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Clinical Chemistry 50: 883-890, 2004. First published March 11, 2004; 10.1373/clinchem.2003.029355
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(Clinical Chemistry. 2004;50:883-890.)
© 2004 American Association for Clinical Chemistry, Inc.

Endocrinology and Metabolism

Osteoclast-Derived Serum Tartrate-Resistant Acid Phosphatase 5b in Albers-Schönberg Disease (Type II Autosomal Dominant Osteopetrosis)

Sari L. Alatalo1, Kaisa K. Ivaska1, Steven G. Waguespack2, Michael J. Econs3, H. Kalervo Väänänen1,a and Jussi M. Halleen1,4

1 Institute of Biomedicine, Department of Anatomy, University of Turku, FIN-20520 Turku, Finland.2 Department of Endocrine Neoplasia and Hormonal Disorders, University of Texas M. D. Anderson Cancer Center, Houston, TX.3 Medicine and Medical and Molecular Genetics, Indiana University, Indianapolis, IN.4 Pharmatest Services Ltd, Turku, Finland.

aAuthor for correspondence. Fax 358-2-3337352; e-mail kalervo.vaananen{at}utu.fi.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Background: Albers-Schönberg disease, or autosomal dominant osteopetrosis type II (ADO2), is caused by ineffective osteoclastic bone resorption resulting from mutations in the chloride channel 7 (ClCN7) gene. Individuals with ADO2 have increased numbers of large ineffective osteoclasts in addition to increased serum total tartrate-resistant acid phosphatase (TRACP) activity.

Methods: We investigated the serum activity of the osteoclast-derived 5b isoform of TRACP (TRACP 5b) and concentrations of the bone formation marker osteocalcin in clinically affected individuals, unaffected gene carriers, and healthy controls from 10 ADO2 families with known ClCN7 gene mutations. Bone fracture prevalence was studied in association with the serum markers.

Results: Similar to total TRACP, TRACP 5b was significantly increased in clinically affected individuals compared with age-matched controls. TRACP 5b correlated significantly with total TRACP (r = 0.833; P <0.001), suggesting that most of the TRACP in the serum of ADO2 patients is osteoclast-derived TRACP 5b. Osteocalcin was significantly increased in affected adults and slightly decreased in affected children. TRACP 5b and total TRACP were significantly increased in clinically affected individuals with severe fractures (P <0.05).

Conclusions: The results indicate that in ADO2, serum TRACP 5b reflects the number of osteoclasts and that the extremely high serum TRACP 5b activity is a specific indicator of the disease. Similar to total TRACP, TRACP 5b appears to be a potentially useful marker to stratify individuals with ClCN7 gene mutations into clinically affected and unaffected gene carriers. It may also have a prognostic value in the prediction of fractures in patients with a ClCN7 gene mutation.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Albers-Schönberg Disease, or type II autosomal dominant osteopetrosis (ADO2), 1 was described for the first time in 1904 by the German radiologist Heinrich Albers-Schönberg (1). ADO2 is the most common form of osteopetrosis with an estimated prevalence of up to 5.5 per 100 000 inhabitants (2)(3), and the disease results from ineffective osteoclast-mediated bone resorption (4)(5). ADO2 is caused by heterozygous mutations in the chloride channel 7 (ClCN7) gene, located on chromosome 16p13.3 (6)(7)(8). The diagnosis of ADO2 is usually made from radiographs, which demonstrate widespread osteosclerosis and the presence of endobones (bone-within-a-bone appearance), most commonly noted in the vertebrae (sandwich vertebrae), pelvis, and at the ends of the long bones (9). Penetrance of the ADO2 phenotype is incomplete, and up to one-third of individuals who inherit a ClCN7 gene mutation will have normal radiographs and no other clinical findings of the disease (8). Although individuals with classic ADO2 can be asymptomatic, clinical manifestations are frequent and can include cranial neuropathies, mandibular osteomyelitis, and multiple nontraumatic fractures, which occur despite the markedly increased bone density (2)(10)(11)(12).

ClCN7 provides the chloride conductance required for efficient proton pumping in the osteoclast ruffled membrane during bone resorption (4). In 2001, Cleiren et al. (7) reported seven distinctive mutations in the ClCN7 gene in ADO2 patients, of which five were missense mutations (G215R, P249L, R286W, R767W, and G765B), one was a deletion of a single amino acid ({Delta}L688), and one was a deletion of two nucleotides causing a frameshift mutation affecting the carboxyl terminus of the protein (2423delAG). In 2003, Waguespack et al. (8) reported two novel missense mutations (L213F and R762L) in the ClCN7 gene. All of the known ClCN7 mutations are located in conserved regions of the gene, in both extracellular and intracellular parts of the transmembrane protein, and it is hypothesized that these mutations cause disease through a dominant negative mechanism. Mutations in both ClCN7 alleles lead to severe recessive osteopetrosis in humans and mice (4) as well as to intermediate autosomal recessive osteopetrosis in humans (13).

A histologic evaluation of bone biopsies from ADO2 patients reveals a marked increase in the number and size of osteoclasts, which demonstrate no signs of active bone resorption (5)(14)(15). Ultrastructural examinations have shown that osteoclasts from ADO2 patients have no ruffled borders, but they do have normal clear zones and numerous lysosomal vacuoles containing dense substances (16). Individuals with ADO2 have significantly increased serum activities of total tartrate-resistant acid phosphatase (TRACP; EC 3.1.3.2) and the BB isoenzyme of creatine kinase (CK-BB) (17)(18)(19). Although both of these enzymes are closely related to osteoclasts, their exact roles have remained enigmatic in osteoclast physiology. One explanation for the increased serum activities of both TRACP and CK-BB may be the significantly increased number of osteoclasts observed in ADO2 (17). Urinary concentrations of bone resorption markers, including type I collagen C- and N-telopeptides, hydroxyproline, and free deoxypyridinoline, are all within reference values in adult ADO2 patients, and serum osteocalcin concentrations are slightly, but not significantly, increased (20).

In human blood, TRACP exists in two differently glycosylated forms: TRACP 5a and 5b. TRACP 5a is derived from inflammatory macrophages and TRACP 5b from bone-resorbing osteoclasts (21). Increased total TRACP activity in serum (the combined activity of TRACP 5a and 5b) has been observed in ADO2 patients, but nothing is known about the isoform distribution. In this study we investigated the serum activity of the osteoclast-derived TRACP 5b isoform in ADO2 patients. We also measured a bone formation marker, total serum osteocalcin, to indirectly assess bone formation rates in ADO2 patients and studied correlations between these serum markers and a disease severity score based on fracture history.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
participants and sample collection
Ten families with ADO2 secondary to heterozygous ClCN7 gene mutations (G215R, R286W, L213F, R762L, and R767W), as described previously by Waguespack and coworkers (8)(18), participated in this study. Serum samples, clinical histories, and available radiographs were obtained from all individuals during 1998–2001. Serum samples were stored in –70 °C throughout the study. A total of 233 individuals were classified into three groups: clinically affected, unaffected gene carriers, and healthy controls. All clinically affected individuals and unaffected gene carriers had a ClCN7 gene mutation, whereas controls did not have a mutation in the ClCN7 gene. The diagnosis of ADO2 (and subsequent classification as an affected individual) was made if there was diffuse osteosclerosis and/or the pathognomonic findings of endobones in any portion of the visualized skeleton and if the individual had diagnostic values for total TRACP and CK-BB, as described previously (18). We defined a gene carrier as any individual with a ClCN7 mutation who had normal radiographs and serum biochemistries, again using the diagnostic cutoffs defined in our previous report (18). Radiographs were not available for 13 individuals with a ClCN7 gene mutation. Because our previous data clearly demonstrated that total TRACP and CK-BB activities effectively differentiated unaffected gene carriers from clinically affected individuals, we classified these individuals as unaffected gene carriers (n = 12) or clinically affected (n = 1) based on biochemistries alone. Additionally, there was one carrier who had slightly increased serum biochemistries but no clear radiographic evidence of osteopetrosis. Because radiographs are considered the gold standard, this individual was classified as a carrier. Finally, controls were family members without a ClCN7 gene mutation or family members related by marriage. The study participants were further stratified into children (age <18 years) and adults (age >18 years). Results from clinically affected individuals and unaffected gene carriers were compared with controls in the same age group.

The research protocol was approved by the Indiana University Institutional Review Board. All participants or their parents (in the case of children under 18 years) gave written informed consent before participating in the study.

measurement of serum tracp 5B and total serum osteocalcin
Serum TRACP 5b activity and total serum osteocalcin were measured with in-house immunoassays, as described previously (22)(23). Serum TRACP 5b results were then compared with total serum TRACP values, as measured previously (18). The intra- and interassay variability (CV) is 3.2% and 6.9%, respectively, for TRACP 5b (22) and <5% and <8%, respectively, for osteocalcin (23).

clinical severity score
The participants were classified into three clinical severity score classes, 0, 1, or 2, based on their fracture history. Individuals with fewer than three fractures, excluding hip and femur fractures, were classified with score 0. Severity score 1 was given to individuals with a history of 3–10 fractures or with 1 hip or femur fracture. The most severely affected individuals were classified as a severity score 2 and had either >10 fractures or >1 hip or femur fracture. Finger and toe fractures were considered as minor fractures and therefore left out of the calculations. Fracture history was unknown for four of the healthy controls, and they were excluded from the fracture analysis.

statistical analysis
Because of the nongaussian distributions, all results are presented as medians with lower and upper quartiles. Comparisons between the groups were made with the nonparametric Wilcoxon test with Bonferroni adjustment. Nonparametric Spearman correlation was used for correlation analysis. A P value <0.05 was considered to be statistically significant. The statistical analysis was performed only for those study subgroups having more than three individuals.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Similar to total TRACP activity in our earlier study (18), TRACP 5b activity was significantly increased in clinically affected individuals compared with age-matched controls in both age groups (Table 1 and Fig. 1, A and B ). Carriers with the ClCN7 gene mutation but without classic clinical findings were indistinguishable from age-matched controls by TRACP 5b. One adult who was classified as an unaffected gene carrier had increased serum total TRACP and CK-BB (18), as well as TRACP 5b. The outlying data points in the adult carrier group in panels A and B in Fig. 1 represent this individual. This individual did not have the classic radiographic findings of osteopetrosis, but there was some mild osteosclerosis noted in an x-ray of the upper humerus. Therefore, because this individual did not clearly fulfill the criteria to be called clinically affected, his data were analyzed as part of the carrier group. Correlation between total TRACP and TRACP 5b was significant in each study subgroup (Table 2 ), and the overall correlation between total TRACP and TRACP 5b was also highly significant (r = 0.833; P <0.001; Fig. 2 ). Serum total osteocalcin was slightly but significantly decreased in clinically affected children compared with healthy controls, not changed in unaffected adult gene carriers, and significantly increased in affected adults compared with adult controls (Table 1 and Fig. 1C ). Osteocalcin was compared with both total TRACP and TRACP 5b in each study subgroup, and a stronger correlation was observed for TRACP 5b than for total TRACP (Table 2 ). The removal of the 13 individuals classified by use of serum biochemistries only did not change the outcome of statistical analysis (data not shown).


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  		Table 1. Characteristics and serum markers of clinically affected individuals, unaffected gene carriers, and healthy controls.1




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  		Figure 1. Serum markers in healthy controls (Ctrl; ), unaffected gene carriers (), and clinically affected individuals ({square}).

(A), serum TRACP 5b activity; (B), serum total TRACP activity; (C), serum total osteocalcin. Dashed lines represent the diagnostic cutoffs used for the determination of sensitivity and specificity for TRACP 5b and total TRACP. The cutoff values for TRACP 5b are 60 U/L (<18 years) and 13 U/L (>18 years), respectively, and for total TRACP are 35 U/L (<18 years) and 17 U/L (>18 years), respectively. Wilcoxon with Bonferroni adjustment: ***, P <0.001; **, P <0.01; *, P <0.05; NS, not significant.


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  		Table 2. Spearman correlation coefficient values for total TRACP, TRACP 5b, and osteocalcin in each study subgroup.1



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  		Figure 2. Scatter plot of serum total TRACP and serum TRACP 5b in all study participants (n = 233).

Ctrl, control.

The usefulness of any diagnostic test lies in its ability to distinguish clinically affected from healthy individuals. We investigated the diagnostic sensitivity and specificity for total TRACP and TRACP 5b in our study population, which is at risk for having a ClCN7 gene mutation and ADO2. We included unaffected gene carriers in this analysis by combining them with healthy controls. Using our results, we determined empiric cutoff values to maximize the separation between clinically affected individuals and others (Fig. 1, A and BUp ). In the pediatric group, both total TRACP and TRACP 5b were 100% sensitive and specific for the diagnosis of ADO2 when the diagnostic cutoffs of 35 and 60 U/L, respectively, were used. In adults, there was some overlap between unaffected gene carriers and clinically affected individuals, which may be attributable to the differential phenotypic expression of ADO2 and also to the classification criteria used in this study. In adults, at a diagnostic cutoff of 17 U/L, the diagnostic sensitivity for total TRACP was 100% and specificity was 98% even when carriers were included in the analysis. For TRACP 5b, the diagnostic sensitivity in the adult group was 97% when the diagnostic cutoff was set at 13 U/L. The diagnostic specificity for TRACP 5b was 99%, and without the one anomalous individual in the carrier group who had increased serum biochemistries, the specificity would have been 100%. One individual with ADO2 had a TRACP 5b value below the cutoff and has had only one fracture during his life. We postulated that his false-negative result may in part be secondary to mild manifestation of ADO2. However, this same individual had a high total TRACP activity and was also the only clear outlier in Fig. 2Up , suggesting that he might have an altered serum TRACP 5a activity.

Individuals with ADO2 had more fractures than unaffected gene carriers and healthy controls, in both children (P <0.05) and adults (P <0.001). All four pediatric individuals with a severity score of 1 or 2 had ADO2. In the adult group, all 12 individuals with a severity score of 2 were clinically affected. Twenty-three adults had a severity score of 1, and they were distributed equally among all populations: 44% (10 of 23) clinically affected, 13% (3 of 23) unaffected gene carriers, and 44% (10 of 23) controls. Adult healthy controls and unaffected gene carriers did not differ in their fracture prevalence; 8% (10 of 122) of healthy individuals and 11% (3 of 28) of unaffected gene carriers had a severity score of 1. In the pediatric group, all controls and unaffected gene carriers had a severity score of 0. Interestingly, a high number of clinically affected individuals did not have severe or multiple fractures, with 40% (15 of 37) of affected adults and 75% (12 of 16) of affected children classified as having a severity score of 0 (Table 3 ).


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  		Table 3. Number of healthy controls, unaffected gene carriers, and clinically affected individuals in each fracture severity score class.1

We also analyzed whether serum markers were correlated to the fracture severity score in clinically affected individuals only because unaffected gene carriers did not differ from age-matched healthy controls in their fracture incidences. Both total TRACP and TRACP 5b showed a strong positive association with fracture severity scores in both the pediatric (n = 16) and adult (n = 37) affected individuals (Table 4 ). In the pediatric group, one individual with a severity score of 1 and both individuals with a severity score of 2 had markedly increased serum activities of both total TRACP and TRACP 5b. However, statistical analysis was not performed because of the small number of individuals in the pediatric group. In the adult group, both total TRACP and TRACP 5b were significantly increased in individuals with severity scores of 1 and 2 compared with individuals with a severity score of 0 (P <0.01 and <0.05, respectively). We observed no statistically significant difference between individuals with severity scores of 1 and 2, but TRACP 5b activity was slightly more increased in the latter group. Total osteocalcin was not associated with fracture severity scores (Table 4 ).


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  		Table 4. Distribution of serum markers in the fracture severity score classes among clinically affected individuals only.1


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Increased serum TRACP in ADO2 patients has been reported by several groups (10)(17)(18)(19). The methods used for TRACP activity measurements in those studies could not distinguish between TRACP 5a and 5b activity, and TRACP activity was determined at pH 5.5 because it was considered the pH optimum for total serum TRACP. This is explained by the fact that the pH optimum for TRACP 5a is 5.0–5.2 and the pH optimum for TRACP 5b is 5.8–6.0 (24); therefore, their combined activity is highest at pH 5.5 in normal adult serum. In the current study, we specifically measured osteoclast-derived TRACP 5b activity at pH 6.1, a pH at which TRACP 5b is almost as active as at its pH optimum and TRACP 5a is inactive. We studied serum TRACP 5b activities from clinically affected ADO2 individuals, unaffected gene carriers, and healthy controls and compared the results of this novel TRACP 5b assay with the results we had obtained previously for total TRACP in this same population (18). The marked increase in TRACP 5b observed in clinically affected individuals and the strong correlation of TRACP 5b with total TRACP activity (r = 0.833; P <0.001) indicate that the majority of total TRACP activity in the serum of ADO2 patients is osteoclast-derived TRACP 5b.

The exact biological function of TRACP remains unknown, but it seems to have an important role in bone resorption. This conclusion can be derived from both TRACP-deficient (25) and TRACP-overexpressing (26) mouse models, which show mild osteopetrosis and osteopenia, respectively. When osteoclasts resorb bone, they secrete acid and proteases into the resorption lacuna between the bone matrix and the cell membrane. The secreted acid and proteases start the resorption process in the lacuna, and the released matrix degradation products undergo endocytosis and transcytosis, and are finally secreted through a functional secretory domain in the basolateral membrane of the osteoclast (27). It has been hypothesized that TRACP may participate in the degradation of organic bone matrix components in the transcytotic pathway of resorbing osteoclasts (28) and that secreted TRACP would be a marker of osteoclast activity. Furthermore, it has been demonstrated that serum TRACP 5b activity is significantly increased in conditions of increased bone resorption, such as osteoporosis and breast cancer with bone metastases (29), and decreased during antiresorptive treatment (22)(30), supporting the hypothesis that TRACP 5b may be a marker of osteoclast activity. However, the extremely high increase in serum TRACP 5b in ADO2 patients is several orders of magnitude higher than in any bone disease with increased bone resorption, despite the fact that bone degradation is significantly decreased in ADO2. An explanation of this contradictory situation may be elucidated by the disease itself. Formation and attachment of osteoclasts is normal in ADO2 patients, but the initial step of bone degradation, demineralization of the hydroxyapatite in bone matrix, is blocked because of the defective ClCN7. It may well be that when osteoclasts from ADO2 patients are not able to resorb bone because of the defect in acidification of resorption lacunae, they will simply produce and release more TRACP 5b with the aim of compensating for the low bone degradation rate. The fact that ADO2 patients have increased numbers of large nonfunctional osteoclasts (5) also suggests that TRACP 5b may be a marker of osteoclast number rather than osteoclast activity.

Very recently Chu et al. (31) presented direct evidence for serum TRACP 5b association with the number of osteoclasts. They showed that serum TRACP 5b had a strong correlation with histologic indices of osteoclasts in patients with renal bone disease. This conclusion is further supported by our previous findings with in vitro cultures of nonresorbing osteoclasts on plastic surface, where significant positive correlation was observed with the TRACP 5b secreted into the culture medium and the number of multinucleated osteoclasts (32). Therefore, in the case of ADO2, the highly increased serum TRACP 5b activity may be attributable to both increased compensatory secretion and increased numbers of inactive osteoclasts.

Bone turnover in ADO2 patients is disturbed mainly because of the bone resorption defect. However, some studies of bone formation markers in ADO2 have shown slightly altered profiles for serum osteocalcin (or bone Gla protein) but unchanged profiles for bone-specific alkaline phosphatase (33)(34). Our findings with serum total osteocalcin are consistent with the previous studies, showing slightly altered serum total osteocalcin concentrations in clinically affected individuals compared with healthy individuals. Although not very dramatic, an interesting finding was that, in the pediatric population, the clinically affected individuals had lower osteocalcin concentrations than controls or carriers. This observation may be explained by the tightly coupled bone resorption and formation mechanism; when bone resorption is decreased as a result of the ClCN7 gene defect, bone formation is also down-regulated. Another explanation may be that the concentrations of serum markers such as osteocalcin vary greatly depending on age and pubertal status in growing children. In adults, clinically affected individuals had small but significant increases in serum osteocalcin, which may result from an increased fracture rate and subsequent fracture healing. However, total osteocalcin did not show any clear association with fracture history as assessed by the three fracture severity score classes. When osteocalcin was compared with total TRACP or TRACP 5b, it correlated more strongly with TRACP 5b than with total TRACP. This suggests that, compared with total TRACP, serum TRACP 5b more specifically reflects events in the bone microenvironment.

Given that the genetic basis of ADO2 has been elucidated, individuals with mutations in the ClCN7 gene can now be distinguished from healthy individuals through targeted genetic testing. However, the penetrance of ADO2 is reported to be 66–94% (2)(3)(8)(10), meaning that not all individuals heterozygous for a ClCN7 gene mutation will develop clinical characteristics of ADO2. The traditional radiographic diagnosis of ADO2 has been the best way to distinguish ADO2 patients from unaffected gene carriers and healthy individuals. However, recent evidence shows that the rapid, easy measurement of serum markers, such as total TRACP and CK-BB (18) and now TRACP 5b, offers a simple, very sensitive and specific way to stratify patients with ClCN7 mutation into clinically affected and unaffected gene carriers and to distinguish individuals with ADO2 from healthy individuals. These tests also permit more widespread testing of at-risk individuals who cannot obtain radiographs or genotyping.

The high fracture frequency in ADO2 patients has been observed by several researchers (2)(10)(11)(12), and we made the same observation in our study. As expected, unaffected gene carriers had normal serum biochemistries as well as a fracture frequency comparable to healthy controls. For the first time, we studied and were able to show a clear correlation of fracture history with both total TRACP and TRACP 5b in ADO2 patients. As our results illustrate, both total TRACP and TRACP 5b are able to distinguish the patients with the most severely fracture histories (severity scores 1 and 2) from milder cases (severity score 0) among individuals with ADO2. Because total TRACP and TRACP 5b appear to correlate with fracture prevalence, another advantage of measuring these serum markers in clinically affected patients may be to determine which individuals are at the highest risk for fracture. Therefore, serum total TRACP and TRACP 5b might have prognostic value in the prediction of fractures in patients with ADO2.

In conclusion, increased serum total TRACP activity in ADO2 patients is attributable to increased osteoclast-derived TRACP 5b, demonstrating that TRACP 5b may be a more specific serum marker for ADO2 than total TRACP. The measurement of serum TRACP 5b permits easy, cost-efficient testing of at-risk individuals with a high diagnostic sensitivity and specificity. The additional advantage over traditional radiographs is the clear association of serum TRACP 5b with fracture history in individuals with ADO2. TRACP 5b may therefore also have prognostic value in the prediction of fractures in patients with ClCN7 gene mutations and clinical manifestations of ADO2.


   Acknowledgments
 
This study was supported financially by the Graduate School of Musculoskeletal Diseases (TULES) and the Academy of Finland. The study was also supported by NIH Grants AR47866 and K24-AR 02095. We thank Tero Vahlberg for valuable assistance in statistical analysis and Pirkko Rauhamäki for technical assistance. We also thank all of the ADO2 families for their gracious participation.


   Footnotes
 
1 Nonstandard abbreviations: ADO2, autosomal dominant osteopetrosis, type II; ClCN7, chloride channel 7; TRACP (5b), tartrate-resistant acid phosphatase (5b); and CK-BB, BB isoenzyme of creatine kinase.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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