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Lack of evidence for rickets in the osteopetrotic rat mutation, toothless
1Department of Anatomy, Indiana University School of Medicine, Indianapolis.
Insights
Rickets, a mineralization disorder, is paradoxically seen in osteopetrotic infants. However, the toothless (tl) rat mutation shows a chondrodysplastic defect, not rickets, differing from osteopetrotic mice.
Area of Science:
- Skeletal Biology
- Developmental Biology
- Genetics
Background:
- Osteopetrosis is a bone disorder often presenting with rickets in infants.
- Rickets has been reported in osteopetrotic mouse (oc) and rat (tl) models.
- The rachitic phenotype in the oc mouse resembles human cases, but the tl rat's phenotype is less understood.
Purpose of the Study:
- To investigate the nature of the cartilage defect in the toothless (tl) rat, an osteopetrotic mutation.
- To determine if the cartilage lesion in tl rats is consistent with rickets.
- To compare the cartilage defect in tl rats with that observed in human osteopetrotic infants and oc mice.
Main Methods:
- Histologic and morphometric analyses of tibial growth plate cartilage in tl rats and normal littermates up to 5 weeks of age.
- Evaluation of femoral ash content, composition, and accretion rates.
Main Results:
- Histologic analysis revealed age-related increases in proliferative zone thickness and decreases in hypertrophic zone thickness in tl rats.
- These changes were most prominent centrally and associated with acellularity and asynchronous chondrocyte differentiation.
- Femoral composition and accretion rates were similar between tl rats and normal controls, ruling out generalized mineralization defects.
Conclusions:
- The cartilage lesion in the toothless (tl) rat does not represent rickets.
- The findings suggest a primary chondrodysplastic disorder in the tl rat, distinct from the rachitic phenotype seen in human osteopetrosis.
- This highlights the genetic and phenotypic heterogeneity of osteopetrotic mutations and their associated cartilage defects.
Abstract:
A common, but paradoxic, feature among osteopetrotic human infants is the presence of rickets. This disorder of mineralization is manifested radiographically and histologically by increased growth plate cartilage and hypertrophic cell zone thickness and excess metaphyseal osteoid and biochemically by decreased serum calcium and phosphorus concentrations. Rickets has also been reported in two osteopetrotic animal mutations, the osteosclerotic (oc) mouse and the toothless (tl) rat. Although the phenotypic expression of the rachitic lesion in the oc mouse closely resembles that in affected humans, the results of the present study show that the lesion in the tl rat does not. Compared with normal littermates, histologic and morphometric analyses of tibial growth plate cartilage in tl rats up to 5 weeks of age showed age-related increases in thickness of the proliferative cell zone and decreases in thickness of the hypertrophic cell zone that were most apparent within the central, but not lateral, regions of the growth plate and areas of acellularity and failure of chondrocytes to transform synchronously from proliferative cell to hypertrophic cell phenotypes. Femoral ash content, composition, and accretion rates did not differ from those in normal rats during the first 5 weeks of life. These findings do not support the rachitic nature of the cartilage lesion in the tl rat. Rather, a chondrodysplastic disorder is suggested, which more closely resembles the cartilage defect present in this mutation.