Table Of ContentMechanical Engineering Series
Hala Zreiqat
Colin R. Dunstan
Vicki Rosen E ditors
A Tissue
Regeneration
Approach
to Bone and
Cartilage Repair
Mechanical Engineering Series
Editor-in-chief
Frederick F. Ling, New York, USA
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Hala Zreiqat · Colin R. Dunstan · Vicki Rosen
Editors
A Tissue Regeneration
Approach to Bone
and Cartilage Repair
1 3
Editors
Hala Zreiqat Vicki Rosen
Tissue Engineering and Biomaterials Department of Developmental Biology
Research Unit Harvard School of Dental Medicine
University of Sydney Boston, MA
Sydney, NSW USA
Australia
Colin R. Dunstan
Biomedical Engineering
University of Sydney
Sydney, NSW
Australia
ISSN 0941-5122 ISSN 2192-063X (electronic)
Mechanical Engineering Series
ISBN 978-3-319-13265-5 ISBN 978-3-319-13266-2 (eBook)
DOI 10.1007/978-3-319-13266-2
Library of Congress Control Number: 2014957869
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Contents
Ligand–Receptor Interactions and Their Implications in Delivering
Certain Signaling for Bone Regeneration ........................... 1
Takenobu Katagiri, Sho Tsukamoto, Kenji Osawa and Shoichiro Kokabu
BMPs and Wnts in Bone and Cartilage Regeneration ................ 17
Di Chen, Shan Li and Tian-Fang Li
Osteocytes and Bone Regeneration ................................ 39
Gerald J. Atkins, Matthew Prideaux and David M. Findlay
Skeletal Stem Cells for Bone and Cartilage Tissue Regeneration ....... 53
Walid Zaher, Adiba Isa and Moustapha Kassem
Manipulation of Macrophages to Enhance Bone
Repair and Regeneration ........................................ 65
Sina Nassiri, Pamela Graney and Kara L. Spiller
Cartilage Regeneration Using Induced Pluripotent Stem
Cell Technologies ............................................... 85
Noriyuki Tsumaki
Alveolar Augmentation: Focus on Growth Factors (BMPs) ............ 99
Ulf M.E. Wikesjö, Cristiano Susin and Jaebum Lee
Bone-Biomimetic Biomaterial and Cell Fate Determination ........... 119
ZuFu Lu, Jiao Jiao Li and Hala Zreiqat
Biomimetic Scaffolds for Craniofacial Bone Tissue Engineering:
Understanding the Role of the Periosteum in Regeneration ............ 147
Michael E. Frohbergh and Peter I. Lelkes
v
vi Contents
Biomaterials Used for Maxillofacial Regeneration ................... 167
Xinquan Jiang and Zhiyuan Zhang
Advances and Applications of Nanomechanical Tools in Cartilage
Tissue Engineering ............................................. 191
Lin Han and Alan J. Grodzinsky
Signalling Pathways in Osteochondral Defect Regeneration ........... 219
Henning Madry and Magali Cucchiarini
Polymer-Assisted Cartilage and Tendon Repair ..................... 229
Gundula Schulze-Tanzil
Ligand–Receptor Interactions
and Their Implications in Delivering
Certain Signaling for Bone Regeneration
Takenobu Katagiri, Sho Tsukamoto, Kenji Osawa and Shoichiro Kokabu
Abstract Cartilage and bone tissue formation is observed not only during
embryonic development but also in some pathological conditions occurring after
birth, including fracture healing. This process is regulated by many stimuli that are
applicable to the reconstitution of skeletal tissues using tissue engineering. In par-
ticular, members of the transforming growth factor (TGF)-β family play a unique
and important role in skeletal tissue formation, wherein they activate specific intra-
cellular signaling pathways by binding two types of serine–threonine kinase recep-
tors and downstream effectors called Smad proteins. The biological activity of
TGF-β family members is positively and negatively regulated at multiple steps by
various molecules found in the extracellular space, on the cell membrane, and in the
intracellular space. The modification of TGF-β family signaling pathways can be
used in tissue engineering approaches for skeletal tissue formation.
1 Introduction
Skeletal tissues mainly consist of cartilage and bone, which are formed during
embryonic development in vertebrates. There are two processes at work in bone
formation—intramembranous ossification and endochondral ossification (Shapiro
2008; Yang 2009). The former process is observed in flat bones, such as the fron-
tal and parietal bones of the skull, whereas most of the long bones are formed
through the latter process. During endochondral ossification, undifferentiated
T. Katagiri (*) · S. Tsukamoto · K. Osawa
Division of Pathophysiology, Research Center for Genomic Medicine,
Saitama Medical University, 1397-1 Yamane, Hidaka-shi, Saitama 350-1241, Japan
e-mail: [email protected]
S. Kokabu
Department of Oral and Maxillofacial Surgery, Faculty of Medicine,
Saitama Medical University, 38 Morohongo, Moroyama-machi,
Iruma-gun, Saitama 350-0495, Japan
© Springer International Publishing Switzerland 2015 1
H. Zreiqat et al. (eds.), A Tissue Regeneration Approach to Bone
and Cartilage Repair, Mechanical Engineering Series,
DOI 10.1007/978-3-319-13266-2_1
2 T. Katagiri et al.
Positive regulations Stimuli Negative regulations
Target cells Scaffold
Skeletal formation
Fig. 1 Both positive and negative regulations of bone formation stimuli can be applied to recon-
stitute skeletal tissues via tissue engineering approaches, which further require cells and scaffolds
mesenchymal cells form cartilaginous rudiments, and the first bone tissue emerges
from terminally differentiated hypertrophic chondrocytes within these rudiments.
The processes involved in bone formation are detected not only during embry-
onic development but also after birth, in pathological conditions such as fracture
healing and ectopic bone formation (Katagiri 2010; Shapiro 2008). The molecu-
lar mechanisms underlying physiological and pathological bone formation can be
applied to reconstitute skeletal tissues via tissue engineering approaches, which
require three critical factors—cells, scaffolds, and stimuli (Fig. 1). In this chapter,
we focus on the positive and negative regulation of the stimuli component of these
critical factors.
2 The Identification of BMPs as Members
of the TGF-β Family
Urist (1965) first reported the experimental induction of bone formation in soft
tissue through the use of bone matrix. He implanted HCl-treated bone matrix
into skeletal muscle tissue and observed the formation of mineralized bone
tissue containing newly generated osteoblasts and bone marrow. In addition, he
showed that bone induction could be applied to the regeneration of bone tissue
with critical defects. Given that the demineralized bone matrix did not contain
any living cells, these findings indicated the presence of a novel bone-inducing
activity within the demineralized bone matrix. This bone-inducing activity was
later named “bone morphogenetic protein (BMP)” (Urist and Strates 1971). BMP
could be extracted from demineralized bone matrix using protein denaturation
reagents such as urea, suggesting that BMP binds tightly to the organic com-
ponents of bone (Sampath and Reddi 1981; Urist and Strates 1971). Molecular
cloning of the bone-inducing activity of bone matrix revealed that this activity
consisted of several related BMPs and that these BMPs belong to the transform-
ing growth factor-β (TGF-β) family, which includes TGF-βs, activin, growth and
differentiation factors (GDFs), and others (Celeste et al. 1990; Ozkaynak et al.
1990; Sampath et al. 1990; Wozney et al. 1988) (Fig. 2). The ectopic bone-induc-
ing activity of BMP is observed only with several specific members, such as
BMP-2, BMP-4, BMP-5, BMP-6, BMP-7, BMP-9, and GDF5, but not with other
Ligand–Receptor Interactions and Their Implications in Delivering … 3
Non-osteogenic Osteogenic
members members
TGF- family
TGF- 1 BMP-2
TGF- 2 BMP-4
TGF- 3
precursor BMP-5
Activin A BMP-6
Activin B dimerization BMP-7 (OP-1)
BMP-8
BMP-3
GDF-10 (BMP-3b) GDF-5 (BMP-14)
GDF-6 (BMP-13)
GDF-7 (BMP-12)
Myostatin (GDF-8)
GDF-11
BMP-9 (GDF-2)
processing BMP-10
GDF-1
GDF-3
active form
BMP-15
GDF-9
Fig. 2 Typical osteogenic and non-osteogenic members of the TGF-β family. The TGF-β family
consists of TGF-βs, BMPs, GDFs, activin, and other members. These proteins form dimers that
are processed to release active ligands. Most BMPs are capable of inducing heterotopic bone
formation in soft tissues (osteogenic); however, TGF-β proteins, activin, and BMP-3 lack this
activity (nonosteogenic)
members of the family or with other growth factors, hormones, or chemical com-
pounds (Kang et al. 2004). The bone-inducing activity of BMPs is both positively
and negatively regulated by a variety of molecules that act at multiple steps in the
signaling pathway, such as during ligand modification, ligand–receptor interac-
tion, and downstream effector activation. In this chapter, we discuss this multistep
regulation of bone-inducing activity and how it might be applied in the recon-
struction of skeletal tissues.
3 Experimental Models for Evaluating Bone Formation
Bone-inducing activity can be directly evaluated in vivo by implanting test sam-
ples into skeletal muscles or subcutaneous sites (Urist 1965; Wang et al. 1988).
Fracture healing is another experimental model that can be used to evaluate the
bone-forming capacity of samples in vivo (Urist 1965). In addition, cell cultures
and ex vivo cultures function as alternative ways to examine a sample’s bone
induction capacity in vitro.
