Deletion of the nuclear localization sequence and C-terminus of parathyroid hormone-related protein decreases osteogenesis and chondrogenesis but increases adipogenesis and myogenesis in murine bone marrow stromal cells.

The N-terminus of parathyroid hormone-related protein regulates bone marrow stromal cell differentiation. We hypothesized that the nuclear localization sequence and C-terminus are involved. MicroRNA and gene expression analyses were performed on bone marrow stromal cells from mice lacking the nuclear localization sequence and C-terminus ( Pthrp ^Δ/Δ ) and age-matched controls. Differentiation assays with microRNA, cytochemical/histologic/morphologic, protein, and gene expression analyses were performed. Pthrp ^Δ/Δ bone marrow stromal cells are anti-osteochondrogenic, pro-adipogenic, and pro-myogenic, expressing more Klf4 , Gsk-3β , Lif , Ct-1 , and microRNA-434 but less β-catenin , Igf-1 , Taz , Osm , and microRNA-22 ( p  ⩽ 0.024). Pthrp ^Δ/Δ osteoblasts had less mineralization, osteocalcin, Runx2 , Osx , Igf-1 , and leptin ( p  ⩽ 0.029). Pthrp ^Δ/Δ produced more adipocytes, Pparγ , and aP2 , but less Lpl ( p  ⩽ 0.042). Pthrp ^Δ/Δ cartilage pellets were smaller with less Sox9 and Pth1r , but greater Col2a1 ( p  ⩽ 0.024). Pthrp ^Δ/Δ produced more myocytes, Des , and Myog ( p  ⩽ 0.021). MicroRNA changes supported these findings. In conclusion, the nuclear localization sequence and C-terminus are pro-osteochondrogenic, anti-adipogenic, and anti-myogenic.
Competing Interests: Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
(© The Author(s) 2015.)