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Core binding factor ? of osteoblasts maintains cortical bone mass via stabilization of Runx2 in mice.

ABSTRACT: Core binding factor beta (Cbf?), the partner protein of Runx family transcription factors, enhances Runx function by increasing the binding of Runx to DNA. Null mutations of Cbfb result in embryonic death, which can be rescued by restoring fetal hematopoiesis but only until birth, where bone formation is still nearly absent. Here, we address a direct role of Cbf? in skeletal homeostasis by generating osteoblast-specific Cbf?-deficient mice (Cbfb(?ob/?ob) ) from Cbfb-floxed mice crossed with mice expressing Cre from the Col1a1 promoter. Cbfb(?ob/?ob) mice showed normal growth and development but exhibited reduced bone mass, particularly of cortical bone. The reduction of bone mass in Cbfb(?ob/?ob) mice is similar to the phenotype of mice with haploinsufficiency of Runx2. Although the number of osteoblasts remained unchanged, the number of active osteoblasts decreased in Cbfb(?ob/?ob) mice and resulted in lower mineral apposition rate. Immunohistochemical and quantitative real-time PCR analyses showed that the expression of osteogenic markers, including Runx2, osterix, osteocalcin, and osteopontin, was significantly repressed in Cbfb(?ob/?ob) mice compared with wild-type mice. Cbf? deficiency also reduced Runx2 protein levels in osteoblasts. The mechanism was revealed by forced expression of Cbf?, which increased Runx2 protein levels in vitro by inhibiting polyubiquitination-mediated proteosomal degradation. Collectively, these findings indicate that Cbf? stabilizes Runx2 in osteoblasts by forming a complex and thus facilitates the proper maintenance of bone mass, particularly cortical bone.

SUBMITTER: Lim KE

PROVIDER: S-EPMC7363154 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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Core binding factor β of osteoblasts maintains cortical bone mass via stabilization of Runx2 in mice.

Lim Kyung-Eun KE Park Na-Rae NR Che Xiangguo X Han Min-Su MS Jeong Jae-Hwan JH Kim Shin-Yoon SY Park Clara Yongjoo CY Akiyama Haruhiko H Kim Jung-Eun JE Ryoo Hyun-Mo HM Stein Janet L JL Lian Jane B JB Stein Gary S GS Choi Je-Yong JY

Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 20150401 4

Core binding factor beta (Cbfβ), the partner protein of Runx family transcription factors, enhances Runx function by increasing the binding of Runx to DNA. Null mutations of Cbfb result in embryonic death, which can be rescued by restoring fetal hematopoiesis but only until birth, where bone formation is still nearly absent. Here, we address a direct role of Cbfβ in skeletal homeostasis by generating osteoblast-specific Cbfβ-deficient mice (Cbfb(Δob/Δob) ) from Cbfb-floxed mice crossed with mice ...[more]

PMID: 25358268

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Project description:Sef (similar expression to fgf genes) is a feedback inhibitor of fibroblast growth factor (FGF) signaling and functions in part by binding to FGF receptors and inhibiting their activation. Genetic studies in mice and humans indicate an important role for fibroblast growth factor signaling in bone growth and homeostasis. We, therefore, investigated whether Sef had a function role in skeletal acquisition and remodeling. Sef expression is increased during osteoblast differentiation in vitro, and LacZ staining of Sef+/- mice showed high expression of Sef in the periosteum and chondro-osseous junction of neonatal and adult mice. Mice with a global deletion of Sef showed increased cortical bone thickness, bone volume, and increased periosteal perimeter by micro-computed tomography (micro-CT). Histomorphometric analysis of cortical bone revealed a significant increase in osteoblast number. Interestingly, Sef-/- mice showed very little difference in trabecular bone by micro-CT and histomorphometry compared with wild-type mice. Bone marrow cells from Sef-/- mice grown in osteogenic medium showed increased proliferation and increased osteoblast differentiation compared with wild-type bone marrow cells. Bone marrow cells from Sef-/- mice showed enhanced FGF2-induced activation of the ERK pathway, whereas bone marrow cells from Sef transgenic mice showed decreased FGF2-induced signaling. FGF2-induced acetylation and stability of Runx2 was enhanced in Sef-/- bone marrow cells, whereas overexpression of Sef inhibited Runx2-responsive luciferase reporter activity. Bone marrow from Sef-/- mice showed enhanced hematopoietic lineage-dependent and osteoblast-dependent osteoclastogenesis and increased bone resorptive activity relative to wild-type controls in in vitro assays, whereas overexpression of Sef inhibited osteoclast differentiation. Taken together, these studies indicate that Sef has specific roles in osteoblast and osteoclast lineages and that its absence results in increased osteoblast and osteoclast activity with a net increase in cortical bone mass.

Project description:Multiple myeloma is a plasma cell malignancy that thrives in the bone marrow (BM), with frequent progression to new local and distant bone sites. Our previous studies demonstrated that multiple myeloma cells at primary sites secrete soluble factors and suppress osteoblastogenesis via the inhibition of Runt-related transcription factor 2 (Runx2) in pre- and immature osteoblasts (OB) in new bone sites, prior to the arrival of metastatic tumor cells. However, it is unknown whether OB-Runx2 suppression in new bone sites feeds back to promote multiple myeloma dissemination to and progression in these areas. Hence, we developed a syngeneic mouse model of multiple myeloma in which Runx2 is specifically deleted in the immature OBs of C57BL6/KaLwRij mice (OB-Runx2-/- mice) to study the effect of OB-Runx2 deficiency on multiple myeloma progression in new bone sites. In vivo studies with this model demonstrated that OB-Runx2 deficiency attracts multiple myeloma cells and promotes multiple myeloma tumor growth in bone. Mechanistic studies further revealed that OB-Runx2 deficiency induces an immunosuppressive microenvironment in BM that is marked by an increase in the concentration and activation of myeloid-derived suppressor cells (MDSC) and the suppression and exhaustion of cytotoxic CD8+ T cells. In contrast, MDSC depletion by either gemcitabine or 5-fluorouracil treatment in OB-Runx2-/- mice prevented these effects and inhibited multiple myeloma tumor growth in BM. These novel discoveries demonstrate that OB-Runx2 deficiency in new bone sites promotes multiple myeloma dissemination and progression by increasing metastatic cytokines and MDSCs in BM and inhibiting BM immunity. Importantly, MDSC depletion can block multiple myeloma progression promoted by OB-Runx2 deficiency.Significance: This study demonstrates that Runx2 deficiency in immature osteoblasts at distant bone sites attracts myeloma cells and allows myeloma progression in new bone sites via OB-secreted metastatic cytokines and MDSC-mediated suppression of bone marrow immunity.

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Core binding factor ? of osteoblasts maintains cortical bone mass via stabilization of Runx2 in mice.

Publications

Core binding factor β of osteoblasts maintains cortical bone mass via stabilization of Runx2 in mice.

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