteo‐Lineage Cells
Osteoblasts include osteogenic progenitor cells, preosteoclasts, and osteoblasts. It is now accepted that the whole process can be divided into three distinct stages of differentiation. In the first stage, the transition in osteoblasts to pre‐osteoblasts is marked by the expression of RUNX2 in osteoblasts. In the second stage, WNT‐β‐catenin signaling acts on pre‐osteoblasts to induce Ostrix expression. In the third stage, the expression of both RUNX2 and Ostrix drives differentiation toward osteoblasts [16]. Osteoblasts are located between the bone matrix, and they are derived from a subpopulation of osteoblasts [17].
Osteoblasts secrete extracellular matrix proteins, such as type I collagen, periostin, osteocalcin, and alkaline phosphatase. Among them, type I collagen plays an important role in bone mineralization by depositing calcium together with the hydroxyapatite form. Moreover, the mechanism of mutual coupling between osteoblasts and osteoclasts maintains bone mass homeostasis. The process of bone maintenance is sensitive to mechanical forces, and in response to mechanical loading, osteoblasts lead to increased bone formation by activating multiple signaling pathways, mainly the WNT‐β‐catenin signaling pathway [18]. There are other conditions such as radiation and diet that also have an impact on osteoblast function [19–21].
1.1.1.1.3 Bone Lining Cells
Bone lining cells are also differentiated from osteoblasts [22]. In general, bone lining cells are defined as elongated, flattened cells on the bone surface in areas where no bone remodeling activity occurs [23]. Bone lining cells, similar to osteoblasts, express some level of alkaline phosphatase. However, bone lining cells phenotypically express intercellular adhesion molecules, but not osteocalcin, which is the major difference between them and osteoblasts [24].
Recent studies have shown that bone lining cells play an important role in bone remodeling. They communicate with osteoblasts deep in the bone matrix through gap junctions and regulate the transformation of HSCs between the undifferentiated state and osteoblasts under different conditions.
In addition, before bone‐forming activity, bone lining cells first remove osteoclast remnants of matrix‐by‐matrix metalloproteinases [25], such as demineralized collagen [26]. Afterwards, osteoblasts can then enter the site to deposit new bone [27].
1.1.1.1.4 Osteoclasts
Osteoclasts are special cells from the monocyte/macrophage hematopoietic lineage, and morphologically, they are multinucleated cells. Their main hallmark is the expression of high levels of tartaric acid‐resistant acid phosphatase and cathepsin K [28]. Osteoclasts play an important role in the coupling of bone formation to bone resorption through the RANK signaling pathway [29].
1.1.1.2 Chondral‐Lineage Cells
Chondrocytes are cells that produce and maintain the cartilage matrix and characteristically express the SOX gene [30]. Prechondrocytes develop from MSCs, which later differentiate into chondrocytes. Growing chondrocytes continue to undergo cell division as they grow, and the divided daughter cells usually form cell clusters distributed in the cartilage matrix. In contrast, older chondrocytes have a basophilic cytoplasmic nature due to an increase in the rough endoplasmic reticulum [31]. Chondrocytes release extracellular matrix and collagen fibers to form elastic and collagen fibers [32].
1.1.1.3 Adipocytes
Adipocytes are abundant and occupy a large amount of space in bone marrow. The types of adipocytes include preadipocytes and mature adipocytes [31]. Adipose precursor cells are a specialized class of cells that do not contain lipid droplets but express adipocyte markers. They are usually present in large numbers in the perivascular area, especially in the intraosseous veins, and are not proliferative. They can maintain vascular function and inhibit bone formation by occupying space [33]. In addition, it is noteworthy that adipocytes have been found to be associated with many pathophysiological mechanisms [34]. For example, preadipocytes and mature adipocytes can recruit multiple myeloma cells via monocyte chemotactic protein‐1 and stromal cell‐derived factor‐1α and produce many secreted factors that support multiple myeloma cells in the bone marrow [35].
1.1.1.4 Cells of the Hematopoietic Systems
1.1.1.4.1 Hemopoietic Stem Cells
HSCs produce billions of new blood cells every day and are responsible for the continuous renewal of blood. It is generally acknowledged that HSCs can further differentiate into two main types: common lymphoid cells and common myeloid cells [36]. HSCs can be obtained from umbilical cord blood, bone marrow, and adult peripheral blood. The most primitive human HSCs were identified as CD34+CD90+Lin‐ [37]. Depleted expression of CD45RA has also been used in combination with the above markers to identify primary HSCs [14]. Most HSCs are in a resting state and are activated upon external stimulation [38].
1.1.1.4.2 Lymphoid Cells
Common lymphoid progenitor cells are differentiated from HSCs stimulated by IL‐7 [39]. Further, stimulated by cytokines such as IL‐3 and IL‐4, lymphoid progenitor cells differentiate into B lymphocytes [40]. Once maturation, B cells enter the circulatory system and eventually localize in the lymphoid follicles of peripheral lymphoid organs [41]. B cells are one of the major specific immune cells, accounting for 20% of peripheral lymphocytes [42]. In addition, lymphoid progenitor cells differentiate into natural killer (NK) cells in response to IL‐15 stimulation [43].
1.1.1.4.3 Myeloid Cells
Common myeloid progenitor cells are differentiated from HSCs in response to stimulation by IL‐3, GM‐CSF, and M‐CSF [44]. Myeloid progenitor cells can differentiate in two directions, toward granulocyte‐macrophage progenitors and megakaryocyte‐erythroid progenitors, depending on the stimulating factors in the bone microenvironment.
The megakaryocyte‐erythroid progenitor cells are stimulated by erythropoietin to produce erythrocytes, the most abundant blood cells in the blood and the main mediator of oxygen transport through the blood in vertebrates, and also have immune functions. Stimulation by IL‐3, IL‐3, SCF, and TPO results in the production of megakaryocytes by megakaryocyte‐erythroid progenitor cells. Megakaryocytes are a type of cell in the bone marrow that form platelets after partial rupture in response to IL‐11 and TPO stimulation. Platelets play an important role in bleeding and clotting processes [45].
Granulocyte‐macrophage progenitor cells can differentiate into primitive granulocytes and monocytes. They differentiate into monocytes under the stimulation of GM‐CSF and M‐CSF. Monocytes differentiate into macrophages under the stimulation of IL‐6, IL‐10, M‐CSF, and IFN‐gamma [46] (Figure 1.2).
Figure 1.2 The differentiation spectrum of human HSCs.
Source: Chen et al. [47]/with permission of Elsevier.
1.1.1.5 Cells of the Immune Systems
Research related to immune cells in the bone microenvironment has gradually entered the osteopathic field in recent years. Bone health is affected by them in various ways, including the immune effects of immune cells and immune factors themselves and the regulation of the bone microenvironment.
1.1.1.5.1 T‐Cells and Natural Killer Cells
T cells not only play a key role in adaptive immunity, but are equally significant in bone immunology. Basically, all T‐cell subtypes have some impact on osteoblasts (mainly osteoclasts). Nevertheless, current studies have identified a capable role for Th17 cells in inducing osteoclast genesis. They characteristically express the cytokines: IL‐17A, IL‐17F, IL‐22, IL‐26, and IFN‐γ [48]. In osteoblasts and stromal cells, it can also induce the expression of macrophage colony‐stimulating factor (M‐CSF) and RANKL expression [49].
Most NK cells have similar osteoimmune functions to lymphocytes. Recent studies suggest that NK cells may be a target for rheumatoid arthritis (RA) treatment, based on the observation of osteoblast death by NK in RA‐induced bone destruction [50, 51].
1.1.1.5.2 Dendritic Cells
Dendritic cells (DCs) are antigen‐presenting cells with the specific role of guiding immune cells to the correct target as soon as possible and avoiding autoimmunity [52]. In fact, they have an indirect role in bone immunity mainly by presenting antigens of T cells [53]. Cytokine signaling about DCs can also regulate their activities and subtype homeostasis [54, 55]. On the other hand, in RA, DCs can be transdifferentiate into osteoclasts in response to stimulation by M‐CSF and RANKL as if they are precursor cells for osteoclasts [56].
1.1.1.5.3 Neutrophils
Neutrophils have a strong presence in bone loss caused by particular inflammation [57]. In the presence of inflammation in systemic tissues, including bone tissue, neutrophils are usually the first to migrate to the site of injury [58] and secrete chemokines, cytokines, and small molecules that are capable of acting as immunomodulators. Most of the current studies task that activated neutrophils directly or indirectly induce osteoclast genesis [59].
1.1.1.5.4 B Cells
B cell production and development are dependent on factors produced by cells in the bone marrow stroma, such as RANKL, OPG, IL‐7, and CXCL12 [60, 61]. B cells themselves produce RANKL [62] since conditional knockdown of RANKL in B lymphocytes can partially counteract the increased number of osteoclasts, thereby protecting against ovariectomy‐induced bone attrition. Interestingly, no effect was observed in T lymphocytes [63]. This suggests the existence of a specific role of B lymphocytes on osteoclasts.
1.1.1.5.5 Osteomacs and Macrophages
Bone marrow macrophages and osteal macrophages, also called bone macrophages, are the resident macrophages in bone and, like many other organs, play a long‐term immune role in the corresponding organ [64]. In vitro and in vivo studies have shown that these bone macrophages play a role in osteoblast differentiation through the production of bone morphogenetic proteins (BMPs) [65] and Oncostatin M [66]. Furthermore, elimination of bone macrophages inhibits further differentiation of primary osteoblasts [67]. If periosteal macrophages are selectively ablated, young mice show reduced bone growth and osteoporosis [68]. Thus, bone macrophages are cells with pleiotropic functions, both in regulating bone mass and in becoming osteoclasts, as well as actively participating in the homeostasis of the immune system.
1.1.2 Extracellular Matrix
In the bone microenvironment, the ECM is involved in regulating various cell behaviors, responses to growth factors, and differentiation. The recent spurt of research on the osteoinductive, osteogenic, and osteogenic potential of ECM‐based scaffolds has advanced the rapid development of regenerative orthopedic medicine. ECM‐modified biomaterials and decellularized ECM scaffolds are two types of scaffolds that are widely used for bone tissue engineering [69].
1.1.2.1 Inorganic ECM
The main inorganic component of hard tissues in the body, such as bones and teeth, is hydroxyapatite (HA, Ca5(PO4)3OH) [70]. The usual biomineralization process, referring to the series of physiologically regulated activities occurring in the bone microenvironment culminates in the deposition of HA. The template for HA deposition is collagen, which is mostly expressed and secreted into the bone matrix by osteoblasts [71].
1.1.2.2 Organic ECM
1.1.2.2.1 Collagenous Proteins
Type I, type III, and type V collagen constitute the richest components of bone in terms of organic ECM. The primary function of collagen is to provide mechanical support and to act as a scaffold for bone cells [72]. The molecular structure of type I collagen is a triple‐helix polypeptide of collagen fibrils. Together with other collagen and non‐collagenous proteins, these fibrils are assembled into fibrils bundles and higher order fibers [73]. Type III and V collagens are less abundant. Their function is to participate in the formation of collagen bundles as described above [74]. Inter‐ and intra‐chain cross‐links of collagen form a tight fibrous structure to maintain bone strength. A deficiency of collagen or a mutation in its structure can greatly alter the ECM and thus greatly increase the risk of fracture [75].
1.1.2.2.2 Noncollagenous Proteins
Proteoglycans Proteoglycan is a structure in which glycosaminoglycan (GAG) residues are covalently bound to proteins. Its species include heparan sulfate, hyaluronic acid, keratin sulfate, chondroitin sulfate, and dermatan sulfate [76]. In the bone microenvironment, small leucine‐rich proteoglycans (SLRPs) are the most important proteoglycans. SLRPs are involved in all steps of the bone formation process such as cell proliferation, osteogenesis, mineral deposition, and bone remodeling [77]. In addition, SLRPs regulate collagen fibrosis, and their dysregulation eventually leads to fibrosis caused by orthopedic injury or genetic defects [78].
γ‐Carboxyglutamic Acid‐Containing Proteinsγ‐Carboxyglutamic acid (Gla) is a glutamate produced by vitamin K‐dependent post‐translational modifications appearing in bone matrix and other calcified tissues [79]. Osteocalcin (OCN), matrix Gla protein (MGP), and periosteal proteins in bone all contain Gla protein [80]. OCN is an important player in osteoblasts performing bone formation and bone reconstruction functions. It contains three Gla residues that regulate calcium metabolism by binding to hydroxyapatite [81]. MGP, on the other hand, regulates the synthesis of osteoblasts, osteocytes, and chondrocytes in the skeleton. It has been reported that bone mineralization is advanced in MGP‐deficient mice [82, 83]. In contrast, intramembranous bone mineralization is reduced in mice overexpressing MGP [84]. In addition, periostin, another Gla‐containing protein, is abundantly expressed by osteoblasts in long bones and is involved in collagen folding and fibrillogenesis [85].
Glycoproteins Glycoproteins have different combinations and positions in the protein chain where covalently linked glycoprotein molecules exist. Among the glycoproteins of the bone microenvironment, osteoprotegerin is the most common and capable of bone mineralization. Osteoblasts highly express osteoprotegerin and secrete it into mineralized tissues. Osteoprotegerin regulates calcium deposition by binding collagen crystals and hyaluronic acid [86]. In the bone microenvironment of the developing skeleton, thrombospondins (TSP), grouped from TSP1 to TSP5, play an important role. One study reported increased bone mass and thickness of cortical bone and promotion of differentiation of osteoblasts in TSP1‐deficient mice, possibly due in part to potential TGF‐β activation [79]. R‐spondins (parietal plate‐specific spondins) are four secreted, homologous glycoproteins belonging to a family of matricellular proteins with a TSP repeat sequence [80]. They are widely expressed in all developmental stages of skeletal tissue and act as an enhancer of the Wnt/β‐catenin signaling pathway through leucine‐rich repeat sequences 4, 5, and 6 of the G protein receptors (Lgr4/5/6). R‐spondin is thought to be a skeletal regulator that controls embryonic bone formation and adult bone remodeling [81].
Small Integrin‐Binding Ligand N‐Linked Glycoproteins/SIBLINGs A kind of glycophosphoproteins generally found in mineralized tissues, named SIBLINGs, consist of bone sialoprotein (BSP) and osteocalcin (OCN) [87].
First, BSP is a glycosylated, non‐collagenous phosphoprotein that is expressed at the onset of hard connective tissue mineralization. It has been shown that mice deficient in BSP have significantly diminished bone deposition and a significantly reduced rate of bone formation, resulting in a decrease in both the length of long bones and the thickness of cortical bone. Thus, BSP has an important function in regulating osteoblast differentiation and initiating bone mineralization [88].
OPN is also an important regulator highly expressed by osteoblasts, bone lineage cells, especially in bone transformation. OPN is enriched in sites that undergo phosphorylation during inhibition of mineralization, such as serine, acidic, and aspartate patterns. In addition, in bone remodeling, OPN is involved in regulating osteoclast production and osteoblast activity [89] (Figure 1.3).
Figure 1.3 Bone microenvironment and diseases.
1.2 Bone Microenvironment and Diseases
1.2.1 Bone Microenvironment in Osteoporosis
The bone microenvironment consists of complex structures and biological systems, including bone cells (BMSCs, osteoblasts, osteoclasts, bone cells, and their precursors), fibroblasts, adipocytes, hematopoietic cells, immune cells, endothelial cells, and a large number of growth and signal factors in extracellular matrix [90]. Proper bone homeostasis maintenance relies on the equilibrium between bone formation and bone resorption. However, patients suffering from osteoporosis have the characteristics that bone resorption is greater than bone formation, which leads to bone loss and fragility‐related fracture [91].
1.2.1.1 Bone Marrow Mesenchymal Stem Cells (BMSCs) and Osteoporosis
BMSCs in patients with osteoporosis show changes in osteogenic ability. It was found that the transcriptome of BMSCs in the bone microenvironment of elderly patients with osteoporosis changed compared to that in elderly patients without osteoporosis [92]. The levels of MAB21L2 and SOST expressed by BMSCs in osteoporosis were remarkably increased, which were inhibitors of BMP transcription and Wnt signal, respectively. BMSCs from patients with osteoporosis expressed higher levels of genes related to osteoclastogenesis, which indicates that their osteogenic ability is limited. At the same time, they enhanced the production of osteoclasts through local release factors. Multiple in vitro studies have found significantly reduced proliferative activity (reduced S‐phase fraction) and differentiation potential (reduced Osterix [Osx] expression and alkaline phosphatase [ALP] activity) and enhanced expression of aging markers in aging mouse BMSCs [93]. Recent experiments have shown that microRNAs in BMSCs of patients with osteoporosis have also changed. For example, overexpression of miR‐21 in BMSCs can enhance osteogenic differentiation and bone formation [94].
BMSCs from patients with osteoporosis showed decreased response to anabolism irritant. As mentioned above, BMSC osteoblasts induced by 25 (OH) D3 are weakened in cells from elderly donators, and a coordination dosage of PTH is required to restore this reaction [95]. BMSCs from elderly subjects showed decreased expression and activity of CYP27B1, which was increased in PTH treatment. In recent experiments, compared with young people, the higher levels of PEHR and CREB activation expressed by BMSCs in the bone marrow of the elderly have been more stable β‐Catenin induced by PTH [96]. Mice knockout of IGF‐1 in BMSC showed a decrease in bone mass. Interestingly, IGF‐1 in BMSC decreased in osteoporotic mice, suggesting that IGF‐1 in BMSC is related to the occurrence of osteoporosis [97]. BMSC in bone microenvironment has undergone many changes in patients suffering from osteoporosis relative to healthy person.
1.2.1.2 Osteoblasts and Osteoporosis
Senile osteoporosis is caused by insufficient osteoblast function, while postmenopausal osteoporosis is mainly caused by an increase in bone resorption activity of osteoclasts due to estrogen deficiency. Various local and systemic factors under physiological and pathological conditions can affect the strict coupling activities of osteoblasts and osteoclasts, leading to the imbalance of bone remodeling and promoting bone resorption. Moreover, the change in osteoblast function plays a significant function in the occurrence of osteoporosis. Abundant experimental studies show that under the condition of osteoporosis, compared to normal osteoblasts, osteoblasts have low proliferation ability and defective function.
Long‐term use of glucocorticoids is a prime reason of osteoporosis. High‐dose and long‐term glucocorticoid stimulation inhibited the proliferation and activity of osteoblasts and promoted the apoptosis of osteoblasts. At the same time, it increases the expression of RANKL, reduced the production of OPG, and enhanced bone resorption [98]. In vitro studies showed that dexamethasone treatment of human osteoblasts could overexpress DKK‐1 mRNA. This indicates that glucocorticoids can inhibit Wnt signal transduction and inhibit osteogenesis. Glucocorticoid can reduce the expression of BMP‐2 and increase its antagonist follistatin to inhibit osteogenesis [99]. PTH and bisphosphonates for the treatment of osteoporosis can change the difference of dexamethasone on BMP and Wnt signal transduction. Interestingly, pretreatment of BMSCs in elderly subjects with dexamethasone increased the expression of PTHR1 and saved the defect of proliferation induced by hormone.
1.2.1.3 Osteoclasts and Osteoporosis
Osteoclast is a highly differentiated multinucleated giant cell, which is the main functional cell for bone tissue resorption and participates in the process of bone remodeling throughout life. Postmenopausal osteoporosis patients produce more osteoclasts by increasing hematopoietic progenitor cells and increasing the recruitment of more osteoclast progenitor cells due to estrogen deficiency. The upregulated expression of osteoclasts leads to the expansion of cortical porosity and absorption regions indicated by bone trabeculae. At the same time, the life of osteoclasts in the bone microenvironment increases, which further prolongs the time of bone loss, deepens the absorption cavity, and increases the brittleness of bone [92].
Some animal experiments have shown that the cytokine tumor necrosis factor‐alpha (TNF‐α), which is mainly secreted by macrophages can increase osteoclast production in ovariectomized mice. TNF and RANKL synergistically increased the differentiation of hematopoietic pluripotent stem cells into osteoclasts, thus increasing the production of osteoclasts [93]. IL‐6 is increased in the bone microenvironment of patients with osteoporosis. IL‐6 is widely considered to be an effective stimulator of osteoclast‐driven bone resorption. In vivo studies showed serious damage to cortical and trabecular bone microstructure, increased osteoclast production, and decreased osteoblast production in transgenic mice overexpressing IL‐6 [94]. The important role of IL‐6 is to promote the expression of signaling molecules downstream of osteoblasts, such as RANKL, so as to enhance the formation and activity of osteoclasts. In addition, IL‐6 increases the promoting effect of IL‐1 and TNF on bone resorption by increasing the pool of osteoclast progenitor cells. IL‐7 is a major osteoclast factor, which stimulates T cells to produce RANKL and TNF and promotes bone loss. IL‐7 can stimulate the increase in TNF in T cells. Moreover, the expression of IL‐7Rα and IL‐7 was upregulated by TNF. Therefore, there may be an interaction mechanism between TNF and IL‐7 [95].
1.2.1.4 Bone Marrow Adipocytes (BMAs) and Osteoporosis
The accumulation of fat in the bone marrow of osteoporosis patients increases. Studies have shown that bone marrow adipocytes (BMAs) can inhibit bone formation and hinder fracture healing, and their content is negatively correlated with bone mass [100, 101]. Bone formation was also enhanced when BMAs decreased. After ablation, BMAs promote the recruitment and differentiation of pre osteoblasts into mature osteoblasts [102]. Recent studies have found that BMA can inhibit the function of osteoblasts by producing IL‐6 [103, 104]. BMAs mediate myeloma induced inhibition of osteoblast formation. Multiple myeloma is characterized by excessive bone resorption and impaired osteogenesis [105]. When BMSCs were cultured with conditional medium from myeloma patients with BMA or pre‐exposed myeloma cells, researchers observed reduced alizarin red S staining, alkaline phosphatase levels, and osteoblast gene expression [106]. BMA and osteoblasts are derived from BMSCs. When the adipogenic differentiation of bone MSCs increases, the osteogenic differentiation will decrease. Therefore, according to the above characteristics, osteogenesis can be changed by changing the differentiation direction of BMSC, so as to change the bone mass [107, 108]. BMAS promote osteoclastogenesis [109]. Adipoqcre; Ranklfl/FL mice showed similar BMAs amplification compared with control Ranklfl/FL mice, but the number of osteoclasts decreased [110].
1.2.2 Bone Microenvironment in Osteoarthritis
Osteoarthritis (OA) is the most common joint disease with predominant damage to articular cartilage and involvement of the entire joint tissue, eventually leading to degeneration, fibrosis, fractures, defects, and damage to the entire joint surface. It is characterized by joint pain, stiffness, hypertrophy, and limited movement, and it occurs most commonly in weight‐bearing joints such as the knee.
1.2.2.1 Subchondral Bone and Osteoarthritis
1.2.2.1.1 Subchondral Bone Cells
Subchondral osteoblasts are derived from BMSCs. Osteoclasts are not only involved in bone resorption in subchondral bone metabolism, but they also play an important role in the formation of H‐type vessels. The histone proteinase K (ctsk) expression of anti‐tartrate acid phosphatase positive (trap+) cells located around the cartilage‐bone junction was lower than that of cells in the bone marrow interstitial space and had fewer nuclei [111]. Vascular‐associated osteoblasts have a high affinity for H‐type vessels, whose endothelial nuclear factor‐κ B ligand (RANKL) expression is supported by receptor activators and induces H‐type vascular anastomosis.
High turnover rate. The relative balance of bone formation and bone resorption establishes a stable microenvironment of subchondral bone. The subchondral bone conversion rate changes in response to changes in mechanical stress to maintain a stable microenvironment. The subchondral bone structure and mechanical support were abnormal in patients with OA. The number of osteoclasts in the bone microenvironment increases. Interestingly, osteocytes and chondrocytes provide the main RANKL. Abnormal mechanical force activates RANKL signaling to promote osteoclast fusion differentiation that promotes osteoclast formation, resulting in bone remodeling [112]. Soluble RANKL can pass through the subchondral bone plate cavity, which can promote the maturation of osteoclasts and play the role of bone resorption. It is found that subchondral bone plays an important role in cartilage injury [113]. Significant increase in osteoclasts near perichondrium trabeculae in subchondral bone marrow [114]. The subsequent remodeling process is related to the growth of blood vessels and nerves and the activity of osteoclasts. This suggests that during the onset of OA, subchondral bone undergoes increased bone remodeling conversion in response to external stimuli.
1.2.2.2 Cartilage and Osteoarthritis
1.2.2.2.1 Cartilage Erosion
There is top‐down erosion from synovial tissue and synovium in the process of cartilage vascular invasion in patients with OA, but the most important is the bottom‐up vascularization of subchondral bone. Matrix digestive proteases, such as MMPs, play an important role in angiogenesis. Subchondral angiogenesis plays a key role in cartilage degradation. In the process of cartilage formation, endothelial cells express more MMP‐9. Knocking out MMP‐9 endothelial cells will lead to the destruction of bone formation ability and the formation of abnormally large bone plates, which indicates that MMP‐9 is pivotal to bone resorption during cartilage formation. When vascular endothelial growth factor (VEGF) is injected into the joints of rabbits, it accelerates the formation of arthritis, and the use of inhibitors of VEGF can protect the articular cartilage [115, 116]. These experiments further suggest that neovascularization has a cartilage resorption effect on OA and endochondral ossification.
1.2.2.2.2 Mechanical Stimulation and Cartilage Homeostasis
Proper mechanical stimulation can maintain the health of articular cartilage. Overload will lead to cartilage fissure and bone atrophy. Research shows body weight, especially in obese individuals, weight load, and daily knee activity are associated with cartilage degeneration, and the knee is more prone to degenerative disease on the medial side [117]. In chondrocyte impact experiments, early mitochondrial dysfunction followed by cell death occurred in chondrocytes, but chondrocytes in the weight‐bearing zone were less likely to die [118]. Appropriate biological load not only promotes the formation of cartilage matrix but also promotes the synthesis of matrix protein, collagen, and GAG. However, when the load is too heavy, p38 will be hyperphosphorylated, and MMP‐13 will be overexpressed, resulting in matrix degradation and proteoglycan loss [119]. In the presence of increased circulatory pressure in vivo, the differentiation of BMSC toward the osteogenic aspect of formation increases due to various effects. MSCs under abnormal stress showed increased angiogenesis [120]. There are several cytokines closely related to angiogenesis in the above medium, such as FGF, TGF‐β, and MMP‐2. Other studies have shown that BMP‐dependent signaling promotes osteogenic differentiation [121]. Thus, as described above, MSC from sclerotic subchondral bone may promote angiogenesis, thereby promoting cartilage degradation.
1.2.3 Bone Microenvironment in Fracture
Bone has the ability to regenerate. Fracture healing restates the mechanism of bone tissue formation in embryogenesis. In this way, fracture healing can restore the original structure and function rather than scar formation. Fracture healing can be divided into intramembrane osteogenesis and endochondral osteogenesis. Endochondral osteogenesis is to form cartilage callus in the area between medullary cavity and cortex and then form new bone through endochondral ossification. In conclusion, the stages of fracture healing are divided into a period of hematoma inflammatory response, cartilage scab formation, hard bone scab formation, and remodeling. Hematoma is a fibrin clot formed by coagulation at the injured bone, with infiltration of mast cells and other inflammatory cells. With the infiltration of fibroblasts and endothelial cells, granulation tissue was formed and gradually degraded to replace hematoma. Chondrocytes produce cartilage matrix and transform granulation tissue into cartilage callus. With the osteoid deposition of hydroxyapatite calcium and osteoblasts, the callus became woven bone. After rearrangement of collagen fibers, bone formation and differentiation of osteoblasts occur.
1.2.3.1 Cells in Bone Microenvironment
1.2.3.1.1 Platelet
Platelets are formed from cytoplasmic fragments of megakaryocytes in bone marrow. After vascular injury, platelets interact with collagen, von Willebrand factor (VWF), and fibronectin under the damaged endothelium to mediate the adhesion and activation of platelets. Platelets can be activated after endothelial cell damage. The particles released by platelets include dense particles α particles and lambda particles [122]. Platelet granules contain many cytokines related to osteogenesis and angiogenesis, and these cytokines play an important role in the healing process of fracture fractures [123]. These cytokines promote the chemotaxis and vascularization of inflammatory cells and the differentiation of BMSC to osteoblasts [124–126]. Among these cytokines, PDGF‐AB and TGF‐β can promote the proliferation and migration of vascular smooth muscle cells. During the inflammatory phase of the hematoma, growth factors can promote the formation of blood vessels and collagen and subsequently support bone healing. TGF‐β1 can inhibit the formation of osteoclasts, PDGF‐AB supports the proliferation of smooth muscle cells, and both the above growth factors promote collagen synthesis and angiogenesis to support bone healing [127, 128]. In addition, platelet‐rich plasma can increase the production of bone morphogenetic protein 2 (BMP‐2) from MSC, so as to comprehensively improve the bone regeneration of bone defect [129].
