Targeted deletion of histidine decarboxylase gene in mice increases bone formation and protects against ovariectomy-induced bone loss.

Abstract

Targeted disruption of the histidine decarboxylase gene (HDC(-/-)), the only histamine-synthesizing enzyme, led to a histamine-deficient mice characterized by undetectable tissue histamine levels, impaired gastric acid secretion, impaired passive cutaneous anaphylaxis, and decreased mast cell degranulation. We used this model to study the role of histamine in bone physiology. Compared with WT mice, HDC(-/-) mice receiving a histamine-free diet had increased bone mineral density, increased cortical bone thickness, higher rate of bone formation, and a marked decrease in osteoclasts. After ovariectomy, cortical and trabecular bone loss was reduced by 50% in HDC(-/-) mice compared with WT. Histamine deficiency protected the skeleton from osteoporosis directly, by inhibiting osteoclastogenesis, and indirectly, by increasing calcitriol synthesis. Quantitative RT-PCR showed elevated 25-hydroxyvitamin D-1alpha-hydroxylase and markedly decreased 25-hydroxyvitamin D-24-hydroxylase mRNA levels. Serum parameters confirming this indirect effect included elevated calcitriol, phosphorus, alkaline phosphatase, and receptor activator of NF-kappaB ligand concentrations, and suppressed parathyroid hormone concentrations in HDC(-/-) mice compared with WT mice. After ovariectomy, histamine-deficient mice were protected from bone loss by the combination of increased bone formation and reduced bone resorption.

• Authors: L A Fitzpatrick, E Buzas, T J Gagne, A Nagy, C Horvath, V Ferencz, A Mester, B Kari, M Ruan, A Falus, J Barsony
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 100 Issue 10 Pg. 6027-32 (May 13 2003) ISSN: 0027-8424 [Print] United States
• PMID: 12716972 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Histidine Decarboxylase
• Calcium

Topics

• Animals
• Bone Density (genetics)
• Bone Development (genetics)
• Bone Resorption (genetics, prevention & control)
• Calcium (metabolism)
• Female
• Femur (cytology, pathology)
• Gene Deletion
• Genotype
• Histidine Decarboxylase (deficiency, genetics)
• Homeostasis
• Mice
• Mice, Knockout
• Osteoporosis (prevention & control)
• Ovariectomy