Absence of response to human parathyroid hormone in athymic mice grafted with human parathyroid adenoma, hyperplasia or parathyroid cells maintained in culture

Abstract

In athymic mice we have developed a model of long-term human PTH hypersecretion, using xenotransplantation of respectively parathyroid gland fragments obtained from patients with primary (primary) or secondary (secondary) uremic hyperparathyroidism (HPT), and parathyroid cells maintained in culture from patients with secondary uremic HPT. Both grafted parathyroid tissue fragments and cultured cells induced prolonged and marked secretion of human intact PTH (iPTH) in nude mice. Despite extremely high plasma iPTH levels, hypercalcemia or hypophosphatemia was not observed. Moreover, PTH secretion was not significantly modified by low-calcium, high-phosphate diet for 3 weeks. Four mice which had a mean plasma human iPTH level of 237+/-152 pg/ml for more than 9 months and 4 age-matched, sham-grafted control mice with undetectable human iPTH levels underwent bone histomorphometry examination. No difference was found between the two groups with respect to active bone resorption surface or number of osteoclasts/mm2. We hypothesize that the characteristic deficit of T cell function and of cytokine and growth factor production may protect nude mice with chronic hypersecretion of human PTH from hypercalcemia and bone lesions. We suggest that this strain of mice could be used for better understanding the relationship between cytokines and bone turnover.

Bone and the Immune System

“…Evidence for a role of T cells in PTH-induced bone resorption came from studies almost two decades ago reporting that transplantation of human parathyroid glands from patients with hyperparathyroidism into T cell deficient nude mice failed to induce bone loss, suggesting a role for T cells in the catabolic activity of PTH (Hory et al , 2000). Follow-up studies by our group almost a decade later confirmed that administration of PTH in TCRβ KO T cell deficient mice does not induce a catabolic effect on the skeleton.…”

T-cells and B-cells in osteoporosis

“…Interestingly, it was reported over a decade ago that transplanted hyperplastic parathyroid glands failed to induce bone loss in T-cell deficient nude mice, suggesting a role for T-cells in the bone loss associated with hyperparathyroidism [45]. More recently our group has reported that, this catabolic response of PTH has now been confirmed to involve, in part, direct PTH signalling in T-cells that induces TNFα that promotes upregulation of CD40 on bone marrow stromal cells.…”

“…More recently our group has reported that, this catabolic response of PTH has now been confirmed to involve, in part, direct PTH signalling in T-cells that induces TNFα that promotes upregulation of CD40 on bone marrow stromal cells. Engagement of the T-cell costimulatory molecule CD40 ligand, with its receptor CD40 on bone marrow stromal cells, promotes proliferative and survival cues that contribute to the catabolic action of PTH [4,43,45,46]. …”

Osteoimmunology: Meeting report from the 32nd Annual Meeting of the American Society for Bone and Mineral Research

“…A role for T cells in effects of PTH in bone was first suggested by Hory et al (16), who reported that transplantation of human parathyroid tissue into nude mice failed to stimulate bone resorption. Subsequent studies by Pettway et al (17) suggested that T cells play a role in the bone-anabolic response to PTH.…”