Latest developments in skeletal dysplasias#


  • Nicola C. Ho,

    Guest EditorSearch for more papers by this author
    • Nicola C. Ho is a pediatrician and medical geneticist. She is Assistant Professor of Pediatrics at Johns Hopkins University School of Medicine, and a research scientist with the National Institutes of Health. Dr. Ho's interests include dysmorphology, skeletal dysplasias, connective tissue disorders, molecular genetics, and study of genetic disorders in inbred populations.

  • Clair A. Francomano

    Guest Editor, Corresponding author
    • Section of Human Genetics and Integrative Medicine, Laboratory of Genetics, NIA/NIH-IRP, Room 4A, 5600 Nathan Shock Drive, Baltimore, MD 21224-6825.
    Search for more papers by this author
    • Clair Francomano is an internist and medical geneticist whose work has centered on the hereditary connective tissue disorders and skeletal dysplasias. She has published widely on the molecular genetics underlying human connective tissue disorders and skeletal dysplasias. She serves on the Advisory Boards for the National Marfan Foundation and the Little People of America. Her current position is Senior Investigator, Laboratory of Genetics, National Institute on Aging.

  • #

    This article is a US Government work and, as such, is in the public domain in the United States of America.

The vertebrate skeleton is a fascinating and complex organ. It consists of bone, cartilage, tendons, ligaments, synovium, and other connective tissues along with vascular, nervous, and hemopoietic components [Johnson, 1986]. The adult human skeleton is composed of 206 bones with blocks of cartilage in specific places, and the individual bones come in varying shapes and sizes. They are intrinsically and extrinsically patterned differently between organisms, enabling them to adapt to a range of specific activities such as flying, swimming, weight-bearing, running, digging, etc.

There are multiple embryologic origins of the vertebrate skeleton. The neural crest cells contribute to the craniofacial skeleton [Noden, 1983], and the cells from the cephalic mesoderm give rise to several cranial bones [Le Douarin et al., 1993]. The paraxial mesoderm undergoes segmentation to form somites and then sclerotomes and dermamyotomes. The sclerotomes eventually give rise to ribs, vertebrae, and intervertebral discs of the axial skeleton, and the dermamyotomes to limb musculature and dermis [Christ and Wilting, 1992]. The lateral mesoderm contributes to the appendicular skeleton and therefore the long bones [Olson et al., 1996].

Skeletogenesis, which is the origin, formation, and development of the vertebrate skeleton, calls for commitment of mesenchymal condensations to reach their destinations, be they the osteogenic, chondrogenic, or other cell lineages. This process requires the activation of regulatory mechanisms that control cell determination and differentiation, the orchestration of bone and cartilage-specific genes and other modifiers [Erlbacher et al., 1995], and the influence of cell–cell and cell–matrix interactions [O'Rahilly and Müller, 1996].

This volume of Seminars in Medical Genetics is dedicated to skeletal dysplasias and the molecular understanding of skeletogenesis. It represents an exciting potpourri of the latest findings of outstanding investigators coming from different backgrounds in human genetics, radiology, mouse embryology, molecular genetics, and cellular and structural biology. Their contributions illustrate the range, the depth, and the pace of recent scientific progress toward understanding the pathogenesis of skeletal dysplasias.

The human osteochondrodysplasias are a diverse and heterogeneous group of genetic disorders of skeletal development. Research in skeletal dysplasias has witnessed rapid progress in the basic biology of thrombospondins, collagens, and proteoglycans, amidst many other protein families that have been shown to possess potent bone- and cartilage-inducing activity in vitro and in vivo. Pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia type 1 are distinct skeletal dysplasias but share overlapping features. Both entities are caused by mutations in the cartilage oligomeric protein gene, COMP, a member of the thrombospondin gene family of matricellular calcium-binding proteins [Briggs et al., 1995; Hecht et al., 1995]. Unger and Hecht's article [2002] gives an overview of the clinical features of PSACH and MED, and the mutations that had been characterized so far. They also discuss the adverse effects of COMP mutations on the cartilage extracellular matrix, i.e., the ability of the protein COMP to bind calcium, the accumulation of the protein in rER cisternae, and the controlling role and modulating effects of chaperones in protein folding.

Mouse models offer a wide range of resources for exploring the genetic mechanisms that control skeletal morphogenesis. In this issue, Cho et al. [2002] describe a novel strategy for studying the role of chondrocytes in normal and abnormal skeletal development. Cho and colleagues generate transgenic mice, harboring a Col2-GFP reporter that marks cells actively engaged in chondrogenesis. By means of conventional fluorescence microscopy and confocal optical sectioning of live embryos and tissues, investigators may visualize living chondrocytes and their immediate precursors in real time, and monitor dynamic events over short time periods. These mice will also serve as an important tool for dissecting the functional genomics of chondrocytes and chondrocytic precursors.

Akirawa-Hirasawa and Yamada have exploited a murine model to study the pathogenetic mechanisms of chondrogenesis. In 1999, these investigators provided molecular evidence that a heparan sulfate proteoglycan, also known as perlecan, is essential for cartilage development. To understand the in vivo functions of perlecan, they created perlecan gene knockout mice (Hspg2-/-), and found that approximately 40% of the homozygous Hspg2−/− mice died approximately embryonic day 10.5 (E10.5) with defective cephalic development [Akirawa-Hirasawa et al., 1999]. The remaining homozygous Hspg2−/− mice had a form of skeletal dysplasia reminiscent of the human dyssegmental dysplasia, Silverman-Handmaker type (DDSH). Recently, Akirawa-Hirasawa and colleagues demonstrated that DDSH is caused by functional null mutations of the HSPG2. Their article in this volume [Akirawa-Hirasawa et al., 2002] reports these findings.

For normal skeletogenesis to take place, the coordination of temporal and spatial gene expression patterns by transcription factors is a crucial prerequisite. Hermanns and Lee explore the topic of disruption of transcriptional regulation and its consequences on the human and murine phenotypes. They outline several transcriptional regulatory mechanisms and discuss various skeletal dysplasias and craniosynostosis syndromes associated with mutations in transcriptional factors, resulting in a variety of defects affecting craniofacial, appendicular, and axial skeletal development. They further categorize them into the following groups: (1) skeletal disorders caused by defects in cell differentiation, proliferation, and survival; (2) those illustrating overlap between cell differentiation and pattern formation; and (3) those that are caused primarily by defects in pattern formation.

A concrete example of a specific transcription factor and its importance in skeletogenesis is presented by Comier-Daire et al. [2002], who performed linkage analysis on 23 families with Leri-Weill syndrome or dyschondrosteosis. This syndrome, a dominant form of skeletal dysplasia associated with a transcription factor SHOX mutation, is characterized by short stature and Madelung deformity of the upper extremity. The mesomelic segments of limbs are predominantly involved. The gene for this disorder, SHOX, had been mapped to the pseudoautosomal region of chromosomes X and Y [Belin et al., 1998]. Comier-Daire and colleagues report their findings of 21 of 23 families concordant with linkage to the pseudoautosomal region of the X chromosome and that 2 of 23 families showing no linkage to the above region are highly suggestive that there may be nonallelic heterogeneity in dyschondrosteosis.

The current research environment is highly dynamic. Voluminous data are generated every passing day. Catalogs and databases are constructed specifically to provide systematic organization and ready accessibility of documented data, thereby serving as useful aids and powerful tools to research. In this volume, Jia et al. [2002] illustrate the value of the Skeletal Gene Database (SGD). SGD is created to provide an invaluable service to the scientific community interested in obtaining information on bone-related genes. It gives a contemporary list of skeletal related genes and their corresponding proteins that are already known and published in the literature as well as novel genes/expressed sequence tags not yet characterized [Ho et al., 2000]. It pools information on all the human and mouse bone-related cDNA libraries that are publicly available from the National Center of Biotechnology Institute (NCBI) Unigene cDNA library list, and has a software incorporated to assist researchers looking for profiles of cDNA tissue expression [Jia et al., 1997]. This comprehensive electronic compendium supplies reference numbers and links to various data sources, including OMIM, Unigene, PubMed, LocusLink, and so on, relevant to the gene in question. It also furnishes hyperlinks to databanks that give major sequence repositories, sources that garner data on gene identification, structure, and expression, genetic and physical maps, cellular regulatory mechanisms and metabolic pathways, as well as databases that focus on genomics, protein, and RNA. Web connections to NCBI Unigene Library Browsers, NHGRI Glossary of Genetic Terms, and ongoing research projects such as National Cancer Institute Cancer Genome Anatomy Project of National Cancer Institute and NHGRI Microarray Project are also installed.

With the rapid advancement of innovative genomic technology coupled with the daunting accumulation of knowledge witnessed in recent years on genes and proteins, there is an urgent call for a set of thorough and meaningful classifications to unite clinical knowledge with basic science, to integrate current research findings with past discoveries, and to facilitate better communication between physicians and scientists. Superti-Furga et al. [2002] highlight the advice of the Working Group to construct a nomenclature on osteochondroysplasias that will better serve the genetic community and that is more in tempo with current research. In this article, they focus on the molecular–pathogenetic classification and advise that all three useful rubrics of classifications, i.e., molecular–pathogenetic, clinical, and radiographic, be placed under the master heading of Nosology.

This volume offers an exciting sampler of recent progress in the field of skeletal dysplasias and skeletogenesis. We wish to express our appreciation and gratitude to all the contributing authors for their efforts and to all our readers, their audience.