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. 2011 Apr;39(3):478-85.
doi: 10.1177/0192623311399788. Epub 2011 Mar 16.

PTHrP treatment fails to rescue bone defects caused by Hedgehog pathway inhibition in young mice

Jillian L Brechbiel  1 , Jessica M Y Ng, Tom Curran
Affiliations

PTHrP treatment fails to rescue bone defects caused by Hedgehog pathway inhibition in young mice

Jillian L Brechbiel et al. Toxicol Pathol. 2011 Apr.

Abstract

The advent of molecular targeted therapies offers the hope of therapeutic advance in the fight against cancer. However, this hope is tempered by recent findings that certain targeted therapies may have unique side effects. The Hedgehog (HH) pathway is a potential target for treatment of several cancers, including basal cell carcinoma and a subset of medulloblastoma. Recent clinical trials in adults have shown responses to HH pathway inhibition in both basal cell carcinoma and medulloblastoma. However, concerns have been raised about the use of HH pathway inhibitors in children because of the role the HH pathway plays in development. Indeed, young mice treated with the HH pathway inhibitor HhAntag developed severe bone defects, including premature differentiation of chondrocytes, thinning of cortical bone, and fusion of the growth plate. In an effort to lessen the severity of bone defects caused by HhAntag, we treated young mice simultaneously with HhAntag and parathyroid hormone-related protein (PTHrP), which functions downstream of Indian Hedgehog to maintain chondrocytes in a proliferative state. The results show that whereas treatment with PTHrP causes a significant increase in trabecular bone, it does not prevent fusion of the growth plate induced by HhAntag.

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Figures

Figure 1
Figure 1. HhAntag treatment causes severe and irreversible bone defects
Wildtype mice were treated with 100mg/kg HhAntag twice daily for six days starting at P10. H&E images (A–D) and MRI (E–H) images of the right tibia of untreated (A, E), 6 days treatment with no rest period (B, F), 6 days treatment with 2 days rest (C, G) and 6 days treatment with 4 days rest (D, H). Arrow in A represents proliferating and prehypertrophic chondrocytes. Arrowhead in A represents hypertrophic chondrocytes. Arrows in (E–H) represent the growth plate region of the tibia. Scale bars in A–D represent 500μm. Scale bars in E–H represent 5mm.
Figure 2
Figure 2. Administration of PTHrP alters bone morphology
Tibia from P14 wildtype mice, untreated (A), or treated with 20μg/kg PTHrP (B), 50μg/kg PTHrP (C) or 100μg/kg PTHrP (D) from P10 to P14, twice daily. Arrow in A shows proliferating and prehypertrophic chondrocytes. Arrowhead in A shows hypertrophic chondrocytes. Asterix in A shows trabecular bone. Scale bars in A–D represent 500μm. The percentage of proliferative/prehypertrophic chondrocytes (E), hypertrophic chondrocytes (F) and trabecular bone (G) within a defined region of the right and left tibias were calculated. The graphs show a representative from each dose category. Standard deviation was calculated from the average of 4 limbs from 2 mice for each dose category. P-value was determined by Student’s T-test; *P<0.001.
Figure 3
Figure 3. PTHrP treatment does not reduce the bone defects caused by HhAntag treatment
Tibia from wildtype P20-old mice, untreated (A, E), treated with 100μg/kg PTHrP and 100mg/kg HhAntag twice daily from P10–P16, and sacrificed 4 days later (B, F), treated with 100μg/kg PTHrP alone from P6–P20 (C, G) and treated with 100μg/kg PTHrP from P6–P20 and 100mg/kg HhAntag from P10–P16 and sacrificed 4 days later (D, H). (E–H) Higher resolution image of the growth plate region shown in A–D, respectively. Scale bars in A–D represent 500μm. Scale bars in E-H represent 100μm.
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