Glucose-Dependent Insulinotropic Polypeptide Receptor Deficiency Leads to Impaired Bone Marrow Hematopoiesis

Abstract

The bone marrow (BM) contains controlled specialized microenvironments, or niches, that regulate the quiescence, proliferation, and differentiation of hematopoietic stem and progenitor cells (HSPC). The glucose-dependent insulinotropic polypeptide (GIP) is a gut-derived incretin hormone that mediates postprandial insulin secretion and has anabolic effects on adipose tissue. Previous studies demonstrated altered bone microarchitecture in mice deficient for GIP receptor ( ), as well as the expression of high-affinity GIP receptor by distinct cells constructing the BM HSPC niche. Nevertheless, the involvement of GIP in the process of BM hematopoiesis remains elusive. In this article, we show significantly reduced representation and proliferation of HSPC and myeloid progenitors in the BM of mice. This was further manifested by reduced levels of BM and circulating differentiated immune cells in young and old adult mice. Moreover, GIP signaling was required for the establishment of supportive BM HSPC niches during HSPC repopulation in radioablated BM chimera mice. Finally, molecular profiling of various factors involved in retention, survival, and expansion of HSPC revealed significantly lower expression of the Notch-receptor ligands Jagged 1 and Jagged 2 in osteoblast-enriched bone extracts from mice, which are important for HSPC expansion. In addition, there was increased expression of CXCL12, a factor important for HSPC retention and quiescence, in whole-BM extracts from mice. Collectively, our data suggest that the metabolic hormone GIP plays an important role in BM hematopoiesis.

The incretin hormone GIP is upregulated in patients with atherosclerosis and stabilizes plaques in ApoE−/− mice by blocking monocyte/macrophage activation

“…Since recent work by Mantelmacher et al. found GIP to increase bone marrow hematopoiesis with the consequence of elevated numbers of differentiated blood leukocytes in mice [15] , we speculate that changes in blood monocytes might not explain our phenotype. Here we found GIP to decrease hepatic proinflammatory cyto- and chemokine levels and to directly inhibit CCR2 expression in monocytes, which was linked to blocked MCP-1-induced monocyte migration In vitro.…”

Protection Against Arthritis by the Parasitic Worm Product ES-62, and Its Drug-Like Small Molecule Analogues, Is Associated With Inhibition of Osteoclastogenesis

“…Analysis of Sca-1 + CD117 + cells within the Lineage neg population showed that PBS-treated CIA animals had an increased proportion of HSCs in the BM compared to both naïve and ES-62-treated CIA animals (Figure 1 F). The BM HSC population is supported and maintained by stromal and OB production of OPN, but analysis of OPN mRNA in the bone-lining cells ( 23 ) of the femurs and tibias showed that OPN mRNA levels were not significantly different in PBS-treated CIA mice relative to naïve and ES-62-treated CIA animals (Figure 1 G). As ES-62 is able to return HSC levels to those found in healthy animals and show evidence of reducing cathepsin K + OC numbers in the joints of arthritic mice, we next aimed to determine specifically whether CIA would affect defined OC progenitor populations in the BM.…”

“…BM cells (10 6 ), or OCs that were pre-treated with SMAs (5 µg/ml) for 24 h, were lysed in RNeasy lysis buffer prior to mRNA extraction using an RNeasy Plus Mini kit (Qiagen, Germany) according to manufacturer’s instructions. Additionally, cleaned and flushed femurs and tibias were then flushed with QIAzol to obtain RNA from bone-lining cells as previously described ( 23 ). cDNA was generated using a high capacity cDNA Reverse Transcriptase kit (Applied Biosystems, Life Technology) before use in PCR amplifications using the StepOne Plus™ real-time PCR system (Applied Biosystems).…”

Incretin Hormones in the Control of Immunometabolism

“…The BM contains controlled specialized microenvironments, or niches, that regulate the quiescence, proliferation, and differentiation of hematopoietic stem and progenitor cells (HSPC). Given the expression of GIPR in cells constituting the BM HSPC niche and the altered architecture and matrix of Gipr −/− bones, we endeavored to study the regulation of BM hematopoiesis by GIP [172]. Indeed, we have shown that GIP supports BM hematopoiesis through its regulation of the hematopoiesis-supportive activity of stromal cells composing the BM HSPC niche [172], therefore suggesting another layer by which GIP may modulate immune responses.…”

“…Given the expression of GIPR in cells constituting the BM HSPC niche and the altered architecture and matrix of Gipr −/− bones, we endeavored to study the regulation of BM hematopoiesis by GIP [172]. Indeed, we have shown that GIP supports BM hematopoiesis through its regulation of the hematopoiesis-supportive activity of stromal cells composing the BM HSPC niche [172], therefore suggesting another layer by which GIP may modulate immune responses. While it is well-established that inflammation increases GLP-1 levels, how inflammatory stimuli mediate GIP secretion remains largely unknown.…”