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-1␣-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-B 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.

Histamine Promotes Osteoclastogenesis through the Differential Expression of Histamine Receptors on Osteoclasts and Osteoblasts

“…13 In summary, our study provides evidence for histamine involvement in osteoclast differentiation and for specific roles of H1R and H2R. We showed that histamine promotes osteoclast differentiation directly through autocrine/paracrine action on the precursors and indirectly through an increased RANKL/OPG expression ratio by osteoblasts.…”

“…8,9 Biopsies from patients with systemic mastocytosis shows evidence of increased cortical and trabecular bone turnover in regions of mast cell accumulation. 31 Using other in vitro models (bone marrow cells or co-culture of osteoblasts and bone marrow), previous studies already showed that histamine promotes osteoclast differentiation 12,13,14,15 and it was suggested that this effect of histamine could be explained by the increased RANKL expression in osteoblasts.…”

“…12 HDC deficiency in mice results in increased bone formation and reduced bone resorption, and protects against ovariectomy-induced bone loss. 13 It was shown in vitro, in bone marrow cultures or co-cultures, that histamine can increase osteoclast differentiation and that H1R and H2R antagonists partially inhibit histamine increase. 12,14,15 Also, it was demonstrated that osteoblasts express H1R and H2R and that histamine increase RANKL expression in these cells.…”

Loci Contributing to Adult Height and Body Mass Index in African American Families Ascertained for Type 2 Diabetes

“…Candidate genes in the LOD-1 interval that have been shown to have a role in limb development include GREM1, gremlin 1 homolog, cysteine knot superfamily (Xenopus laevis) (Khokha et al 2003), and myeloid ecotropic viral integration site homolog 2 (mouse) (MEIS2) (Qin et al 2002). Candidate genes under the more distal portion of the peak include the gene responsible for Marfan's Syndrome, fibrillin 1 (FBN1) (Dietz et al 1991), histidine decarboxylase (HDC) -shown to influence bone formation in animal models (Fitzpatrick et al 2003), and cytochrome P450, family 19, subfamily A, polypeptide 1 (CYP19A1) which has been reported as being associated with adult male height (Ellis et al 2001). The chromosome 17 locus was also detected in Caucasian Americans enrolled in a study of osteoporosis and obesity (Deng et al 2002), where a peak of LOD = 1.50 (p = 0.0043) at 114 cM (D17S785) was reported (Table 3).…”

Histamine Receptor H1 and Dermatopontin: New Downstream Targets of the Vitamin D Receptor

“…The data presented here taken together with the published results indicate a possibility of reciprocal regulation between histamine and vitamin D actions on the decrease of BMD by histamine. (41) One study, in a synchronized resorption model, showed that histamine increases osteoclast activity and number through H1 and H2 receptors, respectively, (42) whereas other studies indicated that the histamine effects on bone resorption were indirect. (43,44) Increased histamine levels were also associated with normal or decreased parameters of bone formation, (45) although a direct effect of histamine on osteoblasts has not been reported.…”