Current Topics in Bone Biology

The following sections are included:

• CONTENTS

• PREFACE

It is a delight to see the fruition of the published book on bone biology and osteoporosis compiled by ICHTS in its 10^th anniversary. ICHTS has come a long way from a small group of scientists gathering at the Sun Valley International Hard Tissue Workshop to a professional organization with over 700 members around the world.

The mission of ICHTS is to promote scientific and professional excellence and to enhance communication among scientists of Chinese heritage and other international scholars in the field of hard tissue research and related areas. As it has grown in the past ten years, ICHTS has gone through excitements, challenges and inevitable growing pains and has mature into a cohesive and strong organization. ICHTS has participated, sponsored, and organized various scientific events to promote information exchanges and research collaborations around the world. In this short overview, we invite you to join us on the growing path of ICHTS and its impact on its members and the overall scientific community.

The following sections are included:

• Introduction

• Skeletal Anatomy
  • Axial and appendicular bones
  • Woven and lamellar bone
  • Cortical and Cancellous Bones
  • Bone Surfaces
  • Composition of Bone

• Skeletal Histology
  • Bone cellularity
  • Bone structural unit

• Osteogenesis
  • Intramembranous ossification
  • Endochondral ossification

• Skeletal Biological Mechanisms
  • Bone growth

• Lifetime Skeletal Changes
  • Fetal skeleton
  • Growing skeleton
  • Adult and aging skeleton

• Skeletal Adaptation to Mechanical and Non-Mechanical Stimuli
  • The mechanostat hypothesis
  • The mechanothreshold mechanism
  • The mechanosensor mechanism
  • The mechanoresponding mechanism
  • The mechanofeedback loop mechanism
  • Utah Paradigm for bone physiology

• Dedication

• References

Mesenchymal stem cells (MSCs) are known to have the capability to differentiate into many cell types of skeletal tissues. MSCs were first identified in the bone marrow but since then they have been isolated and identified in many other tissues. Many possible therapeutic uses of MSCs require a careful review of their sources. Bone marrow, adipose tissue, periosteum, skeletal muscle, adult peripheral blood, umbilical cord blood, vascular pericytes, bone tissue, amniotic fluid, spleen, and dermis are sources of MSCs. Bone marrow is the most established source which has been investigated most, understood best and its use in vivo is promising. Adipose tissue, skeletal muscle and periosteum have also been proven to contain MSCs and may have possible future uses. Recently, MSCs have also been found in adult peripheral blood at low numbers. More research is needed to develop adult peripheral blood as a viable option for MSCs. If it were, the future use of MSCs would be greatly facilitated with the ease of its collection. Evidence of MSCs in the other tissues, such as umbilical cord blood, vascular pericytes, bone tissue, amniotic fluid, spleen, and dermis also existed but they are of limited use.

Osteoclasts, the principal bone-resorbing cells, not only play an essential role in skeletal development and maintenance but are also implicated in the pathogenesis of various bone disorders. Osteoclasts are giant cells that possess distinct morphological features, including mutlinucleation, polarization, ruffled border membrane, a unique cell-bone matrix attachment and special cytoskeleton organization. Osteoclasts differentiate from mononuclear precursors of monocyte/macrophage lineage upon the stimulation of two key factors: M-CSF and RANKL. In addition, osteoclast differentiation is also modulated by a variety of other osteotropic factors such as 1-α,25(OH)₂ vitamin D₃, dexamethasone, IL-1, TNF-α, prostaglandin E₂, IL-11, PTH and estrogen. Osteoclastic bone resorption involves several major steps. It starts with the establishment of a functional resorption compartment and then the formation of ruffled border membrane facing bone. The ruffled border membrane is highly rich in proton pumps which transport protons into the resorption compartment to dissolve inorganic components of bone matrix. Onorganic component of bone is then degraded by various proteolytic enzymes also released through the ruffled border membrane. Finally, degraded products are removed outside of the resorption compartment by transcytosis.

Bone is a living tissue and is maintained by the coordinate action of osteoblasts and osteoclasts. The intercellular communication between these two cells is the quintessential mechanism in bone remodelling. The importance of this interaction is increasingly evident as disruption of this “cross-talk” results in debilitating bone diseases. It has been well established that osteoblasts can regulate osteoclast formation and activation via the production of osteoclastogenic factors. There are now several emerging investigations that have identified novel osteoclast-derived factors that have the potential to control osteoblastic growth and function. This chapter highlights the intercellular communication between osteoblasts and osteoclasts and the impact of this “cross-talk” in bone diseases, including giant cell tumour of bone and other osteolytic bone tumours, osteoporosis, osteopetrosis, osteogenesis imperfecta, Paget's disease, periodontitis, osteoarthritis and aseptic loosening.

The following sections are included:

• Introduction

• Inflammatory Osteolysis
  • TNFα
  • IL-1

• Rheumatoid Arthritis (RA)

• Loosening of Orthopedic Implant

• Periodontal Disease

• Conclusion

• References

This chapter summarizes the recent advances of research in endochondral bone formation, and in cartilage extracellular matrix. Specific emphasis is placed on molecular pathways that regulate endochondral bone formation and a novel extracellular matrix protein family called matrilin. The different aspects of matrilin research are described in detail to serve as an example of the current state of extracellular matrix research with multidisciplinary approaches involving genetics, biochemistry, cell biology, and pathology.

The discovery, purification, and recombinant synthesis of bone morphogenetic proteins (BMPs) constitute a major milestone in the understanding of bone physiology, and this chapter discusses the history of BMPs from Senn's accidental discovery in the 1880s to Urist's monumental discoveries in the 1960s through to the present day and the FDAs decision on the use of BMPs in mainstream medicine, their classification and functions. The role of BMPs in the development and formation of bone in the embryo and in the adult, their clinical applications in orthopaedics, dentistry, gene therapy and in other medical fields, the dosage, carriers for BMPs, and the potential risks that accompany the use of BMPs, are all reviewed and discussed.

Biomechanical tests are designed as an end-point measure in many experimental studies to confirm both pharmaceutical and non-pharmaceutical treatment effects on musculoskeletal tissues, especially on skeletons for the prevention and treatment of osteoporosis and osteoporotic fractures. This chapter introduces basic knowledge and concepts of mechanical testing methodology in studying mechanical properties of bone specimens at organ, tissue and matrix levels. The mechanical testing methods are categorized into both destructive and non-destructive or non-contact ones using both conventional and state-of-the-art testing facilities. Computational modeling method is also briefly introduced. In order to obtain the most update information of testing methods, homepages of some relevant or known research societies and devices suppliers are listed as reference sources to facilitate direct network communication. Practical tips are suggested for preparation and preservation of bone specimens. Factors affecting testing results or data interpretations are summarized to avoid inconsistent and incomparable testing results.

The following sections are included:

• Introduction

• Effects of Estrogen on Bone
  • Effects of ovariectomy on cortical bone
  • Effect of ovariectomy in cancellous bone

• Effects of Androgens on Bone
  • Effects of orchidectomy on cortical bone
  • Effects of orchidectomy on cancellous bone

• Estrogen Receptors

• Androgen Receptors

• Expression on ER and AR in Bone Tissue

• Nongenotropic Action of Sex Steroids

• Effects of Sex Steroids on Osteoblastogenesis

• Effects of Sex Steroids on Cytokines and Growth Factors

• Effect of Sex Steroids on Bone Growth and Maturation

• Effect of Sex Steroids in Skeletal Maintenance in Adulthood

• Relative Role of Steroid Receptors in Bone Metabolism

• Indirect Actions of Sex Steroids on Bone Metabolism

• Summary

• References

Interest in phytoestrogens for maintenance of bone health and delaying or preventing osteoporosis has exploded in the past decade. These substances have estrogen-like activity and are viewed as potential natural alternatives to estrogen replacement therapy. However, the evidence that support beneficial effects of phytoestrogens on bone is still not completely convincing. Data on bone formation in vitro show that phytoestrogens affect osteoblasts and osteoprogenitor cells in a biphasic dose-dependent way, which is estrogen receptor (ER)-dependent and ER-independent. In contrast, studies on bone resorption in vitro show that phytoestrogens only inhibit osteoclast formation and activity. Similar findings were also observed in some animal models in vivo. However, experiments in primates and clinical investigations showed that the beneficial effects of phytoestrogens on bone are not conclusive. Furthermore, peroxisome proliferator-activated receptors (PPARs) as new molecular targets of phytoestrogens, their differential effects on bone, and their interactions with ERs are discussed. Dose-dependent responses of phytoestrogens result from the balance between ERs and PPARs. This newly-proposed mechanisms of action of phytoestrogens are important for the future study to find precise beneficial doses in vivo. Further investigations are needed to find the critical effective doses and evaluate the long-term beneficial effects of phytoestrogens on bone.

The following sections are included:

• Introduction

• Bone Remodeling
  • Bone remodeling at different parts of the skeleton
  • Cortical bone remodeling
  • Trabecular bone remodeling
  • Bone coupling

• Regulation of Bone Resorption
  • Systemic hormones
  • Local factors

• Regulation of Bone Formation
  • Systemic hormones

• References

The following sections are included:

• Introduction

• Regulation of TGFP Signaling

• Smad-Dependent and Independent Pathways

• TGFβ and Other Signaling Cascades

• Endochondral Bone Formation

• Expression of TGFβ and Related Molecules in Chondrocytes

• Effects of TGFβ on Chondrocyte Function

• TGFβ and Osteoarthritis (OA)

• TGFβ and Runx2

• TGFβ and Wnt Signaling

• References

The following sections are included:

• Introduction

• Growth and Development

• Hormonal Status

• Tracking of Bone Mass

• Genetics

• Gender Differences

• Ethnicity/Race

• Fractures during Childhood

• Maximizing Peak Bone Mass
  • Nutrition and peak bone mass
  • Physical activity

• Measurement of Bone Mass in Children

• Factors Interfering with Bone Mass Accrual
  • Smoking
  • Contraceptives
  • The Female Triad

• Summary

• References

Our load-bearing bones, fascia, growth plates, ligaments, tendons and joints have enough strength to keep typical peak voluntary loads on them from muscle forces from breaking them suddenly or in fatigue. The tissue-level biologic machinery that achieves that relationship between an organ's loads and its strength could be named the mechanostat. This article explains in general terms how mechanostats could achieve that relationship for our load-bearing skeletal organs. Bone's mechanostat can provide the illustrative case; analogs of it presumably apply to extraosseous load-bearing organs.

The following sections are included:

• Introduction

• Tissue and Cellular Mechanotransduction
  • Mechanical loading induced adaptation
  • The role of dynamic and temporal mechanical signals
  • Mechanotransduction and interstitial fluid flow
  • Cellular mechanotransduction and fluid flow
  • Fluid convection enhanced metabolic exchange
  • Noninvasive dynamic fluid flow stimuli as a mean of countermeasure
  • The relationship between bone interstitial fluid flow and physical exercise
  • Summary

• Fluid Channels and Porosity in Bone Structure

• Fluid Flow Pathway in Bone — Defined by in vivo Intramedullary Pressure and Streaming Potentials Measurements
  • Experiment design

• Formation of Bone Induced by Fluid Pressure Gradients
  • Experimental design
  • Quantification
  • Results

• Interstitial Fluid Flow Response to Dynamic Components of Loading
  • Experimental Design

• Non-linear Dependence of Loading Intensity, Frequency and Cycle Number in the Maintenance of Bone Mass and Morphology

• Discussion
  • Bone fluid flow contributed from multiple channels of porosity — indicated by relaxation
  • Bone fluid flow induced by dynamic intramedullary pressure
  • Potentials of bone fluid flow in cellular stimulation
  • Fluid pressure gradients as a driving source for fluid movement in bone and initiating bone adaptation
  • Fluid pressure gradients and fluid shear stress
  • Static vs. dynamic loading
  • Cortical bone permeability
  • Summary and significance

• Acknowledgements

• References

The following sections are included:

• Introduction

• Classification of Bone Neoplasms

• Major genetic events in bone tumor development
  • Transforming genes
  • Tumor-suppressor genes
  • Microsatellite instability
  • DNA methylation

• Mediators of Tumor-associated Bone Resorption
  • PTHrP
  • IL-6
  • TGF-β
  • RANKL, RANK and OPG system
  • The role of mediators in common bone tumors

• References

The ability to generate new bone for skeletal use is a major clinical need. Biomimetic scaffolds that interact and promote human osteoprogenitor differentiation and osteogenesis offer a promising approach to generate skeletal tissue to resolve this major healthcare issue. Although autogenous or allogenic bone grafts have been used for many years, a number of disadvantages have limited their use, which leads to the emerging of an attractive new field - tissue engineering. Bone tissue engineering requires three basic elements: 1) a source of osteogenic cells, 2) a source of osteoinductive agents and, 3) an osteoconductive scaffold. Bone formation comprises a complex and temporal sequence of events that begins with the recruitment and proliferation of osteoprogenitors from mesenchymal stem cells.^1-4 Central in this process is a material or scaffold for the migration, attachment and growth of stem/progenitor cells from the surrounding tissue. Mesenchymal cells including osteoblasts, chondroblasts, adipocytes, myoblasts and fibroblasts appear to be derived from a common multipotential mesenchymal stem/progenitor cell residing within bone marrow. A number of studies indicated the ability to generate osteoinductive and osteoconductive biomimetic scaffolds in combination with osteogenic growth factors and gene therapy to create a biomimetic microenvironment for osteoprogenitor growth and, significantly, the potential to generate templates for the development of a living bone substitute for clinical application.

The following sections are included:

• Introduction
  • Recent view of QTLs by the research community
  • Genetic factors affecting bone mineral density (BMD) or osteoporosis
  • The mouse as an excellent animal model for the study of BMD
  • QTLs of BMD identified using the mouse model
  • BMD related QTLs identified using the mouse model
  • New technologies for identifying QTLs that regulate bone quality
  • Confirmation and fine mapping of QTLs
  • Complex and interactions of QTLs detected from mouse model
  • Bioinformatic approaches to identify QTL candidate genes using mouse model
  • Genome resource for positional cloning of genes regulation of BMD
  • Identification and confirmation of QT gene
  • Future directions on the study of QTL genes using mouse model

• References

The following sections are included:

• Introduction

• Bone Remodeling

• Runx2

• Osterix

• LRP5

• OPG-RANKL-RANK
  • Osteoprotegerin (OPG)
  • RANKL and its signaling receptor, RANK

• Alox15

• References

The following sections are included:

• APPENDIX: AN INTRODUCTION TO HOLOGIC TECHNOLOGY

• INDEX