Endocrine Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
Endocrinology. 2010 Aug;151(8):3502-13. doi: 10.1210/en.2009-1494. Epub 2010 May 25.
We have previously shown that differentiation of hypertrophic chondrocytes is delayed in mice expressing a mutated PTH/PTHrP receptor (PTHR) (called DSEL here) that stimulates adenylyl cyclase normally but fails to activate phospholipase C (PLC). To better understand the role of PLC signaling via the PTHR in skeletal and mineral homeostasis, we examined these mice fed a normal or calcium-deficient diet. On a standard diet, DSEL mice displayed a modest decrease in bone mass. Remarkably, when fed a low-calcium diet or infused with PTH, DSEL mice exhibited strikingly curtailed peritrabecular stromal cell responses and attenuated new bone formation when compared with Wt mice. Attenuated in vitro colony formation was also observed in bone marrow cells derived from DSEL mice fed a low-calcium diet. Furthermore, PTH stimulated proliferation and increased mRNAs encoding cyclin D1 in primary osteoblasts derived from Wt but not from DSEL mice. Our data indicate that PLC signaling through the PTHR is required for skeletal homeostasis.
我们之前已经证明，表达一种突变的甲状旁腺素/甲状旁腺素相关肽受体（PTHR）的小鼠（称为 DSEL）的肥大软骨细胞分化延迟，该受体通常可以刺激腺苷酸环化酶，但不能激活磷脂酶 C（PLC）。为了更好地理解 PTHR 介导的 PLC 信号在骨骼和矿物质稳态中的作用，我们研究了这些在正常饮食或钙缺乏饮食下的小鼠。在标准饮食下，DSEL 小鼠的骨量略有减少。值得注意的是，当喂食低钙饮食或输注 PTH 时，与 Wt 小鼠相比，DSEL 小鼠的骨小梁周围基质细胞反应明显受到抑制，新骨形成减少。从喂食低钙饮食的 DSEL 小鼠中分离的骨髓细胞的体外集落形成也明显减少。此外，PTH 刺激 Wt 来源的原代成骨细胞的增殖并增加编码细胞周期蛋白 D1 的 mRNA，但不刺激 DSEL 来源的原代成骨细胞的增殖和增加。我们的数据表明，PTHR 介导的 PLC 信号对于骨骼稳态是必需的。
