Parathyroid Hormone Directs Bone Marrow Mesenchymal Cell Fate

Abstract

Summary Intermittent PTH administration builds bone mass and prevents fractures, but its mechanism of action is unclear. We genetically deleted the PTH/PTHrP Receptor (PTH1R) in mesenchymal stem cells using Prx1Cre and found low bone formation, increased bone resorption and high bone marrow adipose tissue (BMAT). Bone marrow adipocytes traced to Prx1 and expressed classic adipogenic markers and high receptor activator of nuclear factor kappa-B ligand (Rankl) expression. RANKL levels were also elevated in bone marrow supernatant and serum, but undetectable in other adipose depots. By cell sorting, Pref1+RANKL+ marrow progenitors were twice as great in mutant versus control marrow. Intermittent PTH administration to control mice reduced BMAT significantly. A similar finding was noted in male osteoporotics. Thus, marrow adipocytes exhibit osteogenic and adipogenic characteristics, are uniquely responsive to PTH, and secrete RANKL. These studies reveal an important mechanism for PTH’s therapeutic action through its ability to direct mesenchymal cell fate.

Reflections on Cancer in the Bone Marrow: Adverse Roles of Adipocytes

“…Overall, there are a multitude of ways in which MAT and BMAs may contribute to tumor growth, and clinically targeting MAT is an interesting and innovative concept. It is possible that therapies that build bone may also inhibit MAT, as we have recently demonstrated with anti-sclerostin antibodies [54,57], and as others have found with PTH [47] and leptin [69]. The FGF family members may also hold promise for targeting to modulate not only bone, but also MAT.…”

“…These alterations in the host microenvironment ultimately support tumor growth, bone disease, and drug resistance (for example, through induction of MUC1 as recently demonstrated by Bar-Natan et al [44]), and it is very likely that MAT effects MSCs and the BM ECM. Furthermore, MAT has been found to accelerate osteoclastogenesis through secretion of Receptor activator of nuclear factor kappa-B ligand (RANKL) [45–47] as well as chemokine ligand 1 and 2 (CXCL1 and CXCL2) [48], which suggests that MAT may contribute to cancer-induced osteolysis via activation of osteoclast bone resorption. Other researchers have shown that osteoclasts play a key role in determining if a myeloma cell will remain dormant or proliferate [49].…”

“…Many researchers have speculated that MAT impedes bone development due to direct effects on mature osteoblasts or MSCs, but direct evidence is lacking due to the challenges of specifically modulating MAT. Interestingly, many of the signaling pathways in MSCs that induce osteogenic differentiation inhibit adipogenic differentiation, such as Wnt [54,57] and parathyroid hormone (PTH) signaling [47,58]. Thus, increased adipogenesis may decrease the pool of progenitor cells able to undergo osteogenesis, which would decrease the number of osteoblasts in the niche and likely decrease bone volume fractions in cortical and trabecular bone regions.…”

Skeletal Stem Cells: Origins, Functions, and Uncertainties

“…Fate decision of SSCs can also be controlled by hormonal factors such as leptin, an adipokine secreted by adipocytes[77], parathyroid hormone (PTH) and parathyroid hormone-related protein (PTHrP)[78]. Leptin signaling regulates bone mass systemically by acting on Leptin receptor (LepR)-expressing neurons in the hypothalamus[79] and locally by directly binding LepRs on SSCs, osteoblasts and osteoclasts (reviewed in[80]).…”

“…Intermittent administration of PTH stimulates bone formation by increasing osteoblast activity [81] and recruiting bone marrow stromal cells to the osteoblast lineage[82]. Recent studies revealed that PTH could also regulate the SSC fate since conditional knockout of PTH receptor-1 (PTH1R) in skeletal progenitor/stem cells resulted in increased adipogenesis accompanied by high bone resorption[78]. …”