Downloaded from genesdev.cshlp.org on October 2, 2021 - Published by Cold Spring Harbor Laboratory Press REVIEW The genetic transformation of bone biology Gerard Karsenty1 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030 The skeleton, like every organ, has specific developmen- condensations differentiate into chondrocytes forming tal and functional characteristics that define its identity the “cartilage anlagen” of the future bones. In the pe- in biologic and pathologic terms. Skeleton is composed riphery of the anlage, cells from the perichondrium dif- of multiple elements of various shapes and origins spread ferentiate into osteoblasts, while the periphery of the throughout the body. Most of these skeletal elements are anlage become hypertrophic. Eventually, the matrix sur- formed by two different tissues, cartilage and bone, and rounding these hypertrophic chondrocytes calcifies and each of these two tissues has its own specific cell types: blood vessel invasion of the calcified cartilage brings in the chondrocyte in cartilage, and the osteoblast and os- osteoblasts ∼14.5–15.5 dpc (Horton 1993; Erlebacher et teoclast in bone. Finally, each of these cell types has its al. 1995). Once a bone matrix is deposited the bone mar- own differentiation pathway, physiological functions, row forms and the first osteoclasts appear (Hofstetter et and therefore pathological conditions. The complexity of al. 1995). Thus, sequential appearance of a cartilage an- this organ in terms of developmental biology, physiol- lage, calcified cartilage, and then bona fide bone charac- ogy, and pathology, along with the multitude of impor- terizes the endochondral ossification. Regardless of the tant conceptual advances in our understanding of skel- mode of ossification, osteoblast differentiation precedes etal biology, are such that it has become impossible to osteoclast differentiation. present in a short review an up-to-date summary of both One peculiar characteristic of bone resides in its physi- cartilage and bone biology. Thus, this review will con- ology. Bone is the only organ that contains a cell type, centrate only on bone biology beyond embryonic pat- the osteoclast, whose only function is to constantly de- terning. The entire bone field is dominated by the impact stroy the organ hosting it. This destruction, or resorp- of degenerative diseases, such as osteoporosis. This mere tion, of bone occurs throughout life and in healthy indi- fact does influence the research in bone biology and will viduals is counterbalanced by de novo bone formation in influence the topics presented in this review. It is no a process called bone remodeling (Frost 1969). It is surprise that, like for most other organogenesis pro- through bone remodeling that bone mass is maintained cesses, human and mouse genetic studies have been a at a constant level between the end of puberty and go- major driving force in redefining bone biology. Genetic nadal failure, and bone remodeling is the process affected studies have opened new areas of research, elucidated at during osteoporosis, a disease characterized at the cellu- the molecular level some known phenomena, and some- lar level by a relative increase of bone resorption over times challenged untested textbook assumptions, thus bone formation (Rodan et al. 1996). Recently, we have transforming the field profoundly. begun to understand at the molecular level how bone In mammals, bone development is a late embryonic resorption is controlled. It is striking how little we know event as it is the last event of skeleton development. about the molecular mechanisms governing bone forma- Once the mesenchymal condensations prefiguring each tion. future skeletal element have formed, between 10.5 and The first goal of this review is to present an up-to-date 12.5 days postcoitum (dpc) in mouse, they can evolve perspective on the genetic control of cell differentiation along two different paths. In some skeletal elements, in the skeleton. The second goal is to describe our cur- prefiguring part of the skull and the clavicles, the cells of rent understanding of bone physiology and pathology. the mesenchymal condensations differentiate directly The last and most elusive goal is to use our current into osteoblasts that appear at 15.5 dpc of mouse devel- knowledge of bone biology to formulate, along the way, opment (Hall and Miyake 1992; Huang et al. 1997). This some of the novel questions that need to be addressed. process is called intramembranous ossification. For the Before going any further in this review a few definitions rest of the future skeleton, cells of the mesenchymal are important as these words will be commonly used to summarize phenotypic abnormalities. A loss of function of the osteoclast leads to osteopetrosis, a gain of function of the osteoblast leads to osteosclerosis, and a relative This paper is dedicated to the memory of Dr. Louis Avioli. 1Corresponding author. increase of bone resorption over bone formation results E-MAIL [email protected]; FAX (713) 798-1465. in osteoporosis. GENES & DEVELOPMENT 13:3037–3051 © 1999 by Cold Spring Harbor Laboratory Press ISSN 0890-9369/99 $5.00; www.genesdev.org 3037 Downloaded from genesdev.cshlp.org on October 2, 2021 - Published by Cold Spring Harbor Laboratory Press Karsenty Regulation of osteoclast differentiation and function mous manner to differentiate along a particular lineage, thus, one of the challenges in the field will be to identify By far, the aspect of bone biology that has made the most the extracellular signals that induce the expression of progress in the last few years is the genetic control of Pu.1 and of other cell-specific transcription factors in- osteoclast differentiation and function. This is why the volved in osteoclast differentiation. biology of the osteoclast, the cell type resorbing miner- Another transcription factor that plays a critical role alized bone matrix, is discussed first in this review even during osteoclast differentiation is c-fos (for review, see though it is the last specific cell type of the skeleton to Grigoriadis et al. 1995). c-fos is the cellular homolog of appear during development. The systematic and logical the v-fos oncogene and is a major component of the AP-1 study of many mouse mutants generated to study osteo- transcription factor. The first indication that c-fos might clast differentiation or, more often for other reasons, has play a role in bone cell differentiation came from the led to the establishment of a fairly detailed genetic cas- observation that v-fos-containing constructs injected cade controlling either osteoclast differentiation or func- into rodents led to the appearance of osteosarcomas (ma- tion. Some of this progress has important implications lignant tumors of mesenchymal origin with the ability not only for bone resorption but is also, as discussed to form bone tissue) (Ward and Young 1976). Likewise, below, leading to novel hypotheses about the molecular transgenic mice expressing high levels of c-fos in mul- control of bone formation. tiple tissues and cell types eventually developed only The osteoclast belongs to the monocyte/macrophage one type of tumor: chondroblastic osteosarcoma, and cell lineage (Teitelbaum et al. 1996). Phenotypically, the clonal cell lines derived from these transgenic mice have osteoclasts are distinct from other cells in this lineage as altered osteoblastic gene expression (Grigoriadis et al. it is a giant multinucleated cell (1–50 nuclei per cell 1993). Given the results of these overexpression types of depending of the species) found in contact with calcified studies it came as a surprise that the deletion of c-fos in bone surfaces. Only a relatively small number of genes mice led to an early arrest of osteoclast differentiation have been shown to be expressed in osteoclasts and not without any overt consequences on osteoblast differen- in other monocyte/macrophage cells, yet more regula- tiation. As a result of this block in osteoclast differen- tory genes have been shown to control osteoclast differ- tiation, the main phenotype of the c-fos-deficient mice is entiation than for any other cell type in the skeleton. osteopetrosis (Johnson 1992; Wang et al. 1992). The pres- ence of a large number of macrophages in c-fos-deficient mice places c-fos downstream of Pu.1 in the genetic Transcriptional control of osteoclast differentiation pathway controlling osteoclast differentiation (Fig. 1). and function The osteopetrotic phenotype of the c-fos-deficient mice A recurrent theme in bone biology is that many of the was rescued by bone marrow transplantation and by ex- genes that were identified as regulators of cell differen- tiation or function have been known for a long time. Yet, perhaps because bone cells are more difficult to isolate, or because skeletogenesis appeared less attractive ini- tially than other processes of organogenesis, they were not originally studied in the context of the skeleton. Pu.1 function in osteoclast differentiation is one of the best illustrations of this. Pu.1 is an ETS domain-containing transcription factor that is expressed specifically in the monocytic and B lymphoid lineages (Klemsz et al. 1990). It has been known for several years that the deletion of Pu.1 results in a multilineage defect in the generation of progenitors for B and T lymphocytes, monocytes, and granulocytes (Scott et al. 1994; McKercher et al. 1996). The fact that Pu.1 was thought to regulate transcription of c-fms, the gene encoding the receptor for M-CSF (Sherr et al. 1985), which plays an important role in osteoclast biology (see Figure 1. Genetic control of osteoclast differentiation. Osteo- below), led Tondravi et al. (1996) to explore the possibil- clasts differentiate from a myeloid progenitor cell common with ity that Pu.1 might also control osteoclast development. macrophages. This process is under the control of the transcrip- As hypothesized by this group, Pu.1-deficient mice ex- tion factor Pu.1 and of a growth factor, M-CSF.