Rouffet J, Barlet J P
Laboratoire Croissance et Métabolismes des Herbivores, INRA Theix, St Genès-Champanelle.
Arch Physiol Biochem. 1995 Apr;103(1):3-13. doi: 10.3109/13813459509007556.
The discovery of PTHrP was the result of research on the mechanisms by which some cancers cause hypercalcemia (humoral hypercalcemia of malignancy) without necessarily metastasizing to bone. PTHrP is also present in various normal adult and fetal tissues. Its concentration is normally very low (picomolar) in blood, but it is more abundant in milk (nanomolar concentration). PTHrP seems able to exert autocrine/paracrine as well as endocrine effects on bone metabolism. A major role for PTHrP in regulation of fetal bone metabolism has been demonstrated in mice. Homologous recombination has been used in these rodents to remove the major coding exon from one copy of the mouse PTHrP gene in embryonic stem cells. Subsequently generated chimeric mice transmit the mutant PTHrP allele through the germline. Homozygous mutants died immediately after birth and had a multitude of skeletal abnormalities. So PTHrP seems necessary to embryonic development of the skeleton. PTHrP (1-34), like PTH (1-34) fragments, might be responsible for both bone resorption and formation. Although the effects of the carboxyl-terminal fragments are still controversial, PTHrP (107-111) fragment seems able to inhibit osteoclast activity. PTHrP (1-34), whose 8 of the first 13 amino-acids are identical with those in PTH (1-34), acts through the same receptor as PTH on osteoblasts and renal cells membrane. The PTHrP/PTH receptor sequence is now well established. PTHrP-receptor coupling is mediated by cyclic AMP and/or inositols-phosphate. The consequent activation of protein kinase A and intracellular calcium or protein kinase C, respectively, locally induces growth factors or cytokines secretion, responsible for the observed effects. The role of PTHrP appears important during pregnancy and lactation, when it stimulates fetal bone growth by increasing calcium transport from the dam to its fetus and maternal bone resorption allowing calcium supply for milk production, respectively. Such a role would be particularly important in domestic ruminants, which are often simultaneously pregnant and lactating. The role of PTHrP during aging (especially in post-menopausal women in which bone loss may induce osteoporosis) remains unknown and might be of peculiar interest since PTHrP (1-34) and (107-111) are able to restore bone loss induced by ovariectomy in rats.
甲状旁腺激素相关蛋白（PTHrP）的发现是对某些癌症导致高钙血症（恶性肿瘤体液性高钙血症）而不一定转移至骨骼的机制进行研究的结果。PTHrP也存在于各种正常的成年和胎儿组织中。其在血液中的浓度通常非常低（皮摩尔），但在乳汁中含量更高（纳摩尔浓度）。PTHrP似乎能够对骨代谢发挥自分泌/旁分泌以及内分泌作用。在小鼠中已证实PTHrP在调节胎儿骨代谢中起主要作用。在这些啮齿动物中，同源重组已被用于从胚胎干细胞中的一个小鼠PTHrP基因拷贝中去除主要编码外显子。随后产生的嵌合小鼠通过种系传递突变的PTHrP等位基因。纯合突变体在出生后立即死亡，并出现多种骨骼异常。因此，PTHrP似乎对骨骼的胚胎发育是必需的。PTHrP（1 - 34）与PTH（1 - 34）片段一样，可能对骨吸收和形成都有作用。尽管羧基末端片段的作用仍存在争议，但PTHrP（107 - 111）片段似乎能够抑制破骨细胞活性。PTHrP（1 - 34）的前13个氨基酸中有8个与PTH（1 - 34）相同，它通过与PTH相同的受体作用于成骨细胞和肾细胞膜。目前PTHrP/PTH受体序列已明确。PTHrP - 受体偶联由环磷酸腺苷（cAMP）和/或肌醇磷酸介导。随后分别激活蛋白激酶A和细胞内钙或蛋白激酶C，局部诱导生长因子或细胞因子分泌，从而产生观察到的效应。PTHrP在妊娠和哺乳期似乎起着重要作用，在这两个时期，它分别通过增加母体向胎儿的钙转运来刺激胎儿骨骼生长，并促进母体骨吸收以为乳汁生成提供钙。这种作用在经常同时怀孕和哺乳的家养反刍动物中可能尤为重要。PTHrP在衰老过程中的作用（尤其是在绝经后妇女中，骨量流失可能导致骨质疏松）仍然未知，鉴于PTHrP（1 - 34）和（107 - 111）能够恢复大鼠卵巢切除诱导的骨量流失，这可能具有特殊的研究意义。
