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Regulatory T cells are expanded by Teriparatide treatment in humans and mediate intermittent PTH-induced bone anabolism in mice.

ABSTRACT: Teriparatide is a bone anabolic treatment for osteoporosis, modeled in animals by intermittent PTH (iPTH) administration, but the cellular and molecular mechanisms of action of iPTH are largely unknown. Here, we show that Teriparatide and iPTH cause a ~two-threefold increase in the number of regulatory T cells (Tregs) in humans and mice. Attesting in vivo relevance, blockade of the Treg increase in mice prevents the increase in bone formation and trabecular bone volume and structure induced by iPTH Therefore, increasing the number of Tregs is a pivotal mechanism by which iPTH exerts its bone anabolic activity. Increasing Tregs pharmacologically may represent a novel bone anabolic therapy, while iPTH-induced Treg increase may find applications in inflammatory conditions and transplant medicine.

SUBMITTER: Yu M

PROVIDER: S-EPMC5757282 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Regulatory T cells are expanded by Teriparatide treatment in humans and mediate intermittent PTH-induced bone anabolism in mice.

Yu Mingcan M D'Amelio Patrizia P Tyagi Abdul Malik AM Vaccaro Chiara C Li Jau-Yi JY Hsu Emory E Buondonno Ilaria I Sassi Francesca F Adams Jonathan J Weitzmann M Neale MN DiPaolo Richard R Pacifici Roberto R

EMBO reports 20171120 1

Teriparatide is a bone anabolic treatment for osteoporosis, modeled in animals by intermittent PTH (iPTH) administration, but the cellular and molecular mechanisms of action of iPTH are largely unknown. Here, we show that Teriparatide and iPTH cause a ~two-threefold increase in the number of regulatory T cells (Tregs) in humans and mice. Attesting <i>in vivo</i> relevance, blockade of the Treg increase in mice prevents the increase in bone formation and trabecular bone volume and structure induc ...[more]

PMID: 29158349

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Project description:BackgroundTo provide insight into bone turnover, quantitative measurements of bone remodeling are required. Radionuclide studies are widely used in clinical care, but have been rarely used in the exploration of the bone in preclinical studies. We describe a bone planar scintigraphy method for frequent assessment of bone activity in mice across the growing period. Since repeated venous radiotracer injections are hardly feasible in mice, we investigated the subcutaneous route.MethodsRepeated 99mTc-hydroxymethylene diphosphonate (HMDP) tracer bone planar scintigraphy studies of the knee region and µCT to measure femur growth rate were performed in eight mice between week 6 and week 27 of life, i.e., during their growth period. Three independent investigators assessed the regions of interest (ROI). An index was calculated based on the counts in knees ROI (normalized by pixels and seconds), corrected for the activity administered, the decay between administration and imaging, and individual weights.ResultsA total of 93 scintigraphy studies and 85 µCT were performed. Repeated subcutaneous tracer injections were well tolerated and allowed for adequate radionuclide studies. Mean scintigraphic indexes in the knees ROI decreased from 87.4 ± 2.6 × 10-6 counts s-1 pixel-1 MBq-1 g-1 at week 6 to 15.0 ± 3.3 × 10-6 counts s-1 pixel-1 MBq-1 g-1 at week 27. The time constant of the fitted exponential decay was equal to 23.5 days. As control mean femur length assessed by µCT increased from 12.2 ± 0.8 mm at week 6 to 15.8 ± 0.2 mm at week 22. The time constant of the fitted Gompertz law was equal to 26.7 days. A correlation index of -0.97 was found between femur growth and decrease of bone tracer activity count between week 6 and 24.ConclusionThis methodological study demonstrates the potential of repeated bone planar scintigraphy in growing mice, with subcutaneous route for tracer administration, for quantitative assessment of bone remodeling.

Project description:Intermittent parathyroid hormone (PTH) administration augments bone and progressive bone marrow blood vessel (BMBV) ossification occurs with advancing age. Since intermittent PTH administration augments bone, it may also serve to increase BMBV ossification. We assessed the influence of 5- and 10-days of intermittent PTH 1-34 administration on trabecular and cortical bone and BMBV ossification in mature (6-8 mon; n = 30) and middle-aged (10-12 mon; n = 30) male and female C57BL/6 mice. Mice were divided accordingly: control (CON) and 5-days (5dPTH) and 10-days (10dPTH) of PTH. Mice were given PBS (50 μl) or PTH 1-34 (43 μg/kg/d) for 5- and 10-consecutive days. Trabecular bone microarchitecture (i.e., BV/TV [%], Tb.Th [μm], Tb.N [/mm], and Tb.Sp [μm]) was assessed in the distal femoral metaphysis and cortical bone parameters (i.e., Ct.Th [μm] and CSMI [mm4]) at the femoral mid-shaft. BMBV ossification (i.e., ossified vessel volume [OsVV, %] and ossified vessel thickness [OsV.Th, μm]) was assessed in the medullary cavity of the femoral shaft. All parameters were determined by μCT. At this sample size, no gender-related differences were observed so female and male data were pooled. There were no main effects nor interactions for trabecular microarchitecture and Ct.Th. However, CSMI was larger (p < 0.05) in Middle-Age vs. Mature and larger (p < 0.05) in CON and 10dPTH vs. 5dPTH. OsVV tended (p = 0.057) to be higher (0.18 ± 0.04% vs. 0.09 ± 0.02%, respectively) and OsV.Th was higher (p < 0.05; 17.4 ± 1.6 μm vs. 12.1 ± 1.4 μm, respectively) in Middle-Aged vs. Mature mice. OsVV was not altered, but ossified vessels tended (p = 0.08) to be thicker in 10dPTH (17.6 ± 2.0 μm) vs. CON (12.5 ± 1.7 μm). No interactions were observed for OsVV and OsV.Th. In conclusion, this is the first report of ossified BMBV in C57BL/6 mice. The increased OsV.Th in Middle-Aged mice coincides with previous reports of increased OsVV in aged rats. The tendency of augmented OsV.Th in 10dPTH suggests that this treatment may ultimately impair the patency of bone marrow blood vessels.

Dataset Information

Regulatory T cells are expanded by Teriparatide treatment in humans and mediate intermittent PTH-induced bone anabolism in mice.

Publications

Regulatory T cells are expanded by Teriparatide treatment in humans and mediate intermittent PTH-induced bone anabolism in mice.

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