Mouse Models with a Disrupted PTHrP Gene or a Disrupted PTH Gene (PTH−/− Mice)

The study investigated the role of endogenous Parathyroid hormone related peptide (PTHrP) in bone formation by using various genetically modified mouse models. PTHrP knockout mice (PTHrP-/-) died at birth with skeletal abnormalities, but showed increased osteoblastic bone formation, suggesting PTHrP has a catabolic role in bone. However, when PTH gene was also deleted in these mice, bone formation decreased below wild-type levels, indicating that the increased bone formation in PTHrP-/- mice was due to PTH overcompensation. Osteoblast-specific PTHrP knockout mice developed osteoporosis and reduced bone formation, demonstrating that PTHrP is crucial for bone accrual postnatally. Additionally, PTHrP "knock-in" mice lacking the nuclear localization signal (NLS) and C-terminal region suffered from growth retardation and early senescence, with altered gene expression related to proliferation and senescence. These results suggest that PTHrP acts as an autocrine/paracrine regulator of bone formation via the PTH receptor, while the NLS of PTHrP has an intracrine role in stimulating cell proliferation and inhibiting apoptosis. Therefore, PTHrP is a key target for osteoporosis treatment and potentially for therapies aimed at prolonging life.