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

      1 , ,

      Toxicologic pathology

      SAGE Publications

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          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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          Author and article information

          Journal
          Toxicol Pathol
          Toxicologic pathology
          SAGE Publications
          1533-1601
          0192-6233
          Apr 2011
          : 39
          : 3
          Affiliations
          [1 ] Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Pennsylvania, PA 19104, USA.
          0192623311399788 NIHMS441629
          10.1177/0192623311399788
          3576833
          21411723

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