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JMD 2000, Vol. 2, No. 2
Copyright © 2000 American Society for Investigative Pathology & Association for Molecular Pathology

A Comparative Study of Fibrous Dysplasia and Osteofibrous Dysplasia with Regard to GS{alpha} Mutation at the Arg201 Codon

Polymerase Chain Reaction-Restriction Fragment Length Polymorphism Analysis of Paraffin-Embedded Tissues

Akio Sakamoto*, Yoshinao Oda*, Yukihide Iwamoto{dagger} and Masazumi Tsuneyoshi*

From the Department of Anatomic Pathology, * Pathological Sciences, and the Department of Orthopaedic Surgery, {dagger} Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Fibrous dysplasia and osteofibrous dysplasia are both benign fibro-osseous lesions of the bone and are generally seen during childhood or adolescence. Histologically, the features of these bone lesions sometimes look quite similar, but their precise nature remains controversial. Mutation of the {alpha} subunit of signal-transducing G proteins (GS{alpha}), with an increase in cyclic adenosine monophosphate (cAMP) formation, has been implicated in the development of multiple endocrinopathies of the Albright-McCune syndrome and in the development of fibrous dysplasia. We studied GS{alpha} mutation at the Arg201 codon in seven cases of fibrous dysplasia (six monostotic lesions and one polyostotic lesion) and seven cases of osteofibrous dysplasia using formalin-fixed, paraffin-embedded tissue, by means of polymerase chain reaction-restriction fragment length polymorphism and direct sequencing analysis. All of the seven cases of fibrous dysplasia showed missense point mutations in GS{alpha} at the Arg201 codon that resulted in Arg-to-His substitution in three cases and Arg-to-Cys substitution in four cases. On the other hand, the seven cases of osteofibrous dysplasia and the normal bone used as a control showed no such mutation. These data suggest that fibrous dysplasia and osteofibrous dysplasia have different pathogeneses and that the detection of GS{alpha} mutation at the Arg201 codon is quite useful for distinguishing between these lesions.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Fibrous dysplasia is a benign intramedullary fibro-osseous lesion that can occur in any bone. Lichtenstein and Jaffe gave it the name "fibrous dysplasia" in two classic publications in 1938 and 1942.1, 2 Three forms of fibrous dysplasia are distinguishable: a monostotic form, a polyostotic form, and a polyostotic form associated with endocrinopathies and skin pigmentation, also known as the Albright-McCune syndrome.3, 4 Histologically, fibrous dysplasia is composed of slender and curved trabeculae of bone and a cellular proliferation of fibroblast-like cells, which are characteristically associated with long bones. Moreover, some cases of fibrous dysplasia also show sclerotic patterns, particularly in craniofacial bones.5

Mutation of the {alpha} subunit of signal-transducing G proteins (GS{alpha}) at the Arg201 codon stimulating cyclic adenosine monophosphate (cAMP) formation has been identified in various tissues in the Albright-McCune syndrome6, 7 and is also thought to underlie the development of fibrous dysplasia associated with a cellular retraction and deposition of abnormal bone matrix led by increased cAMP formation.5, 8, 9, 10, 11

Osteofibrous dysplasia of long bone is a rare fibro-osseous lesion of unknown pathogenesis described as a distinct entity by Campanacci in 1976.12 Osteofibrous dysplasia is an intracortical lesion which occurs almost exclusively in the tibia or fibula of children younger than 10 years of age and often presents as a painless enlargement of the tibia with anterior or anterolateral bowing. Histologically, osteofibrous dysplasia is characterized by woven bone trabeculae with a rimming of osteoblasts and a cellular proliferation of fibroblast-like cells, and has long been thought to be related to adamantinoma of long bones.13, 14, 15

Fibrous dysplasia sometimes resembles osteofibrous dysplasia histologically. Osteofibrous dysplasia has been considered to be a congenital lesion or a variant of fibrous dysplasia.16 However, the precise nature of fibrous dysplasia and osteofibrous dysplasia remains controversial. Though GS{alpha} mutation in cases of fibrous dysplasia has been extensively studied, such mutation in osteofibrous dysplasia has not been fully evaluated.

In this study, we investigated the occurrence of GS{alpha} mutation at the Arg201 codon in both fibrous and osteofibrous dysplasia with a view to verifying whether the presence or absence of this mutation can help to distinguish between these two lesions.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Specimens
From the histopathology files at our institute, formalin-fixed, paraffin-embedded tissue blocks of seven cases of fibrous dysplasia and seven cases of osteofibrous dysplasia, which had been decalcified in hydrochloric acid for a maximum of 3 days, were used for this study. The seven cases of fibrous dysplasia comprised six monostotic lesions and one polyostotic lesion. None of the patients with fibrous dysplasia exhibited Albright-McCune syndrome. One mature bone specimen obtained from a donor with neither fibrous dysplasia nor osteofibrous dysplasia was used for a comparative control.

Formalin-Fixed, Paraffin-Embedded Tissue DNA Extraction
DNA was extracted from a 30-µm paraffin-embedded tissue section as follows. Paraffin was removed with xylene, and then the sample was washed twice with 100% ethanol and subsequently dried. The tissue was suspended in digestion buffer (100 mmol/L sodium chloride, 10 mmol/L Tris-hydrochloric acid, 25 mmol/L ethylenediaminetetraacetic acid, 0.5% sodium dodecyl sulfate) containing 10 µg proteinase K and incubated overnight at 55°C. DNA, precipitated by adding twice the volume of ethanol, was washed with 70% ethanol before being resuspended in TE buffer (10 mmol/L Tris, 1 nmol/L ethylenediaminetetraacetic acid) for storage at 4°C.

Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP)
We used the PCR-RFLP procedure to detect GS{alpha} mutations at the Arg201 codon (CGT) with strategy primers as reported.17 TableGo 1summarizes the primers used in this study. DNA sequences containing codon 201 of the GS{alpha} gene were amplified using the primers P1 and P2 for 30 cycles (95°C for 60 seconds, 55°C for 60 seconds, and 75°C for 60 seconds). Then 1 µl of the amplified products, which had been diluted 50 times, was amplified by means of nested PCR using the mutant primer P3 and the primer P2 for 20 cycles (94°C for 30 seconds, 55°C for 30 seconds, and 72°C for 30 seconds), since the primer P3 creates a new restriction site for EagI (CGGCCG) through the change to G in the first position of codon 200 in the normal allele, thus enabling the detection of a mutation at the first and the second positions of the Arg201 codon. Substitutions for arginine will not occur even if a point mutation occurs in the third position of codon 201, so this method can be used to detect all of the substitutions for arginine by other amino acids due to a point mutation. EagI digests the 102-bp amplified fragment into two fragments of 79 and 23 bp, thereby revealing the presence of the normal allele, while the mutant allele remains within the undigested 102-bp fragment. Fragments (134 bp) of p53 gene exon 8 were amplified for 40 cycles (95°C for 1 minute, 66°C for 1 minute, and 72°C for 2 minutes) as a positive control to test for the suitability of the respective material for PCR amplification. The DNA bands were analyzed by 3% agarose gel electrophoresis, stained with ethidium bromide, and then photographed.


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  		Table 1. Oligonucleotide Primers Used for PCR Amplification of Gs{alpha} Gene

 
Direct Sequencing
After samples of the digested products were obtained from agarose gels and reamplified by primers P3 and P4 for 20 cycles (95°C for 30 seconds and 55°C for 30 seconds), the amplified product was purified by centrifugal filter devices of Microcon (Millipore, Bedford, MA). After purification, direct sequencing was carried out by the dideoxy chain termination method using a Perkin Elmer ABI Prism 310 sequence analyzer (Perkin Elmer, Foster City, CA). The primer used for direct sequencing was the antisense primer P4. Because codon 201 is located next to the 3' end of the sense primer P3, it was not technically feasible to carry out direct sequencing with the sense primer P3 using the dideoxy chain termination method.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
TableGo 2summarizes the data. The GS{alpha} point mutations at the Arg201 codon occurred in all seven cases of fibrous dysplasia, comprising four cases of G-to-A transition in the first position and three cases of C-to-T transition in the second position at codon 201, corresponding to the previously reported Arg-to-Cys and Arg-to-His substitutions respectively. On the other hand, all seven cases of osteofibrous dysplasia as well as the normal bone used as a control showed no mutation in the GS{alpha} gene at the Arg201 codon (Figures 1Go and 2Go ).



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  		Figure 1. Analysis of GS{alpha} mutations at the Arg201 codon using RFLP. EagI digested the amplified DNA fragments (102 bp) including codon 201 of the GS{alpha} gene into 79-bp and 23-bp fragments in normal bones (lanes 1 and 2) and osteofibrous dysplasia (lanes 11–17). The 23-bp band was not visible in this gel, whereas mutant cases of fibrous dysplasia remained undigested (lanes 3–9). The p53 gene exon 8 segments were amplified in each case. The 134-bp segments are shown for each case. PCR using only primers was used as a negative control (lane 10). The 100-bp ladder was used as a size marker.

 


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  		Figure 2. Direct sequencing by the antisense primer P4 was performed on the fibrous dysplasia sample in lane 5 (Case FD99; 65-year-old female, ilium). The figure shows the GS{alpha} gene antisense sequence and indicates that the second position of codon 201 of the antisense strand was mutated from C to T, this change being the code for histidine instead of arginine (right). In normal bone, sequence analysis was performed after reamplified PCR without subsequent endonuclease digestion. The result was that arginine was encoded, and no mutation was seen (left).

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Clinically, fibrous dysplasia differs from osteofibrous dysplasia with regard to the affected site, affected age group, radiographic appearance and clinical course (Figures 3Go and 4Go ).15, 18, 19 These findings indicate that fibrous dysplasia differs in nature from osteofibrous dysplasia. However, because their histological features are often similar,18 the question of whether osteofibrous dysplasia is actually a separate entity or simply a variant of fibrous dysplasia (Figures 5Go and 6Go ) remains controversial.16



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  		Figure 3. Fibrous dysplasia (12-year-old female, radius). Anteroposterior radiograph reveals a well-circumscribed intramedullary lesion within the proximal radius with a so-called "ground glass" appearance (white arrows).

 


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  		Figure 4. Osteofibrous dysplasia (14-year-old female, tibia). Lateral radiograph reveals an osteolytic intracortical lesion in the tibial shaft with marginal sclerosis (white arrows). In this case, an intramedullary lesion that appears to be a bone infarct can be also observed.

 


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  		Figure 5. Fibrous dysplasia (15-year-old male, femur). Slender curved trabeculae of bone and cellular proliferation of fibroblast-like cells can be observed (A). Note the bone trabeculae have no osteoblastic rimming (B). H&E; original magnifications, x100 (A) and x140 (B).

 


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  		Figure 6. Osteofibrous dysplasia (13-year-old female, tibia). Microscopic features are characterized by woven bone trabeculae with rimming of osteoblasts and a cellular proliferation of fibroblast-like cells. H&E; original magnification, x140.

 
In the present study, we used PCR-RFLP and direct sequencing analysis to detect the occurrence of GS{alpha} mutations at the Arg201 codon in fibrous dysplasias and osteofibrous dysplasias using formalin-fixed, paraffin-embedded decalcified tissue. A variety of techniques has been developed for detecting GS{alpha} mutations. This method of PCR-RFLP analysis can detect GS{alpha} mutations at the Arg201 codon without using any radioactive material, even when the mutations are present in low abundance.17

In addition to the substitution of either Cys or His at Arg,2015, 11 the substitution of Ser has also been detected.17 These somatic mutations in the GS{alpha} gene lead to constitutively activated adenylate cyclase activity,20 elevated cAMP levels, and increased proliferation of hormonally responsive osteoblastic cells, resulting in the overproduction of a disorganized collagenous matrix.5, 8, 9, 10, 11 Thus, both polyostotic and monostotic fibrous dysplasia seem to result from the abnormal proliferation of mesenchymal osteoblast progenitor cells with GS{alpha} mutation. On the other hand, the GS{alpha} mutation may stimulate osteoblastic cell proliferation of early immediate genes, including c-fos. The products of c-fos proto-oncogene have been associated with the control of bone cell proliferation and differentiation.21 The increased production of cAMP in bone cells with GS{alpha} mutations most likely leads to elevated c-fos expression,22 which also plays an important part in the development of fibrous dysplasia.23 There is another possible mutation site in the GS{alpha} gene at Gln227 that has been shown to result in activation. A substitution of either Leu or Arg at Gln227 has been found in certain endocrine tumors,24, 25 but has not yet been identified in association with bone. On the other hand, mutation in the GS{alpha} gene at Gln227 cannot be ruled out by the analysis that was performed in this study.

Alman et al26 demonstrated GS{alpha} mutation in all four of their cases of fibrous dysplasia but not in their one case of osteofibrous dysplasia. We were also able to detect GS{alpha} point mutations at the Arg201 codon, comprising substitutions of Arg-to-Cys or Arg-to-His as others have previously reported,5, 11 in all our seven cases of fibrous dysplasia, but not in any of our cases of osteofibrous dysplasia. We cannot deny the possibility that there were simply not enough mutant cells present to be detected by this method and that there may be a potential problem with recovery of an adequate quality of intact DNA due to decalcification in hydrochloric acid. However, our data support their conclusion that fibrous dysplasia and osteofibrous dysplasia are distinct pathological entities with a different molecular pathobiology.

Komiya et al27 surmised that abnormalities in the blood circulation within the periosteum are probably behind the pathogenesis of osteofibrous dysplasia. Pathological periosteum may stimulate the production of excessive osteoclasts. The tumorous condition of osteofibrous dysplasia can probably be attributed to dysregulation of bone remodeling, in which osteoclastosis is dominant to osteogenesis.

According to the report of Sweet et al,28 when comparing fibrous dysplasia and osteofibrous dysplasia, immunohistochemical staining of cytokeratin (AE1/AE3 + CK-1) seemed to be helpful for distinguishing between these lesions, because isolated cytokeratin-positive cells were seen in the stroma of 28 of 30 cases of osteofibrous dysplasia (93%), but not in any of the 47 cases of fibrous dysplasia (43 monostotic and 4 polyostotic cases).

Not only the clinical, pathological, and immunohistochemical differences, but also the presence or absence of GS{alpha} mutations at the Arg201 codon would seem to suggest that fibrous dysplasia is a different lesion from osteofibrous dysplasia.

We demonstrated GS{alpha} mutation in a series of fibrous dysplasia and osteofibrous dysplasia using paraffin-embedded decalcified tissue by means of PCR-RFLP analysis. GS{alpha} mutation at the Arg201 codon was seen in all of the fibrous dysplasia cases, but not in any of the osteofibrous dysplasia cases. Our data suggest that fibrous dysplasia and osteofibrous dysplasia are of a different pathogenesis. The detection of GS{alpha} mutation at the Arg201 codon would therefore seem to be quite useful for distinguishing between fibrous dysplasia and osteofibrous dysplasia when making a pathological diagnosis.


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  		Table 2. Gs{alpha} Mutations at the Arg201 Codon in Fibrous Dysplasia and Osteofibrous Dysplasia

 

   Acknowledgments
 
The English used in this manuscript was revised by Miss K. Miller of the Royal English Language Center, Fukuoka, Japan.


   Footnotes
 
Address reprint requests to Masazumi Tsuneyoshi, M.D., Department of Anatomic Pathology, Pathological Sciences, Graduate School of Medical Sciences, Kyushu University, 3–1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.

Supported by a grant-in-aid for cancer research from the Fukuoka Cancer Society, Fukuoka, Japan, and a grant-in-aid for general scientific research from the Ministry of Education, Science and Culture (09470052), Tokyo, Japan.

Accepted for publication February 18, 2000.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Lichtenstein L: Polyostotic fibrous dysplasia. Arch Surg 1938, 36:874-898
  2. Lichtenstein L, Jaffe HL: Fibrous dysplasia of a bone: condition affecting one, several or many bones, graver cases of which may present abnormal pigmentation of skin, premature sexual development, hyperthyroidism or still other extraskeletal abnormalities. Arch Pathol 1942, 33:777
  3. Arbright F, Bulter AM, Hampton AO, Smith P: Syndrome characterized by osteitis fibrosa disseminata, areas of pigmentation and endocrine dysfunction with precocious puberty in females. N Engl J Med 1937, 216:727-746
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