Human Molecular Genetics

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Human Molecular Genetics

Pages 1839-1846

©1999 Oxford University Press

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Osteopetrosis and osteoporosis: two sides of the same coin
Introduction
Understanding The Basis Of Human Disease
Animal Models Of Osteopetroses
   Spontaneous mutations
   Genetically engineered mice
   The cathepsin K knockout mouse
Animal Models Of Osteoporosis
   The ovariectomized mouse
   Osteoprotegerin
ETS2 And The Down Syndrome Skeleton
Concluding Remarks
Acknowledgements
References

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Osteopetrosis and osteoporosis: two sides of the same coin

Francesca Lazner, Maxine Gowen¹, Durda Pavasovic, Ismail Kola⁺

Centre for Functional Genomics and Human Disease, Institute of Reproduction and Development, Monash University, Monash Medical Centre, 246 Clayton Road, Clayton, Victoria 3168, Australia and ¹Department of Bone and Cartilage Biology, SmithKline Beecham Pharmaceuticals, King of Prussia, PA 19406, USA

Received April 20, 1999; Accepted May 13, 1999

Together, osteoporosis and osteopetrosis comprise a substantial proportion of the bone diseases that severely affect humans. In order to understand and effectively treat these disorders, an understanding of the mechanisms controlling bone remodelling is essential. While numerous animal models of bone disease have been generated, the lack of correlation between these animal models and human disease has limited their utility in terms of defining therapeutic strategies. The generation and analysis of cathepsin K knockout mice has resulted in a model for pycnodysostosis, a rare human osteopetrotic disease, and is now providing considerable insights into both osteoclast function and potential therapeutic strategies for the treatment of bone disease. This review highlights the importance of genes such as cathepsin K in understanding bone remodelling and illustrates a new trend towards understanding bone disease as a complete entity rather than as a series of unrelated disorders.

INTRODUCTION

Bone development and homeostasis is a complex process in which a balance between bone formation and resorption is delicately maintained. The major effector cells of bone formation and resorption are the osteoblasts and osteoclasts. These cells and their precursors are regulated by a vast array of autocrine and paracrine factors. Perturbation of the balance between bone formation and resorption can result in the formation of either too much bone (osteopetrosis) or too little bone (osteoporosis).

The term osteopetrosis in humans is used to define a number of distinct diseases that can be classified on the basis of severity and age of onset into three major groups: infantile malignant osteopetroses, intermediate mild osteopetroses and adult onset osteopetroses. Similarly, the term osteoporosis defines a group of (apparently) aetiologically distinct diseases. The numerous forms of both osteopetrosis and osteoporosis in humans are shown in Table 1. While osteopetrotic diseases are relatively rare in humans, the prevalence of osteoporosis, some estimates being as high as 40% in Caucasian women over the age of 80 (1), makes bone disease one of the major health issues of present day society.

Table 1. Various forms of osteopetrosis and osteoporosis that affect humans

Type	Subtype	Cause
Osteopetrosis
Infantile malignant	Responsive to bone marrow transplantation	Haematopoietic origin
	Non-responsive to bone marrow transplantation	Non-haematopoietic origin
Intermediate mild	Carbonic anhydrase II deficiency	Mutation in carbonic anhydrase gene
	Pycnodysostosis	Mutation in cathepsin K gene
	Other	Unknown
Autosomal dominant	Type I, uniform increase in bone density	Unknown
	Type II, non-uniform increase in bone denisty	Unknown
Osteoporosis
Primary	Post-menopausal osteoporosis	Loss of sex steroids either directly or indirectly
	Senile osteoporosis	Unknown
Secondary	Endocrine disorders	Hyperparathyroidism
		Cushings syndrome
		Diabetes
		Pregnancy and lactation
		Hyperthyroidism
		Hypogonadism
	Genetic disorders	Osteogenesis imperfecta
		Menkes syndrome
		Homocysteinuria
		Adult hypophosphatasia
	Neoplastic disorders	Multiple myeloma
		Systemic mastocytosis
		Waldenström macroglobulinaemia
	Nutritional causes	Intestinal malabsorption
		Protein malnutrition
		Scurvy
	Drug related	Heparin
		Anticonvulsants
	Other	Immobilization
		Primary biliary cirrhosis
		Rheumatoid arthritis
		Chronic pulmonary disease

UNDERSTANDING THE BASIS OF HUMAN DISEASE

The key to understanding the basis of each of these bone diseases is to determine whether the primary defect resides in the osteoblast or osteoclast lineage or indeed whether the skeletal phenotype arises as a consequence of other immunological and/or endocrinological defects. Osteoclasts, as macrophage-like cells, are derived from the haematopoietic compartment by a differentiation pathway that diverges at a late stage from that of the monocyte/macrophage lineage (2-5). Thus, mutations that alter the differentiation potential of haematopoietic stem cells or precursor cells often result in skeletal abnormalities.

Bone marrow transplantation is the most direct method used to determine where the primary defect resides in osteopetrotic diseases. This technique has provided considerable information regarding the lineage responsible for numerous osteopetrotic diseases (4,6-9) and has also been of therapeutic value in the treatment of some human osteoclast-related disorders. For example, bone marrow transplantation has been used in a number of individuals with infantile malignant osteopetrosis (10-12), but the results have been variable; some individuals have responded to this treatment with a reversal (complete or partial) of the skeletal phenotype, whilst others have shown no response. These and other studies (13-15) suggest, firstly, that the aetiology of disease within this group of phenotypically similar individuals may not be the same. In accord with these findings, morphological investigation of osteoclasts derived from individuals with infantile malignant osteopetrosis show marked heterogeneity with individuals having increased, decreased or normal numbers of osteoclasts, increased volume or number of nuclei and/or lack of ruffled borders and clear zones (13). Secondly, whilst defective cross-talk between cell types is likely, the observation of defective osteoblasts as well as osteoclasts in two cases of human malignant osteopetrosis (15) for which bone marrow transplantation was successful raises the possibility of a multigenic aetiology (15) for this disorder. The difficulties associated with bone marrow transplantation and the variability of success rates, however, limit its use as a therapeutic strategy for the majority of osteopetrotic diseases. No information exists on the value of bone marrow transplantation as a therapeutic strategy in osteoporosis.

Our understanding of human osteopetroses has been greatly aided by the significant number of animal models. In addition to providing clues to the aetiology of this disease in humans, a number of animal models have also provided considerable insight both into the mechanisms of bone formation and resorption and into the ontogeny of the osteoclast.

Finding the exact source responsible for the genesis of osteoporosis has proved more difficult. Genetic, environmental and lifestyle factors have all been associated with the pathogenesis of osteoporosis (1). Despite the abundance of literature on the subject, even the definition of what constitutes primary osteoporosis remains controversial (1). According to the World Health Organisation, osteoporosis is defined as bone mineral density (BMD) (in the spine) >2.5 standard deviations below the `young normal' mean value (16). The inadequacy of this definition is highlighted by evidence that for a given BMD the risk of fracture increases with age (17). The second factor that has hampered the study of osteoporosis is the scarcity of appropriate animal models.

One of the most striking features of the `bone disease field' is the lack of continuity between studies into osteopetrosis and osteoporosis. These two types of disorder affect the same system, the skeletal system, with virtually opposing effects and yet past and present literature (with few exceptions) has failed to explore any overlap. This review will detail a number of animal models of bone disease which have provided considerable advancement in our understanding of the bone remodelling process. In particular, we will focus on those models that may be of use in determining treatment regimes for both osteopetrotic and osteoporotic conditions.

ANIMAL MODELS OF OSTEOPETROSES

The numerous animal models of osteopetroses can be divided into two groups: those arising from spontaneous mutations and those arising through genetic manipulation.

Spontaneous mutations

The animal models of osteopetroses that have arisen as spontaneous mutations include the osteopetrotic (op/op) mouse (18), the osteosclerotic (oc/oc) mouse (19), the grey lethal (gl/gl) mouse (20), the microphthalmic (mi/mi) mouse (21), the toothless (tl) rat (22), the incisor absent (ia) rat (23) and osteopetrotic (os) rabbit (24). These spontaneous osteopetrotic mutants can be categorized into two groups based on the localization of their primary defect to either: (i) the osteoclast or its precursors; or (ii) the bone microenvironment. Such categorization is based upon the success of bone marrow transplantation (or haematopoietic stem cell transplantation) to rescue the osteopetrotic phenotype. On the basis of such a definition, the op/op mouse and tl rat, which cannot be cured by transplantation (9,25) appear to arise from defects in the bone microenvironment. The gl/gl, oc/oc and mi/mi mice and ia rat all appear to arise from an intrinsic defect in the stem cell or osteoclast population, as the osteopetrosis is reversible by bone marrow transplantation (6,8,26,27). The various phenotypic features of the osteopetrotic animals are reviewed extensively elsewhere (13,28,29) but a summary of the phenotypic features of various spontaneous mutant mice is shown in Table 2.

Table 2. Summary of the major phenotypic features of a number of spontaneous mutant strains of mice which display an osteopetrotic phenotype

	op/op osteopetrotic	gl/gl grey lethal	mi/mi microphthalmic	oc/oc osteosclerotic
Lifespan	Reduced	<5 weeks	Variable	<3 weeks
Persistence of primary spongiosa	Yes	Yes	Yes	NR
Metaphyseal sclerosis	Yes	Yes	Yes	Yes
Extramedullary haematopoiesis	Yes	Yes	Yes	Yes
Osteoclasts	None	Decreased numbers	Decreased numbers, abnormal	Small, normal numbers, not functional
Macrophages	Very few, abnormal	Elicited macrophages reduced	NR	NR
Treatment
Haematopoietic transplant	Not effective	Effective	Effective	Not effective
Other	Injection of M-CSF	NR	NR	NR

NR, no reported data.

Of these different animal mutants, the best characterized is perhaps the op/op mouse, which has a mutation in the M-CSF gene. Whilst proving extremely useful for understanding the mechanism of osteoclast development, the op/op mouse has been of little value in identifying possible treatments of human bone disease, principally because no human equivalent of the op/op mutation has been identified to date.

Genetically engineered mice

A number of genetically engineered models of osteopetroses have been generated (Table 3). As with spontaneously derived mutants, these animal models of bone disease have provided considerable information regarding the differentiation [PU.1 (30-32), c-Fos (33, 34) and NF-[kappa]B1/NF-[kappa]B2] or function [c-Src (31)] of osteoclasts. Analysis of the cell types affected in each of the mutant mice allows a prediction of where along the pathway of osteoclast differentiation the gene that has been targeted first acts. Figure 1 demonstrates the initial sites along the pathway of osteoclast formation/function where the various spontaneous and genetically engineered osteopetrotic mutations are thought to act.

Figure 1. The different genes which have been placed, based on the nature and severity of the post-mutation osteopetrotic phenotype, along the osteoclast differentiation/function pathway are shown.

Table 3. Summary of the various genetically engineered murine models of osteopetrosis

Mouse	Phenotype	Marrow transplantation	Human mutation
PU.1 knockout	Fetal lethality/early lethality, absence of osteoclasts	Effective	None identified
c-Src knockout	Lethal 3-4 weeks post-partum, non-functional osteoclasts	NR	None identified
c-Fos knockout	Normal lifespan, reduced osteoclast numbers	Effective	None identified
NF-[kappa]B1/NF-[kappa]B2 double knockout	Normal lifespan, decreased osteoclast numbers	Partially effective	None identified
Cathepsin K knockout	Normal lifespan, progressive osteopetrosis, normal osteoclast numbers	NR	Pycnodysostosis
Osteocalcin genes OG1/OG2 double knockout	Normal lifespan, progressive osteopetrosis, increased bone formation, increased osteoclast numbers	NR	None identified
Osteoprotegerin knockout	Normal lifespan, increased osteoclast numbers	NR	None identified

NR, no reported data.

Whilst these animal models have provided insight into osteoclast ontogeny, it has proven more difficult to gain an understanding of the pathogenesis of the human diseases. The utility of these animal models in the search for therapeutic strategies has been limited either because the phenotype is not restricted to the skeletal system alone, as with PU.1 and c-Fos knockout mice, or because human equivalents of the various mutations have not been identified. In contrast, insights into potential therapeutic strategies for human bone disease have been gained from some of the more recently described animal models of bone disease.

The cathepsin K knockout mouse

Cathepsin K, a cysteine protease that is highly expressed in osteoclasts (35), has been shown to degrade bone collagen as well as other bone matrix proteins (36,37) and as such was proposed to play a major role in osteoclastic bone resorption. A number of different mutations in the cathepsin K gene have been identified in the relatively rare osteopetrotic disease pycnodysostosis (38-40). Pycnodysostosis has been brought to public attention because of suggestions that the French artist Henri Toulouse-Lautrec suffered from this bone disease (41-43).

Targeted mutation of the cathepsin K gene in mice results in many of the phenotypic features of pycnodysostosis, including increased bone density and bone deformity (44,45). Radiographical analyses of these mice have revealed that the phenotype also becomes progressively more pronounced with age (Fig. 2), as does the osteopetrosis associated with pycnodysostosis (46). Interestingly, both the human disease and the cathepsin K knockout mouse display a bias towards abnormalities of bones that are rapidly remodelled during normal bone development and homeostasis. Interestingly, the bones that are more resistant to osteoporotic changes following ovariectomy and orchidectomy in mice (47) are the same as those that do not appear to be susceptible to osteopetrosis in the cathepsin K knockout mouse and in pycnodysostosis.

Figure 2. Radiography of cathepsin K knockout mice and wild-type littermates at 2 months (a and b) and 5 months (c and d) of age. Increased density of both cortical bone and trabecular bone in cathepsin K knockout mice are observed in the region of the distal femur and proximal tibia (arrows). At 5 months of age, cathepsin K knockout mice (b) show almost complete obliteration of the bone marrow cavity in the distal femur (arrow), showing a progressive increase in the severity of osteopetrosis observed.

In addition to these features, the phenotype of the cathepsin K knockout mouse shares other similarities with pycnodysostosis. A reduction in bone marrow cellularity was observed in the cathepsin K knockout mouse (44). In addition, splenomegaly was observed in a subset of the cathepsin K knockout spleens. This finding is consistent with pycnodysostosis in which a number of individuals with pycnodysostosis also display splenomegaly as part of the disease phenotype (48,49). The time frame of appearance of splenomegaly and the cell populations that are increased indicate that the splenomegaly arises as a compensatory mechanism for loss of bone marrow cellularity.

In order for an animal model to closely approximate a human condition, it is important that the same target tissues are affected between the two species. Early data on cathepsin K expression suggested a discrepancy between human and mouse tissues (35,50-52). Figure 3 demonstrates our analysis of cathepsin K expression in the adult mouse carried out by semi-quantitative RT-PCR. Using this technique we have observed a more widespread pattern of cathepsin K expression in the mouse (51). Comparison of the cathepsin K expression pattern detected in human and mouse (Table 4) demonstrates a very similar pattern, with a few interesting exceptions. No expression of cathepsin K was detected in the human brain in any of the studies performed, whereas RT-PCR analysis of mouse brain revealed high expression of cathepsin K. While this finding could simply represent differences in sensitivity, the possibility that cathepsin K plays a different role in the mouse brain cannot be discounted. The cathepsin K knockout mouse provides a valuable tool with which to investigate this. These mice display no neurological defects and histological analysis of various brain regions, including cerebral cortex, brain stem and cerebellum, show no morphological abnormalities (data not shown). In the absence of identifying the cell types in which cathepsin K is expressed in the mouse brain, it is difficult to speculate what role it might play in murine brain. The absence of a brain-related phenotype in the cathepsin K knockout mouse suggests, however, that the function is either minimal, restricted to a region not yet examined or compensated for by other molecules.

Figure 3. RT-PCR analysis of cathepsin K expression in adult mouse organs. Serial dilutions were used to semi-quantitatively analyse the expression of cathepsin K mRNA in a panel of 8-week-old mouse organs. The level of expression was scored on the basis of the lowest dilution at which a product was detected after Southern hybridization with a cathepsin K-specific internal oligonucleotide (lower arrow). Non-reverse transcribed bone RNA was used as a negative control (first panel). High levels of expression were detected in heart, lung, brain and skeletal muscle. An intermediate level of expression was detected in spleen and low levels of expression were detected in kidney, liver, skin and stomach. No PCR products were generated from the thymus or small intestine. The upper arrow denotes the PCR fragments generated and arrowheads indicate primers.

Table 4. Comparison of cathepsin K expression in the human and mouse

Organ	Human expression dataa	Mouse expression data
Heart	++	+++
Lung	+++	+++
Brain	-	+++
Spleen	++	++
Kidney	±	+
Bone	+++	+++
Liver	++	+
Thymus	±	+
Stomach	NR	+
Intestine	++	-
Skin	+	+
Muscle	NR	+++
Pancreas	++	++b

^aThe human data are based on a number of studies carried out by northern hybridization (50,52).
^bMouse expression data for pancreas are taken from Rantakokko et al. (51).
+++, relatively high level of expression; ++, intermediate level of expression; +, low level of expression; ±, extremely low expression; -, no expression; NR, organs for which no data are available.

Unlike other animal models of osteopetrosis such as the PU.1, c-Fos and op/op (M-CSF) knockout mice, which affect haematopoietic differentiation, no other haematopoietic defects were detected in the cathepsin K knockout mouse. This animal model is thus extremely useful in understanding osteoclast function in the absence of other haematopoeitic defects. Osteoclastic resorption of bone is a two-phase process. The first phase is the demineralization of bone. The second phase is the resorption of the organic matrix of bone. Thus the phenotype of the cathepsin K knockout mouse represents the effects of a loss of this latter phase of osteoclast function and, therefore, provides a clear demonstration of the relative contributions of the two phases of osteoclast function in the process of bone remodelling.

In addition to being a good model of pycnodysostosis, the cathepsin K mouse may also prove useful in the understanding and treatment of osteoporosis. Clearly, loss of cathepsin K function results in a decrease in osteoclastic bone resorption. Administration of cathepsin K antagonists may have potential in the treatment of osteoporosis, in which the rate of bone resorption exceeds that of formation. Indeed, administration of cathepsin K antagonists in mice has been successful in inhibiting bone resorption both in vitro and in vivo (53).

Furthermore, recent data suggest that cathepsin K may play a pivotal role in the pathogenesis of post-menopausal osteoporosis. It is well established that the loss of oestrogen after menopause is causative in the development of post-menopausal osteoporosis. Oestrogen has been shown to down-regulate cathepsin K expression (54). Thus, in the absence of oestrogen, expression of cathepsin K may be deregulated such that osteoclast activity is increased. This possibility suggests that cathepsin K may be the (or at least a) mediator by which the post-menopausal loss of oestrogen results in bone loss.

ANIMAL MODELS OF OSTEOPOROSIS

The relative abundance of osteopetrotic mouse mutants, both spontaneous and genetically engineered, has in the past provided few clues as to mechanisms by which osteoporosis could be induced in mice. As a consequence, very few animal models of osteoporosis have been identified or generated. One of the two mouse models for osteoporosis is that induced by ovariectomy and orchidectomy of mice. Removal of ovaries or testes and the consequent abrogation of gonadal steroid expression induces osteoporosis in much the same way that post-menopausal loss of oestrogen induces osteoporosis. The only other example of genetically induced osteoporosis has come from the loss of function of an osteoclast-associated gene which will be discussed subsequently. Thus, identification of genes that can be used to induce osteoporosis in mice are of considerable importance, as are the few models that have already been identified, in understanding the pathophysiology of this common disease.

The ovariectomized mouse

Ovariectomy of mice induces an osteoporotic phenotype that resembles that seen in post-menopausal osteoporosis in humans. With the absence (until recently) of other appropriate animal models of osteoporosis, ovariectomy has been used extensively in the investigation of this human disorder. Ovariectomy induces increases in both osteoclastogenesis and osteoblastogenesis (55-57), in a situation that is similar to post-menopausal osteoporosis where both bone formation and bone resorption are increased, with the latter exceeding the former. In addition, ovariectomy in the rat induces apoptosis of osteocytes (58), thus potentially reducing the ability of bone to respond appropriately to mechanical loading. Due to its wide range of target tissues, loss of oestrogen by ovariectomy also results in a wide variety of other phenotypic changes, including mammary gland and uterine atrophy, increased serum cholesterol levels and increased body weight. Oestrogen, as a therapeutic agent in the treatment of osteoporosis, may potentially induce changes in these other organ systems. With the increased risk of cervical and breast cancers, as well as congestive heart failure and thromboembolic events, in response to oestrogen replacement regimes (59,60), the usefulness of this hormone or its mimetics is controversial. Instead, researchers are beginning to turn to downstream targets of oestrogen. The finding that cathepsin K can be regulated by oestrogen provides an exciting possibility as a therapeutic agent downstream of oestrogen and especially given the absence of non-skeletal effects of cathepsin K deficiency in mice.

Osteoprotegerin

Osteoprotegerin (OPG), a member of the TNF family of receptors, has also been shown to play a critical role in bone remodelling, and addition of recombinant OPG in vitro and in vivo has been shown to inhibit osteoclastogenesis (61). Transgenic mice overexpressing OPG develop a generalized osteopetrosis (61). Targeted mutation of OPG in mice results in severe osteoporosis (55). Whether OPG is affected in any of the human osteoporoses remains to be shown. However, as the first animal model of osteoporosis that does not have any other obvious abnormalities, investigation of this animal may provide significant insights into the pathogenesis/treatment strategies of at least some forms of human osteoporosis. As such it confirms the importance of OPG in bone remodelling, but perhaps more importantly demonstrates, as with cathepsin K, that an individual molecule can be manipulated to alter the balance of bone formation and bone resorption in either direction.

ETS2 AND THE DOWN SYNDROME SKELETON

In addition to the `classical' bone diseases, a number of other human disorders also display a skeletal phenotype. One example is Down syndrome, which occurs due to trisomy of chromosome 21 and is associated with a distinct skeletal phenotype, including shortened stature, compression of the cervical vertebrae, incomplete closure of the cranial sutures, decreased BMD and an increased prevalence of osteoporosis (62-67). Given the large number of genes affected by trisomy of chromosome 21, identifying which genes are associated with the skeletal aspects of the Down syndrome phenotype has proved an important challenge. Ets2, a transcription factor, is one of the genes localized to chromosome 21. The Ets2 overexpression transgenic mouse displays virtually all of the skeletal defects observed in Down syndrome (68).

This animal model has therefore provided significant insight into the aetiology of the Down syndrome skeletal phenotype. Intriguingly, the phenotype of the Ets2 transgenic mouse closely resembles that seen in the gl/gl mouse (69). It is therefore possible to speculate that Ets2, or a closely related family member (keeping in mind that PU.1 is also a member of the Ets family of transcription factors), may play a role in the phenotype observed in the gl/gl mouse. The implications of such studies for our understanding of bone disease are two-fold. Firstly, they provide clues as to other genes that may play a role in bone development and disease. Secondly, they can provide some information regarding how the skeleton is affected by multigenic disorders or complex traits.

CONCLUDING REMARKS

The study of animal models of bone diseases, both osteopetrotic and osteoporotic, has clearly identified how disturbing the function of certain genes and/or certain cell types contributes to abnormal bone remodelling and perturbation of homeostasis. As the role that genes such as cathepsin K play in bone cell function, skeletal development and remodelling become defined, novel pathogenetic pathways involved in the genesis of human bone disease may be identified or pathways already known may become better understood. The key to treatment of such bone disorders may therefore emanate from identifying appropriate targets within these pathogenetic pathways that can be manipulated either through agonist or antagonist molecules or by gene therapy. This review has attempted to highlight the importance of understanding bone disease and in particular osteoporosis and osteopetrosis as a whole rather than as individual disorders, in the belief that such an approach will expedite our understanding of these diseases.

ACKNOWLEDGEMENTS

This work was supported in part by SmithKline Beecham Pharmaceuticals and the National Health and Medical Research Council of Australia.

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