HO-1 expression increases mesenchymal stem cell-derived osteoblasts but decreases adipocyte lineage

Abstract

Human bone marrow mesenchymal stem cells (MSC) are pleitrophic cells that differentiate to either adipocytes or osteoblasts as a result of cross-talk by specific signaling pathways including heme oxygenase (HO)-1/-2 expression. We examined the effect of inducers of HO-1 expression and inhibitors of HO activity on MSC differentiation to the osteoblast and adipogenesis lineage. HO-1 expression is increased during osteoblast stem cell development, but remains elevated, at 25 days. The increase in HO-1 levels proceed an increase in alkaline phosphatase (AP) activity and an increase in BMP, osteonectin and RUNX-2 mRNA. Induction of HO-1 by osteogenic growth peptide (OGP) was associated with an increase in BMP-2 and osteonectin. Exposure of MSC to high glucose levels decreased osteocalcin and osteogenic protein expression, which was reversed by upregulation of the OGP-mediated increase in HO-1 expression. The glucose mediated decrease in HO-1 resulted in decreased levels of pAMPK, pAKT and the eNOS signaling pathway and was reversed by OGP. In contrast, MSC-derived adipocytes were increased by glucose. HO-1 siRNA decreased HO-1 expression but increased adipocyte stem cell differentiation and the adipogenesis marker, PPARγ. Thus, upregulation of HO-1 expression shifts the balance of MSC differentiation in favor of the osteoblast lineage. In contrast, a decrease in HO-1 or exposure to glucose drives the MSC towards adipogenesis. Thus targeting HO-1 expression is a portal to increased osteoblast stem cell differentiation and to the attenuation of osteoporosis by the promotion of bone formation.

ApoA1

“…Adipocyte enlargement is associated with an increase in the release of TNFα, IL-1, IL-6 and increased insulin resistance. [6][7][8]25 Induction of HO-1 has been shown to enhance cell survival and moderate the diabetic state and obesity. [37][38][39] Induction of HO-1 gene expression in vivo and in cell culture is associated with an increase in pre-adipocytes, a reduction in the number of enlarged adipocytes, but an increase in small adipocyte and adiponectin levels.…”

“…[37][38][39] Induction of HO-1 gene expression in vivo and in cell culture is associated with an increase in pre-adipocytes, a reduction in the number of enlarged adipocytes, but an increase in small adipocyte and adiponectin levels. 8,23,25,40 HO-1 is induced by a broad spectrum of inducers such as statins, curcumin and ApoA1 mimetic peptides 41 and has been shown to play a crucial role in protection against oxidative insult in diabetes and cardiovascular disease. 41 A decrease in HO-1 expression results in increased insulin resistance and adiposity in Zucker rats and ob mice.…”

Hypoxia Promotes Osteogenesis of Human Placental-Derived Mesenchymal Stem Cells

“…HO-1 can inhibit the maturation and mineralization of rat osteoblast (Lin et al 2010). On the contrary, others reported that HO-1 can increase the osteogenic differentiation of human MSCs (Vanella et al 2010). In addition, the activation of HO-1 regulates osteoclastogenesis and bone reabsorption during fracture repair (Komatsu and Hadjiargyrou 2004).…”

“…HO activity was measured as previously described (Vanella et al 2010) with minor modification (Fig. 1A, C).…”

Characterisation of the relationship between Heme-oxygenase-1 and adiponectin

“…Treatments were limited to mature adipocytes in order to reduce the potential for confounding effects on the differentiation process, as has been reported by others [238,242,276,277], and incubation periods were limited to 24-48 h to reduce the likelihood of secondary effects. As expected, treatment with two widely used inducers of HO-1, CoPP and Hemin, resulted in increased HO-1 expression at both the mRNA and protein level.…”