Acvr1 deletion in osteoblasts impaired mandibular bone mass through compromised osteoblast differentiation and enhanced sRANKL‐induced osteoclastogenesis

Nov 30, 2020Journal of cellular physiology

Removing Acvr1 in bone-forming cells reduces jawbone mass by weakening bone cell development and increasing bone breakdown signals

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Abstract

Conditional knockout mice lacking the BMP type I receptor Acvr1 exhibit mandibular bone loss at postnatal days 21 and 42.

Bone loss in the mandible is observed in an age-dependent manner in the knockout mice.
Compromised differentiation of is linked to the decreased bone mass.
Enhanced formation is associated with the changes in osteoblasts in vivo.
Deletion of Acvr1 in mandibular bone marrow stromal cells significantly impairs osteoblast differentiation.
Coculturing wild type bone marrow macrophages with Acvr1-deficient BMSCs induces increased proliferation and differentiation of osteoclasts.
The increased osteoclastogenesis may be partly due to the secretion of soluble receptor activator of nuclear factor-κB ligand ().

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Bone morphogenetic protein (BMP) signaling is well known in bone homeostasis. However, the physiological effects of BMP signaling on mandibles are largely unknown, as the mandible has distinct functions and characteristics from other bones. In this study, we investigated the roles of BMP signaling in bone homeostasis of the mandibles by deleting BMP type I receptor Acvr1 in lineage cells with Osterix-Cre. We found mandibular bone loss in conditional knockout mice at the ages of postnatal day 21 and 42 in an age-dependent manner. The decreased bone mass was related to compromised osteoblast differentiation together with enhanced osteoclastogenesis, which was secondary to the changes in osteoblasts in vivo. In vitro study revealed that deletion of Acvr1 in the mandibular bone marrow stromal cells (BMSCs) significantly compromised osteoblast differentiation. When wild type bone marrow macrophages were cocultured with BMSCs lacking Acvr1 both directly and indirectly, both proliferation and differentiation of were induced as evidenced by an increase of multinucleated cells, compared with cocultured with control BMSCs. Furthermore, we demonstrated that the increased osteoclastogenesis in vitro was at least partially due to the secretion of soluble receptor activator of nuclear factor-κB ligand (), which is probably the reason for the mandibular bone loss in vivo. Overall, our results proposed that ACVR1 played essential roles in maintaining mandibular bone homeostasis through osteoblast differentiation and osteoblast-osteoclast communication via sRANKL.

Key numbers

Decrease in Tissue Mineral Density

Measured in male cKO mice compared to controls.

Decreases in N. Ob/BS and Ob. S/BS

Impaired Activity

Observed in both male and female cKO mice at postnatal day 42.

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Acvr1 deletion in osteoblasts impaired mandibular bone mass through compromised osteoblast differentiation and enhanced sRANKL‐induced osteoclastogenesis

Abstract

Key numbers

Full Text

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