This study investigates the potential clinical utility of expanding the hematopoietic stem cell (HSC) niche in the bone marrow (BM) with parathyroid hormone (PTH). Although still controversial, several lines of evidence suggest that osteoblasts support HSC expansion and/or survival in the BM, and therefore comprise at least part of the HSC niche. HSCs are found in close association with osteoblasts, osteoblasts support progenitor cells in in vitro BM cultures1 , selective depletion of osteoblasts from adult mice causes a decrease in HSC in the BM2 , and interventions that increase bone trabecular surface area in mouse BM increase HSC numbers3,4 . The laboratory of Dr. David Scadden published previously that in vivo administration of PTH leads to increased osteoblast numbers, increased bone trabeculae, and an increase in the number of HSC3 . Furthermore, PTH administration enhanced survival in a mouse BMT model in which suboptimal numbers of HSC were transplanted. These exciting findings suggest that PTH could provide therapeutic benefit to patients undergoing BMT.
The discovery that PTH stimulates bone formation is not new, but this anabolic function is a bit counterintuitive. The role of PTH in vivo is to increase plasma calcium levels by promoting calcium release from the bone, increasing calcium absorption in the GI tract, and increasing renal tubular calcium resorption. Consistent with its effect to induce release of calcium from bone, continuous administration of full-length (84 amino acid) PTH leads to bone loss and can cause osteoporosis. In contrast, intermittent PTH administration leads to bone formation. Furthermore, the 34 aa amino terminus of PTH maintains the anabolic activity of full-length PTH without causing bone loss. The PTH amino-terminal fragment, known as teriparatide, has been used in promising clinical trials for treating osteoporosis, and was used in this study.
Three clinically relevant scenarios were tested in this manuscript using murine models. First, PTH was administered to test for enhancement of mobilization. Pre-treatment with PTH led to a two-fold increase in the number of HSC in the peripheral blood with no effect on the WBC. These findings suggest that PTH can enhance PBSC mobilization by expanding the BM HSC pool. The investigators next tested whether PTH could prevent the depletion/exhaustion of HSC that can occur with repeated rounds of chemotherapy followed by G-CSF to promote WBC recovery. Mice were exposed to five rounds of cytoxan, each of which was followed by treatment with G-CSF alone or G-CSF plus PTH. After this regimen, PTH led to an increase in the number of HSC in the BM and the number of HSC that could be mobilized into the peripheral blood in response to G-CSF, suggesting that PTH can protect the marrow from the HSC depletion that can occur with repeated rounds of chemotherapy. The third clinical question addressed was really a continuation of this group’s previous studies. The investigators had already shown that PTH administration enhanced survival after lethal radiation and administration of low doses of HSC. Here they proved that this effect of PTH was mediated, at least in part, via its ability to promote (indirectly) HSC self-renewal.
In Brief
Clinical studies are underway to determine whether PTH can promote engraftment in adult recipients of cord blood transplants. Clinical trials using PTH in the setting of BMT for lymphoma are also being initiated. Perhaps future studies will reveal other therapeutic indications for PTH. There are other features of the HSC niche that could be targeted. For example, the sinusoidal endothelium in the BM also supports HSC survival/proliferation, and enhancement of these cells may also provide important clinical benefits. Pharmacological agents could also be targeted to pathways that regulate HSC interactions with the niche, such as those stimulated by notch, N-cadherin, and/or angiopoietin.
