The midregion, nuclear localization sequence, and C terminus of PTHrP regulate skeletal development, hematopoiesis, and survival in mice

Abstract

The functions of parathyroid hormone-related protein (PTHrP) on morphogenesis, cell proliferation, apoptosis, and calcium homeostasis have been attributed to its N terminus. Evidence suggests that many of these effects are not mediated by the N terminus but by the midregion, a nuclear localization sequence (NLS), and C terminus of the protein. A knock-in mouse lacking the midregion, NLS, and C terminus of PTHrP (Pthrp(Delta/Delta)) was developed. Pthrp(Delta/Delta) mice had craniofacial dysplasia, chondrodysplasia, and kyphosis, with most mice dying by d 5 of age. In bone, there were fewer chondrocytes and osteoblasts per area, bone mass was decreased, and the marrow was less cellular, with erythroid hypoplasia. Cellular proliferation was impaired, and apoptosis was increased. Runx2, Ocn, Sox9, Crtl1, beta-catenin, Runx1, ephrin B2, cyclin D1, and Gata1 were underexpressed while P16/Ink4a, P21, GSK-3beta, Il-6, Ffg3, and Ihh were overexpressed. Mammary gland development was aberrant, and energy metabolism was deregulated. These results establish that the midregion, NLS, and C terminus of PTHrP are crucial for the commitment of osteogenic and hematopoietic precursors to their lineages, and for survival, and many of the effects of PTHrP on development are not mediated by its N terminus. The down-regulation of Runx1, Runx2, and Sox9 indicates that PTHrP is a modulator of transcriptional activation during stem cell commitment.

The p27 Pathway Modulates the Regulation of Skeletal Growth and Osteoblastic Bone Formation by Parathyroid Hormone–Related Peptide

“…Other in vivo genetic mouse models have also indicated that the midregion and C-terminus of PTHrP are functional. (8) Cell cycle regulation is conducted by sequential activation of a family of serine-threonine kinases called cycle-dependent kinases (CDKs). Tight CDK regulation involves cyclin-dependent kinase inhibitors (CKIs), which ensure the correct timing of CDK activation in different phases of the cell cycle.…”

Phospholipase A2-activating protein is associated with a novel form of leukoencephalopathy

“…Specifically, disruption of cell-cell adhesion function of Armadillo results in construction defects of the axonal scaffold (Loureiro and Peifer, 1998). Interestingly, a recent study suggested that PLA 2 a regulates the Wnt/b-catenin pathway (Han et al, 2008), which is implicated in neurogenesis, CNS morphogenesis, hirsutism, sweat gland morphology, short tendons, and kyphosis (Toribio et al, 2010;Haara et al, 2011;Joksimovic and Awatramani, 2014;Zhang et al, 2014). In this pathway, b-catenins transduce Wnt signals during embryonic development.…”

Parathyroid hormone-related peptide (PTHrP): prokaryotic expression, purification, and preparation of a polyclonal antibody

“…PTHrp gene knockout mice present dyschondroplasia, hump, and mammary dysplasia (Toribio et al, 2010). PTHrP induces osteoclast formation, and decreases osteoblast function in diabetes-related osteopenia patients (Lozano et al, 2009).…”