Loss of Parafollicular Cells during Gravitational Changes (Microgravity, Hypergravity) and the Secret Effect of Pleiotrophin

Hypergravity) and the Secret Effect of Pleiotrophin. PLoS ONE 7(12): e48518. doi:10.1371/journal.pone.0048518 Loss of Parafollicular Cells during Gravitational Changes (Microgravity, Hypergravity) and the Secret Effect of Pleiotrophin Elisabetta Albi 0 Francesco Curcio 0 Renza Spelat 0 Andrea Lazzarini 0 Remo Lazzarini 0 Samuela Cataldi 0 Elisabetta Loreti 0 Ivana Ferri 0 Francesco Saverio Ambesi-Impiombato 0 Bin He, Baylor College of Medicine, United States of America 0 1 Laboratory of Nuclear Lipid BioPathology, Centro Ricerche Analisi Biochimico Specialistiche , Perugia , Italy , 2 Department of Clinical and Biological Sciences, University of Udine , Udine , Italy , 3 Institute of Pathologic Anatomy and Histology, University of Perugia , Perugia , Italy It is generally known that bone loss is one of the most important complications for astronauts who are exposed to longterm microgravity in space. Changes in blood flow, systemic hormones, and locally produced factors were indicated as important elements contributing to the response of osteoblastic cells to loading, but research in this field still has many questions. Here, the possible biological involvement of thyroid C cells is being investigated. The paper is a comparison between a case of a wild type single mouse and a over-expressing pleiotrophin single mouse exposed to hypogravity conditions during the first animal experiment of long stay in International Space Station (91 days) and three similar mice exposed to hypergravity (2Gs) conditions. We provide evidence that both microgravity and hypergravity induce similar loss of C cells with reduction of calcitonin production. Pleiotrophin over-expression result in some protection against negative effects of gravity change. Potential implication of the gravity mechanic forces in the regulation of bone homeostasis via thyroid equilibrium is discussed. - Parafollicular cells or Thyroid C cells are generally known for producing calcitonin, a hormone involved in calcium homeostasis with hypocalcemic and hypophosphatemic effects but it has been highlighted their role in the production of numerous regulatory peptides such as somatostatin and ghrelin [1], katacalcin I, katacalcin II, gastrin-releasing peptide, thyroliberin and helodermin [2]. Moreover C cells, under regulation by thyrotropin (TSH) because of TSH receptor (TSHR) expression, are involved in the hypothalamic-pituitary-thyroid axis [3]. Accumulating evidence showed that C-cells express thyrotropin releasing hormone (TRH) carrying out paracrine activity on follicular cells and inducing in them TRH-Rs expression [4]. In this way C cells are responsible for intrathyroidal regulation of follicular cells by permitting an interrelationship between the two endocrine populations [5]. Studies on the behavior of the thyroid C cells in follicular pathological conditions are contradictory. Maternal hypothyroidism induced by 131I leaded to the development of hyperplasia and hyperthrophy of calcitonin-positive cells in the pups at the time of birth [6]. Differently, hypothyroidism evoked by propylthiouracil attenuated density of parafollicular cells [7]. In addition less numerous C cells were found in simple and hyperactive goitre in comparison with normal thyroid parenchyma while proliferative changes concerned only follicular cells [8]. It is possible that the variance of results was due to greater complexity of the intrathyroidal regulatory pathway involving several C cell functions. Space missions are an excellent model to study the simultaneous changes in bone and follicular thyroid metabolism, both affected from C cells. In fact, spaceflight generated a skeletal adaptive response resulting in the loss of bone mass with the change of osteoblast differentiation and morphology [9], calcium metabolism and biochemical markers of bone turnover [10], bone formation and resorption processes [11]. Changes in blood flow, systemic hormones, and locally produced factors were indicated as important elements contributing to the response of osteoblastic cells to loading [9] but research in this field still has many questions. It has been demonstrated that in the longest mice permanence (91 days) on International Space Station (ISS) during the Mice Drawer System (MDS) mission, animals presented a bone loss but transgenic mice over-expressing pleiotrophin (PTNTG), molecule that produces positive effects on bone turnover, had an osteoblast activity higher than that observed in wild type (WT) mice, indicating that the expression of the PTN during the flight resulted in some protection against microgravitys negative effects [12]. In the same experimental model, the structure of thyroid follicles appeared more organized, TSHR more expressed, cAMP release under TSH stimulation more intense in spaceflight mice than in control animals. The thyroid of PTN-TG mice was characterized by poorly developed follicles that were heterogeneous because of the variable size of both cells and colloidal spaces and the variability increased strongly in space environment Figure 1. Effect of the gravity change on thyroid tissue of WT animals. a) Morphology analysis of parafollicular thyroid cells. vivarium 1: mice maintained in vivarium cages (control for experiment in hypogravity); hypogravity: experimental mouse in space; vivarium 2: control for experiment in hypergravity; hypergravity: experimental mice in 26g centrifuge. Hematoxylin-eosin staining, 406 magnification, 1 mm scale bar. F = follicle. b) Ratio between the number of follicular cells of three follicles delimiting a parafollicular area and the number of cells C in this area. The values are expressed as mean 6 SD of three independent fields observed in duplicate (7 and 13 sections). (Significance, **P,0.001 space versus vivarium 1 and 2 g versus vivarium 2). doi:10.1371/journal.pone.0048518.g001 together to an increase of TSHR and cAMP although with lower values than those of WT mice [13]. In spite of the existence of data on thyroid follicular cells changes during space missions, no observation has ever been recorded on thyroid parafollicular cells in the space environment. Here we reported the results of the behavior of C cells obtained by using the same mice of the same experimental model of Tavella et al. [12] and Masini et al. [13] to understand their interaction with bone metabolism. To test the role of the physical force of gravity on the modifications obtained 1. How thyroid parafollicular cells sense the change of the gravity We have previously demonstrated that while in the thyroid gland of WT control mice the follicles had variable size and spatial orientation, spaceflight animals presented a more homogenous thyroid tissue structure, with ordered follicles and reduction of interfollicular space [14]. Since most species C cells are mainly concentrated in the middle third of each thyroid lobe, the so-called C-cell region [15], we have focused the attention on this specific area. (...truncated)