Mice deficient in small leucine-rich proteoglycans: novel in vivo models for osteoporosis, osteoarthritis, Ehlers-Danlos syndrome, muscular dystrophy, and corneal diseases (original) (raw)

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01 September 2002

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Laurent Ameye, Marian F. Young, Mice deficient in small leucine-rich proteoglycans: novel in vivo models for osteoporosis, osteoarthritis, Ehlers-Danlos syndrome, muscular dystrophy, and corneal diseases, Glycobiology, Volume 12, Issue 9, 1 September 2002, Pages 107R–116R, https://doi.org/10.1093/glycob/cwf065
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Abstract

Small leucine-rich proteoglycans (SLRPs) are extracellular molecules that bind to TGFβs and collagens and other matrix molecules. In vitro, SLRPs were shown to regulate collagen fibrillogenesis, a process essential in development, tissue repair, and metastasis. To better understand their functions in vivo, mice deficient in one or two of the four most prominent and widely expressed SLRPs (biglycan, decorin, fibromodulin, and lumican) were recently generated. All four SLRP deficiencies result in the formation of abnormal collagen fibrils. Taken together, the collagen phenotypes demonstrate a cooperative, sequential, timely orchestrated action of the SLRPs that altogether shape the architecture and mechanical properties of the collagen matrix. In addition, SLRP-deficient mice develop a wide array of diseases (osteoporosis, osteoarthritis, muscular dystrophy, Ehlers-Danlos syndrome, and corneal diseases), most of them resulting primarily from an abnormal collagen fibrillogenesis. The development of these diseases by SLRP-deficient mice suggests that mutations in SLRPs may be part of undiagnosed predisposing genetic factors for these diseases. Although the distinct phenotypes developed by the different singly deficient mice point to distinct in vivo function for each SLRP, the analysis of the double-deficient mice also demonstrates the existence of rescuing/compensation mechanisms, indicating some functional overlap within the SLRP family.

Accepted on April 26, 2002;

Structure of the small leucine-rich proteoglycans

Small leucine-rich proteoglycans (SLRPs) belong to the leucine-rich repeat (LRR) superfamily of proteins (Hocking et al., 1998). Members of the LRR superfamily may contain up to 38 LRRs. The LRR domain is 20 to 29 amino acids long with asparagine (N) and leucine (L) residues in conserved positions (Hocking et al., 1998; Iozzo, 1999). The LRR is a structural motif used in diverse molecular recognition processes, including cell adhesion, signal transduction, DNA repair, and RNA processing (Kobe and Deisenhofer, 1994). It consists of a β‐sheet (LxxLxLxxNxL) parallel to an α-helix (xaxx±a±±±±a±±x) where a is an aliphatic amino acid, x is any amino acid, and ± is frequently a gap.

Within the LRR superfamily, the SLRPs form a specific subgroup (Iozzo and Murdock, 1996). The SLRP family is uniquely characterized by cysteine-rich clusters, which form disulfide bonds and flank the central LRRs (see Figure 1 for example of SLRP structure). There are four similarly spaced cysteine residues in the amino terminal end and two cysteine residues in the carboxy terminal end. The SLRPs are called small to distinguish them from other much larger proteoglycans, like versican or aggrecan. The SLRP protein cores have a mass of approximately 40 kDa, compared with more than 200 kDa for versican and aggrecan (Iozzo, 1998).

The SLRP family is rapidly growing and includes today 13 members (Table I). So far, all SLRPs are extracellular except for one member (nyctalopin), which is a glycosylphosphatidylinositol-anchored protein (Bech-Hansen et al., 2000; Pusch et al., 2000). Most (but not all) SLRPs are proteoglycans (at least in some tissues and at some developmental stage or age). At least one member, asporin, is placed in the SLRP family based on gene sequence homology, even though it does not contain glycosaminoglycan chains. Molecular modeling and electron microscopy suggest that SLRPs are nonglobular, horseshoe-shaped, solenoid-like molecules (Figure 2) (Scott, 1996; Weber et al., 1996). The concave surface of the horseshoe-shaped SLRPs is formed by the LRR’s β-sheets, whereas the LRR’s α‐helices and the SLRP’s diverse carbohydrate moieties flank the horseshoe convex surface.

Based on the genomic organization, structure of the amino terminal cysteine cluster, and similarity of the amino acid sequences, most SLRPs can be grouped into three classes (Table I) (Iozzo, 1999; Lorenzo et al., 2001). Class I consists of decorin (DCN) (Ameye et al., 2002b; Danielson et al., 1993; Krusius and Ruoslahti, 1986; Scholzen et al., 1994; Vetter et al., 1993), biglycan (BGN) (Fisher et al., 1989; Wegrowski et al., 1995; Young and Chen, 2002), and asporin/PLAP (Lorenzo et al., 2001; Henry et al., 2001; Yamada et al., 2001). Class I SLRPs are secreted with a propeptide that in some cases can be cleaved by bone morphogenetic protein-1 under age and tissue-specific conditions (Scott et al., 2000). They contain 10 LRRs and a unique N-terminal cysteine sequence (CX3CXCX6C) and are encoded by eight exons (see Figure 1 for BGN structure). Asporin is not a proteoglycan, but DCN and BGN are. They carry one and two chondroitin or dermatan sulfate chains, respectively. The attachment of chondroitin versus dermatan sulfate chains is tissue-specific (Hocking et al., 1998).

Class II consists of fibromodulin (FM) (Antonsson et al., 1993; Säämanen et al., 2001), lumican (LUM) (Grover et al., 1995; Hassell et al., 1998; Ying et al., 1997), keratocan (Liu et al., 1998; Tasheva et al., 1997, 1998), PRELP (Bengtsson et al., 1995; Grover et al., 1996), and osteoadherin/osteomodulin (Sommarin et al., 1998). Class II SLRPs contain 10 LRRs and the characteristic N-terminal cysteine sequence CX3CXCX9C. They are encoded by three exons, with a large central exon encoding almost all 10 LRRs. Except for PRELP, they all carry polylactosamine or keratan sulfate chains in the LRR region and sulfated tyrosine residue in the N-terminal end (see Figure 1 for FM structure).

Class III consists of epiphycan/PG-Lb/DSPG3 (Deere et al., 1996; Johnson et al., 1997), mimecan/osteoglycin (Tasheva et al., 1997, 1999; Funderburgh et al., 1997; Ujita et al., 1995), and opticin/oculoglycan (Friedman et al., 2000; Hobby et al., 2000; Reardon et al., 2000; Takanosu et al., 2001). Class III SLRPs contain only six LRRs and the characteristic N‐terminal cysteine sequence CX2CXCX6C. They are encoded by seven exons; the last three encode all the LRRs. They all contain sulfated tyrosine residues in the N-terminal end.

The two remaining SLRPs, chondroadherin (Grover et al., 1997; Landgren et al., 1998; Neame et al., 1994) and nyctalopin (Bech-Hansen et al., 2000; Pusch et al., 2000) do not belong to the three previously described classes. Based on their amino acid sequences, they are most closely related to each other than to any other SLRPs (Bech-Hansen et al., 2000). Both contain 11 LRRs and are encoded by 3 exons, but their N‐terminal cysteine sequence is different: CX3CXCX8C for chondroadherin and CX3CXCX6C for nyctalopin.

During evolution, the SLRP family appears to have arisen from several duplication events, which resulted in their current clustered organization on different chromosomes. In humans, for example, DCN (Vetter et al., 1993), LUM (Grover et al., 1995), keratocan (Tasheva et al., 2000a), and epiphycan (Danielson et al., 1999) (Class I, II, II, and III, respectively) map to chromosome 12q23. Asporin (Lorenzo et al., 2001; Henry et al., 2001), osteoadherin, and mimecan (Tasheva et al., 2000b) (Class I, II, and III, respectively) are found on chromosome 9q32. FM (Sztrolovics et al., 1994), PRELP (Grover et al., 1996), and opticin (Hobby et al., 2000) (Class II, II, and III, respectively) locate to chromosome 1q32. BGN (class I) is unique by its location on chromosome X (Xq28) (Fisher et al., 1991). In each cluster, the genes of the class I SLRPs lie 5′ to the genes of class II members with the class II genes lying themselves 5′ to the class III genes (Henry et al., 2001). It is believed that the genes are organized in clusters of four with some genes still to be discovered (Lorenzo et al., 2001).

The expression pattern of the SLRPs varies widely from one proteoglycan to another. In general, class I SLRPs tend to be more ubiquitous than class II members with the distribution of class III SLRPs being the most tissue-specific.

Several SLRPs bind to the collagens type I, II, V, VI, XII, and XIV (Bidanset et al., 1992; Font et al., 1993, 1996; Hedbom and Heinegärd, 1993; Oldberg et al., 1989; Witsch-Prehm et al., 1995; Schönherr et al., 1995a,b; Whinna et al., 1993; Wiberg et al., 2001). By doing so, they modulate collagen fibrillogenesis in vitro (see Hocking et al., 1998, for a review). It is generally accepted that (1) horseshoe-shaped SLRPs interact with collagen molecules by their concave surface, and (2) the space inside the horseshoe accommodates a single triple helix of collagen (Weber et al., 1996). Figure 2 shows a 3D structure of DCN including the region believed to bind the collagen. This computerized image was modeled based on the crystal structure of the porcine ribonuclease inhibitor, a molecule that also contains LRRs and shares 18% identical residues with DCN. Structure–function studies showed that the DCN LRR repeats IV and V (Svensson et al., 1995) specifically bind to the C terminus of type I collagen (Keene et al., 2000).

At least three SLRPs (DCN, BGN, and FM) bind to the transforming growth factor beta (TGF-β) (Hildebrand et al., 1994), a multifunctional cytokine involved in inflammation, apoptosis, cell proliferation, and differentiation (Piek et al., 1999). Due to its TGF-β binding ability, DCN has been successfully used as an antifibrotic agent to overcome the overproduction of TGF-β in experimental glomerulonephritis (Border et al., 1992; Isaka et al., 1996). Recent data suggests that the collagen-bound DCN sequesters TGF-β in the extracellular matrix without inactivating it completely (Hausser et al., 1994; Markmann et al., 2000; Schönherr et al., 1998). Based on in vitro studies, a complex picture is beginning to emerge indicating that SLRPs control cell differentiation and proliferation in a cell-specific fashion (Schönherr et al., 2001; Kresse and Schönherr, 2001) with each cell type responding with unique sets of signaling factors (Santra et al., 1997; Iozzo et al., 1999a,b; Xaus et al., 2001).

To better understand the SLRP functions in vivo, four SLRPs (BGN, DCN, FM, and LUM) have been disrupted by gene targeting. In addition, double SLRP-deficient mice (deficient in BGN and DCN, FM and LUM, or BGN and FM) have also been generated by interbreeding the single SLRP-deficient mice. The rest of this review focuses on what we have learned about SLRP biology from these animal models.

SLRP single-deficient mice

BGN-deficient mouse

BGN is highly expressed in bone (Bianco et al., 1990). For several years, it was suspected to be involved in bone growth because patients with Turner syndrome (i.e., females that lack a second X chromosome) have short stature and low levels of BGN, whereas patients with supernumerary X chromosomes present increased limb length and levels of BGN (Vetter et al., 1993). The targeted disruption of BGN confirmed that it was involved in the regulation of postnatal skeletal growth (Xu et al., 1998). BGN-deficient bones grow more slowly than their wild-type counterparts, and by 9 months BGN-deficient femurs are significantly shorter than wild-type femurs. BGN knockout mice also fail to achieve peak bone mass due to a decrease in bone formation explained by a lower osteoblast number and a lower osteoblast activity (Xu et al., 1998). The phenotypical analysis of BGN-deficient mice demonstrates that BGN is a positive regulator of bone formation that controls peak bone mass. Peak bone mass, achieved by skeletal growth, is the most critical risk factor for human osteoporosis. By its inability to achieve a high peak bone mass, the BGN knockout mouse thus constitutes a good animal model for studying osteoporosis.

The cellular and molecular mechanisms leading to osteoporosis in the absence of BGN have been partially identified (Chen et al., 2002). In vitro experiments demonstrate that with age, the number of bone marrow stroma cells (BMSCs; the osteogenic precursors) decreases more rapidly in the BGN knockout than in the wild type (Chen et al., 2002). Though the number of BMSCs isolated from 6-week-old BGN knockout mice is not statistically different from wild-type controls, the difference becomes statistically significant at 3 months and grows even larger by 6 months.

Other experiments indicate that the BGN deficiency also impairs the metabolic activity of the BMSCs. BGN-deficient BMSCs are less responsive to exogenous TGF-β and show an increased rate of apoptosis, two possible explanations for the lower number of BMSCs observed at 3 and 6 months in the BGN knockout. BGN-deficient BMSCs also produce less type I collagen, indicating that the composition of the extracellular matrix may be regulated by specific matrix components like BGN. Any one of the defects in BMSCs (lower number, decrease response to growth factors, increased rate of apoptosis, synthesis of an abnormal extracellular matrix) or any combination could contribute to and/or explain the osteoporosis developed by the BGN knockout mice in vivo.

Reminiscent of the altered bone phenotype, 1 day after birth, a broader than normal metadentin is observed in the BGN-deficient first molar, along with an altered and heterogeneous dentin mineralization (Goldberg et al., 2002). Structural defects are also observed in the forming enamel. In addition, the thickness of the forming enamel is dramatically increased. These results suggests that BGN exerts a negative control on enamel formation and that its absence derepressed ameloblast synthetic and secretory pathways. Altogether, these results stressed the important role played by BGN in all mammalian mineralized tissues.

In addition, the BGN-deficient mice also develop osteoarthritis and ectopic tendon ossification (Ameye et al., 2002a) Both may result from joint instability and mechanically compromised tendons (Ameye et al., 2002a,b). The BGN deficiency induces morphological changes in collagen fibrils from a wide variety of tissues, including tendons (Goldberg et al., 2002; Ameye et al., 2002a; Corsi et al., 2002) (Table II). In the absence of BGN, irregular fibrils with a cross-sectional contour presenting notches and protuberances are frequently observed in type I collagen-rich matrices, such as skin, bone, and tendons. Longitudinal sections of collagen fibrils in BGN knockout also demonstrate marked diameter variability along individual fibril axes.

In addition to these qualitative morphological defects, the absence of BGN introduces quantitative variations in the range, mean and distribution profiles of the collagen fibril diameters compared to the wild type (Goldberg et al., 2002; Ameye et al., 2002a; Corsi et al., 2002). Interestingly, although the morphological defects are the same in all extracellular matrices, the quantitative alterations are tissue-specific (Corsi et al., 2002). For example, the BGN deficiency increases the average fibril diameter in bone and skin dermis, while it decreases it in the patella and tail tendons (Ameye et al., 2002a; Corsi et al., 2002). The tissue-specific effects of the BGN deficiency could result from tissue differences in the amount and/or temporal expression of BGN during collagen fibrillogenesis or from a modulation of the control exerted by BGN on collagen fibrillogenesis by other local components of the extracellular matrix. Though in vitro the collagen binding ability of BGN and the inferred effect of BGN on collagen fibrillogenesis is controversial (Hocking et al., 1998), the in vivo data clearly establish that BGN plays a critical role in collagen fibrillogenesis.

BGN also binds to α-dystroglycan, a component of the dystrophin-associated protein complex localized in the muscle cell membrane (Bowe et al., 2000). BGN binding appears to occur through the glycosaminoglycan chains, leaving open the possibility that other proteoglycans may also interact with dystroglycan. Mice deficient in BGN display a mild muscular dystrophic phenotype characterized by membrane disruption and cell death of a subpopulation of myofibers (Rafii et al., 2000). These results suggest that BGN may play a role in muscular dystrophies and in the future treatments of these pathologies.

DCN-deficient mouse

The targeted disruption of DCN was the first in vivo demonstration of the importance of the SLRPs for proper collagen fibrillogenesis (Danielson et al., 1997). In the absence of DCN, the collagen fibrils of the skin and tail tendon show the same qualitative morphological defects as in the absence of BGN (Corsi et al., 2002; Danielson et al., 1997). The DCN deficiency also introduces tissue-specific variations in the range, mean, and distribution profiles of the collagen fibril diameters compared to the wild type. In some tissues, these variations are distinct from those observed in the absence of BGN (Corsi et al., 2002) (Table II). Consistent with the high level of expression of DCN in the dermis, DCN-deficient mice have fragile skin, characterized by a markedly reduced tensile strength and a thinner than normal dermis. The collagen alterations observed in the skin of the DCN knockouts are probably responsible for the reduced mechanical properties of the skin because skin strength correlates directly with the characteristics of the collagen fibril network (Dombi et al., 1993). The phenotype of the DCN- deficient mice, including the collagen defects, closely mimic the cutaneous defects observed in the human Ehlers-Danlos syndrome (EDS) (Danielson et al., 1997), a clinically and genetically heterogeneous connective tissue disorder characterized by skin hyperextensibility, joint hypermobility, and tissue fragility (Mao and Bristow, 2001).

Both DCN and BGN single deficiencies introduce changes in collagen fibril size and shape in bone (Table II) (Corsi et al., 2002). However, in contrast to BGN deficiency, DCN deficiency does not affect bone mass and does not appear to lead to any other major phenotypic changes in bone at the histological or macroscopic level (Corsi et al., 2002). Despite their high level of homology (57% identity at the amino acid level), BGN and DCN have distinct functions in vivo. These functional specificities may partially result from differences in the glycosaminoglycan chains: BGN most often has two chondroitin or dermatan sulfate chains, whereas DCN contains only one.

In addition to modulating the morphology of the collagen fibrils, DCN deficiency also induces changes in collagen orientation. In the absence of DCN, the collagen fibrils in the periodontal ligament display a random orientation instead of their usual parallel orientation (Hakkinen et al., 2000).

Besides its action on collagen fibrillogenesis, DCN is also known to control cell division (Santra et al., 1997). In vitro, the ectopic expression of DCN in a wide variety of malignant cell lines and in normal fibroblasts stops cell growth (Hakkinen et al., 2000; Santra et al., 1997). The inhibitory action of DCN on cell division has been confirmed in vivo by the data gathered from DCN-deficient mice. Compared to wild-type mice, the number of fibroblasts in the periodontal ligament is doubled in DCN‐deficient mice (Hakkinen et al., 2000). This hypercellularity probably results from an increased proliferation in the absence of inhibitory signals from DCN. In agreement with this interpretation, the lack of DCN also accelerates lymphoma tumorigenesis in a mouse model predisposed to cancer (Iozzo et al., 1999b). In parallel to its regulatory action on cell division, DCN may also limit apoptosis. Indeed, DCN-deficient mice subject to unilateral ureteral obstruction have increased apoptosis (and collagen turnover) indicating that DCN may have a protective function in acquired tubulointerstitial fibrosis (Schaefer et al., 2002).

The DCN-deficient mice were also instrumental to demonstrate the importance of DCN in Lyme disease. Lyme disease is an infectious disease caused by the tick-borne spirochete Borrelia burgdorferi (Steere, 2001). Spirochetes deposited by the ticks in the dermis bind to DCN (Guo et al., 1995). The DCN-deficient mice display an increased resistance to Lyme disease, suggesting that DCN could be a limiting factor as a substrate for the adherence of B. burgdorferi in the dermis (Brown et al., 2001).

FM-deficient mouse

FM is relatively abundant in tendons. Mice deficient in FM are predisposed to ectopic tendon ossification and develop osteoarthritis (Ameye et al., 2002a). At the histological level, FM‐deficient mice have abnormal and less numerous collagen fibril bundles in the tail (Svensson et al., 1999). At the ultrastructural level, collagen fibrils with irregular cross sections are observed (Ameye et al., 2002a; Svensson et al., 1999). Compared to wild type, the average fibril diameter is decreased both in Achilles and patella tendons due to a higher number of small fibrils in the fibril population (Ameye et al., 2002a; Svensson et al., 1999). The ratio of LUM to FM was estimated to be 1:3 in wild-type tendons. In absence of FM, the amount of LUM protein in tail tendon is multiplied by a factor of four despite a decrease at the mRNA level (Svensson et al., 1999). Therefore, it was hypothesized that in absence of FM, LUM binds to the sites normally used by FM, suggesting that LUM and FM compete for the same binding sites on collagen fibrils. This was later confirmed by binding competition experiments (Svensson et al., 2000).

LUM-deficient mouse

LUM is a major component of the cornea. Mice deficient in LUM develop progressive corneal opacification with age, demonstrating that although LUM is not necessary for embryonic corneal development, it is essential for postnatal corneal maturation (Chakravarti et al., 1998). Absence of LUM results in irregular, thicker than normal, loosely packed collagen fibrils associated with a dramatic disruption in the lamellar organization of the fibrils (Table II) (Chakravarti et al., 1998, 2000; Quantock et al., 2001). These collagen defects are mainly restricted to the posterior part of the cornea, where the mature collagen fibrils are located and where LUM is more highly expressed in normal animals (Chakravarti et al., 2000). The structural alteration of the collagen fibrils is probably directly responsible for the corneal opacification, as corneal transparency arises from minimal scattering of light by a lattice arrangement of uniformly thin, regularly interspaced collagen fibrils (Maurice, 1957). Supporting this hypothesis, in vivo confocal microscopy demonstrates that the posterior stroma of the cornea, where the collagen defects are mainly concentrated, is highly reflective to light (Chakravarti et al., 2000; Jester et al., 2001).

In addition, LUM-deficient mice also develop EDS-like skin laxity. Compared to wild type, the LUM-deficient mice display a 86% reduction in skin tensile strength, an increased incidence of skin lesions, along with a disorganized abnormally loose dermis containing altered collagen fibrils (Table II) (Chakravarti et al., 1998).

Double jeopardy: mice deficient in more than one SLRP

The structural similarities and partially overlapping tissue distributions of the SLRPs suggested that different SLRPs might share redundant functions and that partial rescue and/or compensation mechanisms by other members of the family might take place in singly SLRP-deficient mice. In a rescue situation, the total amount of the extracellular matrix components would stay the same whereas in a compensation situation, the amount of one or several molecules would be increased. An increased protein level could be achieved either by an increased level of expression (regulated at the transcriptional or translational level) or by a decreased rate of degradation. The increased amount of LUM in FM-deficient tendon was the first evidence of the existence of compensation mechanisms between SLRPs (Svensson et al., 1999). In this context and in order to further investigate the in vivo functional relationships between SLRPs, double SLRP-deficient mice were generated. Double deficient mice are critical tools to convincingly demonstrate the existence of redundant functions between molecules because if such redundant functions exist, the effects of a double deficiency will be synergetic instead of additive.

BGN/DCN double knockout

BGN and DCN were obvious candidates to generate a double SLRP-deficient mouse because of the high level of similarity between these two Class I SLRPs. The phenotype of the double knockout is severe. They cannot breed, and the number of double-deficient animals obtained for heterozygous breeders is much lower than the expected Mendelian frequencies (Corsi et al., 2002).

The phenotypic analysis of the double knockout reveals that the bone phenotype is more severe and develops earlier than in the BGN single-deficient mice (Corsi et al., 2002). At 2 months, when a decrease in bone mass is barely detectable in the BGN-deficient animal, cortical and trabecular bone mass are severely reduced in the double knockout compared to the wild type. Thus the effects of the BGN and DCN double deficiency are synergistic in bone even if bone is not affected by the DCN deficiency. Despite their distinct functions (demonstrated by the distinct phenotypes developed by the BGN and DCN single-deficient mice), BGN and DCN are therefore still sufficiently similar to partly rescue or compensate their absence in the singly deficient mice. In addition to the bone phenotype, the double knockout displays skin fragility reminiscent of the skin phenotype observed in the DCN-deficient mice.

Not surprisingly, the ultrastructure of the collagen fibrils in absence of BGN and DCN is altered (Table II) (Corsi et al., 2002). The most dramatic changes are observed in bone. In single-deficient animals, the collagen fibrils conserve a roughly circular cross-section despite the presence of protuberances and notches. In double-deficient animals, the circular aspect of the cross-sections is completely lost and replaced by a hieroglyphic-like morphology due to highly interconnected fibrils displaying a wide variety of shapes.

Altogether, the BGN/DCN double-knockout phenotype is reminiscent of a specific subtype of human EDSs, the progeroid variant (OMIM 130070) (Corsi et al., 2002). Fibroblasts from this variant have a defective xylosylprotein 4-β-galactosyltransferase I, an enzyme necessary for the synthesis of glycosaminoglycan chains (Quentin et al., 1990). The fact that the absence of BGN and DCN in the mouse mimics a human syndrome in which glycosaminoglycan-free DCN and BGN are produced underlies the potential functional importance of the glycosaminoglycan chains in BGN and DCN.

FM/LUM double knockout

FM and LUM double-deficient mice were generated to define more precisely the role of these two Class II SLRPs in the regulation of collagen fibrillogenesis in (flexor) tendon development (Ezura et al., 2000). Both SLRPs compete for the same binding sites on the collagen fibrils with FM having the higher affinity (Svensson et al., 2000). The collagen defects observed in the FM and LUM single- and double-deficient mice were compared to each other at different key developmental steps (initial fibril assembly, fibril growth initiation, maturation), while in parallel the temporal expression of FM and LUM in wild-type tendons was determined (Pellegata et al., 2000).

Collagen defects similar to those reported herein are observed during the flexor tendon development of these three SLRP knockouts. In the absence of LUM, the collagen defects are observed early but tend to disappear with time. In the absence of FM, defects similar to those observed in the absence of LUM are observed early but become more severe with time. In the double-deficient mice, the phenotype is more severe than the single-deficient phenotypes early but comparable with the FM single-deficient mice at maturation. It appears that LUM and FM both influence the initial assembly of the fibril, whereas FM, in addition, influences the fibril growth and its maturation. During the wild-type flexor tendon development, the amounts of LUM and FM peak early before decreasing significantly, with LUM being down-regulated before FM. These temporal expression profiles of LUM and FM fit the temporal evolution of the collagen defects observed in the FM and LUM single- and double-deficient mice. These results demonstrate that FM and LUM act at different developmental/maturation stages and have distinct functions in the regulation of collagen fibrillogenesis.

BGN/FM double knockout

BGN and FM are coexpressed in tendons, cartilage, and bone. BGN/FM double knockouts were generated to study potential in vivo interactions between Class I and II SLRPs. The double-deficient mice develop sequentially and progressively gait impairment, ectopic tendon ossification, and severe premature osteoarthritis (Ameye et al., 2002a). In several instances, compared to the effects of the single deficiencies, the effects of the double deficiency are synergistic, indicating the existence of rescuing/compensatory mechanisms in single mutants and the presence of redundant functions between BGN and FM (Ameye et al., 2002a).

The phenotype probably results primarily from collagen defects in tendons. In addition to displaying abnormal collagen fibrils, the BGN/FM-deficient tendons have a higher plasticity than their wild-type counterparts, judged by biomechanical testing (Ameye et al., 2002a). The reduced stiffness in tendon is thought to destabilize the knee joint and allow abnormal impact during joint movement, leading eventually to cartilage erosion. In parallel, joint instability is thought (but not proven) to create abnormal mechanical tensions within tendons that trigger their ossification. Supporting this hypothesis, increased use of the joints, induced by treadmill running, amplifies both tendon ossification and osteoarthritis in the double-deficient mice (Ameye et al., 2002a). Considering the fact that TGF-β is implicated both in ossification and cartilage metabolism, and that it binds to BGN and FM, it is additionally tempting to speculate that abnormalities in TGF-β distribution and function in the BGN/FM knockout contribute to the ectopic ossification and cartilage destruction. The BGN/FM double knockout constitutes a valuable animal model for spontaneous osteoarthritis, characterized by an early onset and a rapid progression of the disease.

Conclusion and future directions

The major advance brought by the generation of SLRP-deficient mice in our understanding of SLRP function in vivo is the crucial role played by SLRPs in the control of collagen fibrillogenesis. All four tested SLRP deficiencies lead to defects in collagen type I fibrils and most of the diseases developed by the deficient mice appear to result from these collagen defects. Although the collagen phenotypes developed by the different single-deficient SLRP mice are distinct, implying distinct in vivo function for each SLRP, the existence of rescuing/compensation mechanisms in the double-deficient mice indicates some functional overlap within the SLRP family. Taken together, the diverse collagen phenotypes demonstrate a cooperative, sequential, timely orchestrated action of the SLRPs that altogether shape the architecture and mechanical properties of the collagen matrix.

SLRP-deficient mice develop a wide array of diseases that include osteoporosis, osteoarthritis, muscular dystrophy, EDS, and corneal diseases. Not unexpectedly, the disease(s) developed by the different SLRP-deficient mice reflects the major physiological site(s) of expression of the targeted SLRP(s). The diseases developed by these new animal models indicates that mutations in SLRPs may be part of yet undiagnosed predisposing genetic factors for these diseases.

The SLRP family is rapidly growing, constantly creating new possibilities for future investigations. Recently, mutations in two SLRPs have been shown to be responsible for two human ocular disorders. Mutations in nyctalopin result in congenital stationary night blindness, a retinal disorder characterized by abnormal night vision (Bech-Hansen et al., 2000; Pusch et al., 2000), whereas mutations in keratocan result in cornea plana, a corneal disorder characterized by a flattened forward convex curvature of the cornea and a decreased refraction (Pellegata et al., 2000). Generation of nyctalopin and keratocan “knock-in” mouse models harboring one of these mutations will constitute valuable tools to unravel the molecular pathways underlying these diseases. Other obvious future research directions include the generation of knock-in mice harboring mutations leading to the synthesis of nonproteoglycan forms of SLRP to investigate the functional role played by the glycosaminoglycan chains or the generation of SLRP/TGF-β double genetically modified mice to study the in vivo interrelationships between SLRPs and TGF-βs. Finally, the phenotypic characterization of the available deficient mice is only partially completed. Further analysis will probably bring new exciting insights into their in vivo functions.

Abbreviations

BGN, biglycan; BMSCs, bone marrow stroma cells; DCN, decorin; EDS, Ehlers-Danlos syndrome; FM, fibromodulin; LRR, leucine rich repeat; LUM, lumican; SLRP, small leucine rich proteoglycan; TGF, transforming growth factor.

Fig. 1. Biglycan (A) and fibromodulin (B) structure. DS/CS: dermatan/chondroitin sulfate chains, pre: prepeptide, pre-pro: pre-propeptide.

Fig. 2. Modeling of DCN structure based on the crystal structure of the porcine ribonuclease inhibitor. Included with permission of the American Society for Biochemistry and Molecular Biology, Inc., from I.T. Weber, R.W. Harrison, and R.V. Iozzo, 1996, “Model Structure of Decorin and Implications for Collagen Fibrillogenesis,” Journal of Biological Chemistry, vol. 271, 31767–31770. DCN (in white) is predicted bind to collagen (shown in green) within the groove of the predicted horseshoe-shaped structure.

Table I.

Small leucine-rich proteoglycan classification

Classes of SLRPs were developed based on gene structure and DNA and protein homology. The first column lists different classes of SLRPs. The second column shows the members of the SLRP family belonging to each class. The third column lists the number of exons in the gene, the number of LLRs in the protein in each class, and the sequence of the amino terminal cysteine cluster (where C represents a cysteine and X any amino acid).

Table I.

Small leucine-rich proteoglycan classification

Classes of SLRPs were developed based on gene structure and DNA and protein homology. The first column lists different classes of SLRPs. The second column shows the members of the SLRP family belonging to each class. The third column lists the number of exons in the gene, the number of LLRs in the protein in each class, and the sequence of the amino terminal cysteine cluster (where C represents a cysteine and X any amino acid).

Table II.

Comparisons of the mean diameters and diameter ranges of collagen type I fibrils between wild-type and SLRP-deficient tissues

Alterations in mean diameter and diameter range of collagen type I fibrils in absence of biglycan (BGN), decorin (DCN), fibromodulin (FM), and lumican (LUM). Comparisons were made between the various knockout mice to their wild-type littermates (BGN-deficient/wild type, for example). The first column lists the genotypes of the mice used for the ultrastructural analysis. Tissue source used for the analysis is listed in the second column, and the diameter for the two genotypes being compared is shown in the third column. The range in diameter size for a specific genotype and tissue is shown in the fourth column and the number of samples tested (N) shown in the fifth column. The age of the mice that the tissue was taken from is shown in the sixth column. The original citation used to assemble the data is found in the last column. NA= not available.

Table II.

Comparisons of the mean diameters and diameter ranges of collagen type I fibrils between wild-type and SLRP-deficient tissues

Alterations in mean diameter and diameter range of collagen type I fibrils in absence of biglycan (BGN), decorin (DCN), fibromodulin (FM), and lumican (LUM). Comparisons were made between the various knockout mice to their wild-type littermates (BGN-deficient/wild type, for example). The first column lists the genotypes of the mice used for the ultrastructural analysis. Tissue source used for the analysis is listed in the second column, and the diameter for the two genotypes being compared is shown in the third column. The range in diameter size for a specific genotype and tissue is shown in the fourth column and the number of samples tested (N) shown in the fifth column. The age of the mice that the tissue was taken from is shown in the sixth column. The original citation used to assemble the data is found in the last column. NA= not available.

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