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Review | A TRENDS Guide to Mouse Models of Human Diseases TRENDS in Genetics, Vol.17 No.10, October 2001

William McLean andBjorn R. Olsen*

Dept of Cell Biology,

Harvard Medical School,

240 Longwood Avenue,

Boston, MA 02115, USA.

*e-mail: bjorn_olsen@

hms.harvard.edu

Genetic disorders of the skeleton are a diverse group ofdiseases. More than 200 different forms of osteochondro-dysplasias have been described to date1, and many otherdiseases also have skeletal manifestations. Studies of natu-rally occurring and engineered mutant mice have led to adramatic increase in the understanding of skeletal devel-opment (Fig. 1) and have in many cases been integral tothe discovery and understanding of human diseases. Thisreview describes recent mouse models in the areas of osteoporosis, osteopetrosis and chondrodysplasias.

OsteoporosisOsteoporosis is defined as a generalized and significantreduction of bone mass, as a result of bone catabolismexceeding bone anabolism. Numerous factors have beenimplicated in the development of osteoporosis. Polymorph-isms in the COL1A1 gene2 and possibly in other genes, suchas the genes for vitamin D (Ref. 3) and the calcitonin re-ceptor4, have been associated with osteoporosis. Linkagestudies have also implicated the interleukin 6 (IL-6) gene5.

Several syndromes exist in which osteoporosis is afeature and the affected genes are known. Such syndromesinclude infantile Refsum disease6 (phytanic acid storagedisease; PEX2 gene), hypergonadotropic ovarian dysgenesis7

(follicle-stimulating hormone receptor), cerebro-oculo-facio-skeletal syndrome8 (ERCC6 gene), Menkes syndrome9

(Cu++-transporting ATPase, alpha polypeptide) andWerner syndrome10 (RECQL2 gene).

A limited number of mutant mouse strains exist thatdisplay osteoporosis as part of their phenotype, but theyhave had little impact on the study of human disease as noneof them have human counterparts. Mice that are deficient inthe small proteoglycan biglycan display reduced growthrate and decreased bone mass after birth11; this is the firstexample of progressive osteoporosis caused by the lack ofa noncollagenous extracellular matrix protein. Mice thatare deficient in another extracellular matrix component,

osteonectin, have decreased osteoblast and osteoclast num-bers, leading to decreased bone remodeling with a negativebone balance and profound osteopenia12. Osteopontin isone of the major noncollagenous bone matrix proteins andosteoclasts can bind to osteopontin through αvβ3 integrinreceptors.The importance of this interaction for bone re-sorption is shown by the finding that osteopontin-nullmice are resistant to ovariectomy-induced bone resorptioncompared with wild-type mice13, which are not resistant.

Osteoprotegerin (OPG) is a secreted protein that in-hibits osteoclast formation by blocking interaction betweenRANK ligand on the surface of osteoblasts and RANK onosteoclasts. As expected, adolescent and adult OPG–/–

mice exhibit a decrease in total bone density14.The c-Abl non-receptor tyrosine kinase is expressed at

high levels in hyaline cartilage in the adult, bone tissue innewborn mice, and osteoblasts and associated neovascu-lature at sites of endochondral ossification in the fetus.c-Abl–/– mice have long bones with thin cortices and re-duced trabecular bone volume owing to delayed maturationof osteoblasts15.

Insulin receptor substrates (IRS1 and IRS2) are essentialfor intracellular signaling by insulin and IGF-I, anabolicregulators of bone metabolism. Mice lacking the Irs1 genehave reduced osteoblastic proliferation and differentiation,and osteoclastogenesis is impaired, resulting in severelow-turnover osteopenia16.

Mice homozygous for a disruption of the klotho locus(KL–/– or klotho mouse) exhibit multiple pathological fea-tures resembling human aging17. A decrease in bone for-mation exceeds a decrease in bone resorption, resulting innet bone loss.This pathophysiology resembles that of senileosteoporosis in humans.

OsteopetrosisOsteopetrosis is a consequence of an abnormality of osteo-clasts causing defective bone resorption and a failure of

Mouse models of abnormal skeletaldevelopment and homeostasisWilliam McLean and Bjorn R. Olsen

Studies of a number of mouse mutations with skeletal defects have contributedsignificantly to the understanding of bone development and homeostasis. In many cases,such mutants are also genetic models of disorders in humans, characterized by reducedbone mass (osteoporosis), increased bone mass (osteopetrosis), or abnormalities inendochondral ossification (chondrodysplasias).

In association with MKMD

http://research.bmn.com/mkmd

bone remodeling. This results in excessively dense bonesowing to unopposed osteoblast activity. The bones be-come hard, but are brittle and more often fractured thanare normal bones.

Several mouse models exist for osteopetrosis. Four ofthese models arose from spontaneous mutations and includethe osteopetrotic (csf1op, formerly op/op) mouse, the osteosclerotic(Tcirg1oc, formerly oc/oc) mouse, the microphthalmic (mitfmi,formerly mi/mi) mouse and the grey lethal (gl/gl) mouse.The genetic alterations in all but the last of these fourmutants have now been identified.

In csf1op mice, the production of functional macro-phage colony stimulating factor (M-CSF or CSF-1) pro-tein is impaired because of a defect in the coding regionof the gene, and CSF-1 deficiency results in defects inmacrophage and osteoclast differentiation. The failure ofosteoclast differentiation results in impaired bone resorp-tion and remodeling, leading to systemic osteopetrosis18.

Tcirg1oc is an autosomal recessive lethal mutation thatimpairs bone resorption by osteoclasts. Positional cloningrevealed the presence of a 1.6 kb deletion, including the translation start site, in the mouse homolog of thehuman gene encoding the osteoclast-specific 116 kDasubunit of the vacuolar proton pump. The inactivationof this osteoclast-specific ATPase subunit is responsiblefor the lack of the enzyme in the apical membranes ofosteoclastic cells in Tcirg1oc mice, thereby preventing theresorptive function of the cells19. The human homologis mutated in some patients with infantile malignant osteopetrosis20.

The mouse mitfmi gene encodes a basic helix–loop–helixprotein that functions as a homo- or heterodimeric transcription factor. Mutations in mitfmi affect four celltypes: melanocytes, mast cells, pigmented epithelial cellsand osteoclasts. Dominant-negative, but not recessive,mutations in mitf produce a defect in osteoclasts and osteopetrosis21.

Numerous engineered mouse models of osteopetrosisalso exist.These have provided insight into osteoclast diff-erentiation and function. Strains important to the studyof differentiation include mice with abnormalities in Pu.1(Ref. 22), c-Fos (Ref. 23), Traf6 (Ref. 24), tnfrsf11a (re-ceptor activator of nuclear factor-κB or RANK; Ref. 25),tnfsf11 (RANK ligand; Ref. 26) and NF-κB1/NF-κB2(Ref. 27). Those important for the study of osteoclastfunction include mice with defects in c-src (Ref. 28),Atp6i (Tcirg1; Ref. 29), Acp-5 (Ref. 30), Clcn-7 (Ref. 31)and cathepsin K (Ref. 32). Only those mutants that have ahuman counterpart will be discussed.

RANK–/– mice are characterized by osteopetrosis result-ing from a block in osteoclast differentiation25. RANK ex-pression provides a necessary and specific signal for thedifferentiation of osteoclasts.The human gene for RANK,TNFRSF11A, maps to the same region as familial expansileosteolysis (FEO) and one form of familial Paget disease ofbone (PDB2; Ref. 33), and duplication events have beenidentified in this gene in both disorders. Although theyare not phenocopies of the mouse RANK-null phenotype,they are obviously the consequence of a disruption inbone homeostasis.

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TRENDS in Genetics, Vol.17 No.10, October 2001 A TRENDS Guide to Mouse Models of Human Diseases | Review

TRENDS in Genetics

Bone

Hypertrophiccartilage

Proliferatingcartilage

Bone

Col X

Ihh

PTHrP

Cartilage

Hypertrophic cartilage

Mesenchymalcondensation

Figure 1. Sequence ofevents duringendochondralossificationAt the top of the figure, thestages leading from amesenchymal condensation (left)to a bone with growth plates anda central marrow cavity (right)are illustrated. Differentiation ofchondrocytes within themesenchymal condensationresults in a cartilage model ofthe future bone. Hypertrophy ofchondrocytes within the cartilageand formation of a sleeve ofbone around the hypertrophiccartilage is followed by invasionof the hypertrophic cartilage byblood vessels, osteoblasts andosteoclasts. This results in theformation of a primary ossificationcenter. Formation of secondaryossification-centers in theepiphyseal regions result ingrowth plates at the two ends.The differentiation of osteoclastsfrom monocytes is regulated bya number of genes described inthe text; the differentiation ofosteoblasts from mesenchymalprecursors is controlled by atranscription factor,Cbfa1/Runx2, as described inseveral recent reviews67,68.At the bottom of the figure,areas of mesenchymalcondensation (left) and growthplates (right) are illustrated athigher magnification. Within amesenchymal condensation,cells are recruited into a centralarea of high cell density. Genesthat regulate the condensationprocess and differentiation ofcells within the condensationinclude CDMP-1 and SOX9.Within a growth plate,chondrocytes proliferate anddifferentiate to hypertrophy underthe control of a large number ofgenes. As described in the text,such genes include thoseencoding parathyroid-hormone-related peptide (PTHrP) andIndian hedgehog (Ihh). Thesecytokines are expressed inspecific regions within the growthplates; PTHrP is expressed inproliferating cartilage and Ihh incells (prehypertrophic cells)between proliferating andhypertrophic cartilage.Hypertrophic chondrocytesexpress a unique collagenmolecule, collagen X (Col X),which is commonly used as amarker for hypertrophic cartilage.Proteolytic digestion of thehypertrophic cartilage matrixand apoptosis of hypertrophicchondrocytes allows trabecularbone to be deposited below thegrowth plate by osteoblasts.

Mice with targeted disruption of the Clcn7 gene displaysevere osteopetrosis and retinal degeneration31. Osteoclastsare present in normal numbers but they fail to acidify theextracellular resorption lacunae, and therefore fail to resorbbone. Clcn7 is highly expressed in the ruffled membrane ofosteoclasts and provides the chloride conductance requiredfor efficient proton pumping by the H+-ATPase. Based onthe similarity between Clcn7–/– mice and human infantilemalignant osteopetrosis, the human CLCN7 gene wasscreened for mutations in patients with the disease; a mu-tation in CLCN7 was identified in a patient with the disorder.

Cathepsin K is a cysteine protease that is highly ex-pressed in osteoclasts. Targeted mutation of the cathepsin Kgene in mice results in a phenotype resembling pycno-dysostosis caused by mutations in the human cathepsin Kgene (Ref. 32).The phenotype (increased bone density andbone deformity) becomes progressively pronounced withage, as does the osteopetrosis associated with pycno-dysostosis. In both humans and mice, the bones that aremore rapidly remodeled are more severely affected.

ChondrodysplasiasThese disorders are caused by generalized defects in thedifferentiation and proliferation of chondrocytes, or inthe matrix produced by them in the cartilage anlagen ofthe bones in the endochondral skeleton. During endo-chondral ossification, the cartilage is replaced by boneand bone marrow except in growth plates and on jointsurfaces (Fig. 1). As abnormalities causing chondrodys-plasias affect cartilage, growth plate and articular cartilagemay also be affected, resulting in bone and joint abnor-malities (osteochondrodysplasias).

Chondrodysplasias can be divided into two maingroups.The first group consists of disorders that result frommutations in signaling molecules, transcription factorsand components of biosynthetic pathways. The secondgroup is comprised of disorders caused by mutations inextracellular matrix molecules.

Signaling molecules, transcription factors andcomponents of biosynthetic pathways The proliferation and differentiation of chondrocytes duringendochondral ossification and in growth-plate cartilage arecontrolled by local and systemic factors (Fig. 1). Severalmouse models have enabled studies of these factors.

The fibroblast growth factors (FGFs) and their receptors(FGFRs) are important regulators of bone growth.Achondroplasia, the most frequent form of dwarfism inhumans, is caused by activating mutations in one of thereceptors, FGFR3 (Ref. 34). Fgfr3 null mice show in-creased long-bone growth, suggesting that Fgfr3 is a nega-tive regulator of bone growth35. Over the past two years,several mouse models of specific human mutations havebeen produced36,37.This has enabled a careful analysis of theachondroplasia phenotype and disease variability, and offerspromising models for the development of specific therapy.

The importance of local signaling within growth-platecartilage is further highlighted by studies of parathyroid-hormone-related peptide (PTHrP) and its G-protein-coupledreceptor (PTHrPR1). PTHrPR1 is expressed in proliferatingand prehypertrophic chondrocytes in growth plates andmediates the ability of PTHrP to maintain chondrocytes ina proliferative state38. Mice homozygous for a PTHrP-nullmutation die shortly after birth and display widespreadabnormalities of endochondral ossification characterizedby a marked decrease in chondrocyte proliferation andaccelerated differentiation39. Mice lacking the PTHrP re-ceptor usually die at mid-gestation; however, those thatdo survive display accelerated chondrocyte differentiation40.Studies of these mice played an important role in dissect-ing the Indian hedgehog (Ihh), PTHrP and the PTHrP receptor pathway involved in the control of chondrocytehypertrophy in growth plates, and they provide a valuablemodel for human conditions caused by mutations in thePTHrP receptor. Loss-of-function mutations in the receptorcause Blomstrand chondrodysplasia41, whereas activatingmutations result in Jansen-type metaphyseal chondrodys-plasia42–44. Studies of the mouse models45,46 demonstratethat the activating mutations seen in the Jansen-type dis-order cause a marked deceleration of chondrocyte differ-entiation, in contrast to the accelerated differentiationseen in mice with null mutations in the PTHrP receptor.

Gdf-5/Cdmp1 is a member of the transforminggrowth factor-beta (TGFβ) superfamily and is expressedat sites of skeletal morphogenesis. Gdf-5 is predomi-nantly expressed in the cartilage primordia of the appen-dicular skeleton. Naturally occurring mutations in Gdf-5that lead to a defect in development of the appendicularskeleton have been identified in both mice and humans.The autosomal recessive syndromes brachypodism (Gdf5bp,formerly bp) in mice and chondrodysplasias Grebe type andHunter–Thompson type in humans, are all characterizedby shortening of limb skeletal elements with disruption ofone or more joints. Both Gdf5bp and Hunter–Thompson-type disorders are the consequences of a missense mutationresulting in loss of function of Gdf-5 (Refs 47,48).Grebe-type chondrodysplasia is much more severe thanthe Hunter–Thompson type and this is thought to occurbecause the Grebe mutation C400Y in the functional do-main of the protein leads to the loss of function of othermembers of the TGFβ superfamily with which Gdf-5heterodimerizes49. Transgenic mice expressing Gdf-5 underthe control of three different promoter/enhancer se-quences have recently been generated50. The mice exhibitchondrodysplasia with expanded growth-plate cartilage,consisting of an enlarged hypertrophic zone and reducedproliferating zone.

Mutations affecting the transcription factor Sox9 areresponsible for the autosomal dominant skeletal malfor-mation syndrome campomelic dysplasia51. SOX9 is amember of the SOX (SRY-related HMG box) gene familyand is involved in chondrogenesis and sex determination.

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Review | A TRENDS Guide to Mouse Models of Human Diseases TRENDS in Genetics, Vol.17 No.10, October 2001

Until recently, no mouse model existed for the disorder,which has, to a degree, hindered the understanding ofthe molecular pathogenesis.A Sox9 mutant mouse has nowbeen generated52; heterozygotes display a partial pheno-copy of campomelic dysplasia with hypoplasia and bend-ing of many skeletal structures. Studies of these mice havedemonstrated that Sox9 has not only a role during mesen-chymal condensation of cartilage primordia, but also arole in controlling the differentiation of chondrocyteswithin growth plates (Fig. 1). In the growth plates ofSox9+/– mice, there appears to be an increase in the sizeof the hypertrophic zone and premature mineralization.This finding supports recent work identifying Sox9 as atarget for PTHrP signaling53.

Another transcription factor that has been shown tobe important for skeletal development is Atf-2. The DNAtarget sequence for Atf-2 is the widely distributed cAMPresponse element (CRE). Atf-2 mutant mice demonstratedecreased postnatal viability and growth, with defects ingrowth plates similar to human hypochondroplasia54.The mutant mice show a reduction in the length of thespine and limbs. The limb shortening is more severe inthe proximal segments. In growth plates, clusters of cellsinstead of ordered columns of chondrocytes are seen,and in-growth of blood vessels is lacking. No human dis-order caused by mutations in Atf-2 has been identified;however, it is probable that Atf-2 regulates a pathway thatis vital for normal growth-plate function.Therefore, Atf-2mutant mice may become important in future studies ofkey regulatory pathways.

The X-linked dominant male-lethal mouse mutationstattered and bare patches are homologous to human X-linkeddominant chondrodysplasia punctata (CDPX2, Conradi–Hünermann or Happle syndrome) and CHILD syndrome(congenital hemidysplasia with ichthyosiform erythro-derma and limb defects), two rare human skeletal dys-plasias. These disorders also affect the skin and can causecataracts and microphthalmia in surviving affected hetero-zygous females. They have recently been shown to resultfrom mutations in genes encoding enzymes involved insequential steps in the conversion of lanosterol to choles-terol. The gene mutated in bare patches/CHILD syndromeencodes a 3β-hydroxysteroid dehydrogenase55,56, and thegene mutated in tattered/chondrodysplasia punctata is∆8–∆7 sterol isomerase emopamil binding protein57,58.These mutations are very exciting as very little is knownabout the role of cholesterol in development, despite awealth of information about its biology. It has been postulated that the skeletal defects seen in these disordersare related to the need for Indian hedgehog to be modi-fied by the covalent attachment of cholesterol. Work iscurrently being carried out to identify perturbations inhedgehog signaling59. Studies using these mice are likely tobe extremely useful as they will uncover an area of skeletal development that has until now received relativelylittle attention.

Extracellular matrix moleculesThe extracellular matrix molecules that are associated withchondrodysplasias can be divided into collagenous andnon-collagenous matrix components.The collagens are themost abundant extracellular matrix proteins; mutationsaffecting types II, IX, X and XI have all been identified asleading to osteochondrodysplasias. Several mouse models ofthese so-called collagenopathies exist. For a descriptionof these mutants, see review by Mundlos and Olsen60.

Several noncollagenous components have been impli-cated in cartilage development and maintenance. Mutationsin some genes, such as COMP (cartilage oligomeric matrixprotein), have been identified as being responsible forhuman chondrodysplasias61. Other noncollagenous com-ponents, such as aggrecan62 and cartilage link protein63

are altered in mouse models that give rise to chondrodys-plastic phenotypes. Cartilage link protein stabilizes aggre-gates of aggrecan and hyaluronan; these aggregates incombination with a three-dimensional collagen fibril scaf-fold give cartilage its tensile strength and elasticity.Targetedmutations in cartilage link protein of mice cause defects incartilage development and delayed bone formation withshort limbs and craniofacial anomalies. Homozygous mu-tant mice show characteristics of spondyloepiphyseal dys-plasias such as small epiphyses, slightly flared metaphysesof long bones, and flattened vertebrae. Aggrecan appearsmuch reduced in the hypertrophic zone of growth platesand there are decreased numbers of prehypertrophic andhypertrophic chondrocytes. Indian hedgehog expression inprehypertrophic chondrocytes is much reduced, and apop-tosis in hypertrophic chondrocytes appears to be inhibited.The results indicate that cartilage link protein plays an essen-tial role in chondrocyte differentiation and maturation.

Mutations leading to alterations in perlecan are knownboth in mouse models64,65 and in a human disorder66.Perlecan, a large multi-domain heparan sulfate proteoglycan,interacts with extracellular matrix proteins, growth factorsand receptors, and influences cellular signaling. Micelacking the perlecan gene (Hspg2) have severe chondro-dysplasia with dyssegmental ossification of the spine andchondro-osseous abnormalities similar to a lethal auto-somal recessive disorder in humans termed dyssegmentaldysplasia Silverman–Handmaker type (DDSH).Three dif-ferent mutations in HSPG2 have been identified in DDSHpatients. The mutations are predicted to cause a frame-shift, resulting in a truncated protein core. The cartilagematrix from these patients stains poorly with antibodyspecific for perlecan, but there is staining of intracellularinclusion bodies. The truncated perlecan is not secretedby patient fibroblasts, but is degraded to smaller frag-ments within the cells. Thus, it has been concluded thatDDSH is caused by functional null mutations in HSPG2.

Concluding remarksOsteochondrodysplasias and disorders of bone homeostasisare a complex group of diseases. Many of the causative

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TRENDS in Genetics, Vol.17 No.10, October 2001 A TRENDS Guide to Mouse Models of Human Diseases | Review

genes have been identified using a candidate gene approachbased on what is generally known about the developmentof cartilage and bone. Other genes involved have beenidentified either through positional/positional candidategene cloning or by the serendipitous finding of skeletalabnormalities in engineered mouse models. It is probablethat the continued generation of mutant mouse strainswill lead to a dramatic increase in the number of genes inthis second category.This holds great promise for the futureas the field not only continues to explore the role ofknown effectors of skeletal development, but also identi-fies and characterizes new genes with unexpected rolesin skeletal biology.

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TRENDS in Genetics, Vol.17 No.10, October 2001 A TRENDS Guide to Mouse Models of Human Diseases | Review