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Tibial Dyschondroplasia 40 Years Later

R. M. Leach, Jr.^*,1 and E. Monsonego-Ornan

^* The Pennsylvania State University, University Park, 16802; and Institute of Biochemistry and Nutrition, The Hebrew University, Rehovot 76100, Israel

¹ Corresponding author: lnr{at}psu.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION REFERENCES

 
Tibial dyschondroplasia is a disease of rapid growth rate that occurs in many avian species. It is characterized by an avascular lesion in which the life span of the growth plate chondrocyte is essentially doubled. A characteristic pattern of gene expression and gene product localization has emerged that mimics the pattern observed with endoplasmic reticulum (ER) stress in growth plate chondrocytes. This activates a cell-survival mechanism called autophagy. The initial phases of this mechanism appear to originate in the avascular transition zone of the growth plate. Because specific genes and gene products are associated with autophagy and ER stress, it should now be possible to identify the mechanisms involved in the development of this cartilage abnormality. The potential biochemical pathways responsible for initiating ER stress are discussed.

Key Words: tibial dyschondroplasia • gene expression • endoplasmic reticulum stress • autophagy

	INTRODUCTION

TOP ABSTRACT INTRODUCTION REFERENCES

 
We have just passed the 40th anniversary of the initial description of avian dyschondroplasia. This skeletal abnormality has intrigued a wide variety of scientists: poultry scientists, skeletal biologists, and pathologists. The techniques used to study this skeletal disease reflect the scientific advances in our knowledge of and approaches to skeletal biology. Whereas early studies relied on descriptive techniques, contemporary approaches use genomics in an attempt to understand the metabolic defect responsible for the development of this cartilage lesion.

This review is an attempt to summarize the status of our current knowledge on the development of this skeletal abnormality. It represents an update on information provided in previous reviews by Leach and Lilburn (1992), Orth and Cook (1994), Farquharson and Jefferies (2000), and Praul et al. (2000).

Etiology
The lesion occurs spontaneously in many rapidly growing avian species. Because of the wide variation in incidence, a number of strategies have been used to stabilize its occurrence for experimental studies. These include establishment of genetic lines with high or low incidence, and induction of the lesion with copper-deficient diets, dietary dithiocarbamates, perturbed Ca:P ratios, Fusarium mycotoxins, and excess sulfur amino acids such as homocysteine.

The Lesion
The lesion is characterized by a mass of avascular cartilage in the metaphysis of the proximal ends of the tibiotarsus and tarsalmetatarsis. Histologically, the tissue can easily be distinguished from normal cartilage tissue when stained with Alcian blue/periodic acid-Schiff reagent (Leach and Nesheim, 1965). Although chondrocytes appear homogeneous under these staining conditions, heterogeneity is observed with other staining procedures (Hargest et al., 1985).

At the ultrastructural level, chondrocytes undergo specific morphological changes. Although some cells observed in the proximal and mid regions were apoptotic, necrotic rather than apoptotic chondrocytes were observed in severe lesions (Hargest et al., 1985). Similar results were reported by Ling et al. (1995) and Haynes and Walser (1986), who observed intracellular lipid accumulation and necrotic cells. Symptoms of energy depletion appear to be a common theme in these ultrastructural studies.

Mammalian Skeletal Dysplasias (Tibial Dyschondroplasia-like)
There are several mammalian skeletal diseases with lesions similar to tibial dyschondroplasia (TD). Schmid metaphyseal chondrodysplasia is an inherited condition in humans that is caused by a mutation in collagen X, a hypertrophic chondrocyte specific collagen (Chan and Jacenko, 1998). A similar mutation has been described in pigs (Nielsen et al., 2000).

Jansen’s metaphyseal chondrodysplasia in humans is a skeletal deformity characterized by delayed endochondral maturation. This condition has been traced to a mutation in the parathyroid hormone (PTH)/parathyroid hormone-related peptide (PTHrP) receptor (Schipani et al., 1995). The mutation in a single nucleotide results in a constitutively active receptor. Targeted overexpression of PTHrP in mice chondrocytes also results in a similar chondrodysplasia (Weir et al., 1996).

Studies with transgenic mice have also identified other genes that are important in cartilage vascularization. For example, disrupting several components of the vascular endothelial growth factor signaling system results in an avascular TD-like lesion (Gerber et al., 1999). Ablation of metalloproteinase (MMP)-9 or MMP-13 results in an avascular lesion in young mice (Vu et al., 1998; Inada et al., 2004; Stickens et al., 2004). Stickens et al. (2004) found a more extreme phenotype in mice lacking both MMP-9 and MMP-13, which resembled TD lesions and was characterized by diminished extracellular matrix (ECM) remodeling and delayed vascular recruitment.

Finally, osteochondrosis is a focal disorder of endochondral ossification that occurs in swine and horses (Carlson et al., 1995). This condition shares many features with TD. In fact, several investigators (Poulos, 1978; Thorp et al., 1993) have used the term "osteochondrosis/ dyschondroplasia." Knight et al. (1990) reported that copper supplementation reduces the prevalence and severity of osteochondrosis in young foals.

Normal Growth Plate Biology
Morphologically, the growth plate can be divided into 3 major zones: proliferating, prehypertrophic, and hypertrophic (Howlett, 1979). The mineralized hypertrophic cartilage is vascularized by metaphyseal blood vessels and replaced by trabacular bone (Figure 1). This process is completed every 48 h (Gay and Leach, 1985).

View larger version (27K): [in this window] [in a new window]   Figure 1. Diagram of the proximal end of the tibia from a normal chicken and a chicken with tibial dyschondroplasia (TD). Note the differences in penetration of the metaphyseal blood vessels. Shading depicts differences in expression genes associated with chondrocyte hypertrophy, such as type X collagen, osteopontin, and bone sialoprotein. Abbreviations: AC = articular cartilage; PZ = proliferative zone; TZ = transition zone; PHZ = prehypertrophic zone; HZ = hypertrophic zone; BV = metaphyseal blood vessels; TB = trabacular bone; RE = resorbing edge.

Control of Growth Plate Metabolism
Van Der Eerden and Wit (2003) have provided an excellent overall view of the systemic and local factors controlling the growth plate. The major systemic control occurs via growth hormone (GH) and insulin-like growth factors (IGF). Since the original somatamedin hypothesis of Salmon and Daughaday (1957), a number of variations in the hypothesis have been proposed. Instead of GH influencing growth plate physiology exclusively by stimulating the production of IGF by the liver, it is clear that GH can act directly on growth plate chondrocytes. Furthermore, the growth plate tissue is also capable of synthesizing both IGF I and IGF II.

Less is known about the relative importance of GH and the IGF signaling system in the avian growth plate. Chondrocytes have been shown to express the GH receptor (Monsonego et al., 1993, 1997) as well as genes for IGF I, IGF II, and IGF receptor and binding proteins (Leach et al., 2006). Research with cultured growth plate chondrocytes favors a role for IGF in chondrocyte hypertrophy (Rosselot et al., 1994).

The Indian hedgehog (Ihh)/PTHrP pathway is the key regulatory system controlling chondrocyte differentiation (Kronenberg, 2003). Expression of the genes for these peptide growth factors and their receptors has been shown to be localized in the transition and early hypertrophic zones of the growth plate (Lanske et al., 1996; Vortkamp et al., 1996; Ben-Bassat et al., 1999; Webster et al., 2003).

Van Der Eerden and Wit (2003) also pointed out that several other growth factors are involved in local regulation of growth plate metabolism. These include fibroblast growth factors; the transforming growth factor family, which includes bone morphogenic proteins; and vascular endothelial growth factor. All of these signaling systems have been shown to be present in the avian growth plate (Thorp et al., 1995; Law et al., 1996; Luan et al., 1996; Twal et al., 1996; Ren et al., 1997; Grimsrud et al., 1998; Praul et al., 2002).

Gene Expression in the TD Lesion: An Emerging Pattern
Several of the early investigations focused on type X collagen for several reasons. First, TD resembles metaphyseal dysplasia, a disease in humans caused by a mutation in this collagen gene. Secondly, type X collagen is a marker for chondrocyte hypertrophy and is initially expressed in the prehypertrophic zone, where the TD lesion appears to initiate.

Chen et al. (1993) used in situ hybridization to study type X collagen expression in normal and TD growth plate tissue (see Figure 1). Expression was observed in the proximal and distal edges of the lesion, with no positive activity in the center of the lesion. Since that time, similar results have been reported for other matrix proteins such as osteopontin (Knopov et al., 1995) and bone sialoprotein (Pines et al., 1998). Immunostaining for osteonectin and fibroblast growth factor has shown a similar pattern (Twal et al., 1996; Wu et al., 1996). Two laboratories (Praul et al., 1997; Rath et al., 1998) have reported staining for apoptosis in TD lesions, whereas Ohyama et al. (1997) reported opposite results.

This results in an enigma: how can the cells in the center of the lesion be "dead," yet appear to be perfectly normal at the resorbing edge of the lesion? It would appear that the majority of chondrocytes in the lesion have used some type of survival technique. Autophagy (self-eating) is a prosurvival mechanism with specific biochemical and morphological changes (Levine and Yuan, 2005; Yorimitsu and Klionsky, 2007). Autophagy provides a protective mechanism for cell survival in stressful conditions such as nutrient or growth factor depletion and hypoxia. In normal growth plate physiology, the process could be performing a cytoprotective role in protecting chondrocytes from premature apoptosis under conditions of low oxygen tension (Srinivas and Shapiro, 2006).

There are several possible roles for autophagy in relation to the development of the TD lesion. The process could be up-regulated in response to the hypoxia associated with the expansion of the avascular transition zone. The second possibility relates to the role of autophagy in the cell-repair mechanism by removing damaged proteins or misfolded proteins. This accounts for the reports that autophagy plays an important role in cell survival after endoplasmic reticulum (ER) stress (Ogata et al., 2006; Yorimitsu and Klionsky, 2007).

Tsang et al. (2007) studied the in vivo impact of ER stress in terminally differentiating hypertrophic murine chondrocytes by expressing a misfolded mutant collagen X, which accumulated in the chondrocytes. Histological and gene expression analyses showed that these chondrocytes survived ER stress but that terminal differentiation was interrupted and endochondral bone formation was delayed, producing a chondrodysplasia phenotype. This altered differentiation involved cell-cycle reentry, the re-expression of genes characteristic of a prehypertrophic-like state. The following findings with TD lesions closely resemble these observations:

• intracellular retention of ECM proteins (Chen et al., 1993; Tselepis et al., 1996);
  
• retention of a specific form of collagen II (Chen et al., 1993);
  
• retention of proliferating cell nuclear antigen (Pines et al., 1998) with no bromodeoxyuridine staining (Farquharson et al., 1992);
  
• normal expression pattern of the PTH receptor (Ben-Bassat et al., 1999);
  
• reexpression of collagen II (Chen et al., 1993);
  
• diffuse expression of Ihh in the hypertrophic zone (Webster et al., 2003); and
  
• delay in endochondral bone formation (Gay and Leach, 1985).
  

Thus, these observations support the conclusion that the pattern of gene expression and gene products observed with the TD lesion can be viewed as a survival mechanism in response to stress, which targets chondrocytes in the vicinity of the distal proliferative and transition zones. It should be noted that the pattern of gene expression has been observed with chicks from genetic lines (Chen et al., 1993; Pines et al., 1998), Ca:P imbalanced diets (Tselepis et al., 1996; Webster et al., 2003), and thiram induction (Knopov et al., 1995).

Can We Connect the Dots?
What is the connection between autophagy-ER stress and rapid growth rate, dithiocarbamates, copper, Ca:P ratio, and vitamin D? In TD, chondrocytes distal to the transitional zone initiate collagen X (marker of hypertrophy) synthesis but fail to export this protein to the ECM (Chen et al., 1993). Is this due to increased hypoxia as a consequence of the failure of metaphyseal blood vessel penetration, which could trigger the ER stress response aspect of autophagy? Dithiocarbamates such as thiram and disulfiram, as well as homocysteine, could exacerbate the hypoxia through interference with copper enzymes and other aspects of cellular oxidative metabolism. This could compromise chondrocyte energy metabolism and the ability of the ER to secrete ECM proteins.

The key system regulating the progression of chondrocyte hypertrophy is the Ihh/PHTrP signaling system, which is localized at the site of origin of the TD lesion. The expression of all these genes is localized in the transition zone and prehypertrophic zone of the normal avian growth plate (Vortkamp et al., 1996; Ben-Bassat et al., 1999; Webster et al., 2003). In the TD lesion, expression of the PTH receptor is normal (Ben-Bassat et al., 1999), whereas expression of Ihh is found throughout the TD lesion (Webster et al., 2003). Expression of PTHrP is not observed in the TD lesion (Webster et al., 2003), suggesting an imbalance in the Ihh/PTHrP signaling system. However, Farquharson et al. (2001), using different methodology, found both the PTHrP gene and peptide to be present in chondrocytes isolated from TD lesions. They concluded that PTHrP distribution was not responsible for the changes in chondrocyte differentiation associated with the TD lesion.

Systemic PTH can also activate the chondrocyte PTH receptor in conditions of hyperparathyroidism. In fact, this likely contributes to the pathology associated with calcium or vitamin D deficiency. We previously hypothesized (Praul et al., 2000) that the Ca:P imbalanced diets used to induce TD could be doing so through the induction of mild hyperparathyroidism. The elevated level of PTH could directly inhibit chondrocyte hypertrophy through the PTH receptor, which is present in the transition zone of the growth plate. Unfortunately, data obtained from an experiment to test this hypothesis were equivocal (Praul et al., 2000).

The Vitamin D Connection
Several laboratories have reported that treatment with 1,25-diOH D₃ will "cure" TD (Edwards, 1990; Rennie et al., 1995). In many cases, the term "cured" is used for a reduction in incidence or severity. Furthermore, this response occurs on diets adequate in vitamin D₃. In a later report, Whitehead et al. (2004) used pharmacological doses of vitamin D₃ to reduce or eliminate TD. Most, if not all, studies with vitamin D use the Ca:P imbalanced diet as a method of inducing TD. These results have several possible interpretations.

It is well established that vitamin D can inhibit the synthesis and release of PTH by the parathyroid gland, thus relieving mild hyperparathyroidism. This may occur even under conditions of normal calcemia. Feeding rats 3 times the normal amount of vitamin D₃ increased serum 25-OH D₃ and lowered serum 1,25-diOH D₃ and PTH. Serum calcium, phosphorous, alkaline phosphase, and weight gain were normal (Vieth et al., 2000).

An alternate hypothesis states that 1,25-diOH D₃ is needed for normal chondrocyte metabolism (Boyan et al., 1999). Additional support for this concept comes from research with transgenic mice (Goltzman, 2007). Although hypocalcemia is the major factor in the development of the rachitic lesion, evidence was provided that the vitamin D metabolite (1,25-diOH) also has a role in chondrocyte metabolism. Other evidence for a vitamin D connection comes from the laboratory of Soares (Xu and Soares, 1997; Xu et al., 1997, 1998). These investigators reported that TD chondrocytes were more resistant to the action of vitamin D₃ and had lower expression levels of calbindin. This observation is consistent with the report that lesion chondrocytes have a lower vitamin D receptor number and reduced affinity (Berry et al., 1996).

Recently, Rath et al. (2007) attempted to determine whether thiram induced TD through an interaction with vitamin D. The results showed that vitamin D had no activity in modulating the occurrence of TD induced by thiram. This suggests that the dithiocarbamates and vitamin D are operating through independent pathways, another challenge to connecting the dots.

Synopsis
It is clear that the pathological changes associated with TD closely mimic those reported by Tsang et al. (2007) for ER stress and autophagy. In dealing with the question of what could trigger ER stress, there are 2 important points to remember. First, TD is a disease of rapid growth rate. Second, the epiphyseal growth plate, the tissue responsible for longitudinal bone growth, undergoes a series of intricate biochemical and physiological steps in a short time (48 h). The avascular transition zone would appear to be the critical area for the development of these changes. How genetic selection for resistance or susceptibility, dithiocarbamates, and the Ca:P-vitamin D axis converge to create this cartilage abnormality remains the challenge for future research. Because specific genes are associated with autophagy and ER stress, we have the potential tools to answer this final question.

	ACKNOWLEDGMENTS

 
The authors were supported by BARD Research Grant Award IS-3403-03R. We also wish to acknowledge the assistance of Patti Burns and Linda Houtz for manuscript preparation and Donna Sosnoski for preparation of the figure.

Received for publication June 21, 2007. Accepted for publication June 21, 2007.

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