Loss of Parathyroid Hormone Receptor Signaling in Osteoprogenitors Is Associated With Accumulation of Multiple Hematopoietic Lineages in the Bone Marrow

Abstract

Osteoblasts and their progenitors play an important role in the support of hematopoiesis within the bone marrow (BM) microenvironment. We have previously reported that parathyroid hormone receptor (PTH1R) signaling in osteoprogenitors is required for normal B cell precursor differentiation, and for trafficking of maturing B cells out of the BM. Cells of the osteoblast lineage have been implicated in the regulation of several other hematopoietic cell populations, but the effects of PTH1R signaling in osteoprogenitors on other maturing hematopoietic populations have not been investigated. Here we report that numbers of maturing myeloid, T cell, and erythroid populations were increased in the BM of mice lacking PTH1R in Osx‐expressing osteoprogenitors (PTH1R‐OsxKO mice; knockout [KO]). This increase in maturing hematopoietic populations was not associated with an increase in progenitor populations or proliferation. The spleens of PTH1R‐OsxKO mice were small with decreased numbers of all hematopoietic populations, suggesting that trafficking of mature hematopoietic populations between BM and spleen is impaired in the absence of PTH1R in osteoprogenitors. RNA sequencing (RNAseq) of osteoprogenitors and their descendants in bone and BM revealed increased expression of vascular cell adhesion protein 1 (VCAM‐1) and C‐X‐C motif chemokine ligand 12 (CXCL12), factors that are involved in trafficking of several hematopoietic populations. © 2022 American Society for Bone and Mineral Research (ASBMR).

Parathyroid hormone 1 receptor signaling mediates breast cancer metastasis to bone in mice

“…Studies of the bone and its microenvironment have demonstrated that the osteoblast lineage plays unique roles in supporting hematopoiesis and maintaining bone homeostasis. Previous studies from our laboratory have demonstrated that increased of expression of Vcam1 and Cxcl12 is implicated in the trafficking of B cells and hematopoietic populations ( 29 , 30 ) within the bone marrow. VEGF overexpression, acting through VEGF1 and VEGFR2, promotes bone resorption, possibly due to excessive osteoclast resorption ( 44 ).…”

“…We recently performed RNA-Seq on osteoprogenitors from bones of PTH1R fl/fl and PTH1R OsxKO mice ( 29 ). We examined the expression pattern of several genes implicated in the breast–bone vicious cycle in the bone microenvironment and found that conditional ablation of PTH1R in osteoblasts is associated with increased expression of Pthlh , Cxcl12 , Tgfb2 , Tgfb3 , Tnf, Flt1 (encoding VEGFR1), and Vcam1 ( Figure 1E ).…”

“…To provide a syngeneic background for the 4T1 tumor injections, the PTH1R OsxKO mice were backcrossed to a Balb/c background, which decreased their survival. In the absence of doxycycline, PTH1R OsxKO mice do not survive past 1 month of age ( 29 , 30 ). Unfortunately, on the Balb/c background, doxycycline-mediated delay of PTH1R deletion until postnatal life did not prolong survival, thus limiting the use of postnatal PTH1R OsxKO mice in our studies.…”

Engineering of a NIR-activable hydrogel-coated mesoporous bioactive glass scaffold with dual-mode parathyroid hormone derivative release property for angiogenesis and bone regeneration

“…However, the treatment with MBGS and MBGS/PTHrP-2 barely induces newly visible vascular formation around the implant. This phenomenon can be attributed to the NIR-controlled long-term sustained and on-demand pulsatile release of PTHrP-2 by the CBP/MBGS/PTHrP-2, which enables it to continually stimulate early vascularization and promote more osteoblasts to participate in the bone remodeling, thus resulting in a remarkably improved bone reparative effect [ 52 ]. In contrast, the burst PTHrP-2 release of MBGS/PTHrP-2 prevented it from supplying sustained and sufficient PTHrP-2 to trigger angiogenesis for bone regeneration.…”

Osteoblast Lineage Support of Hematopoiesis in Health and Disease

“…PTH1R Osx‐KO mice also exhibit an accumulation of myeloid, T, and late‐stage erythroid cells in the bone marrow with a decrease in cellularity in the spleen, suggesting dysregulated trafficking of hematopoietic cells between these two organs. ( 107 ) Bulk RNAseq of PTH1R Osx‐KO mice found increased expression of Vcam1 and Cxcl12 , two important mediators of HSC/HSPC retention and migration.…”