BMP9 Reduces Bone Loss in Ovariectomized Mice by Dual Regulation of Bone Remodeling

Abstract

Bone remodeling is dynamic and is tightly regulated through bone resorption dominated by osteoclasts and bone formation dominated by osteoblasts. Imbalances in this process can cause various pathological conditions, such as osteoporosis. Bone morphogenetic protein 9 (BMP9), a biomolecule produced and secreted by the liver, has many pharmacological effects, including anti-liver fibrosis, antitumor, anti-heart failure, and antidiabetic activities. However, the effects of BMP9 on the regulation of osteoblast and osteoclast functions and the underlying molecular mechanism(s) have not yet been investigated. In this study, BMP9 increased the expression of osteoblastogenic gene markers, such as ALP, Cola1, OCN, RUNX2, and OSX, and ALP activity in MC3T3-E1 cells by upregulating LGR6 and activating the Wnt/β-catenin pathway. BMP9 also suppressed receptor activator of nuclear factor-κB (NF-κB) ligand (RANKL)-induced osteoclast differentiation of bone marrow macrophages (BMMs) by inhibiting the Akt-NF-κB-NFATc1 pathway. More importantly, in an ovariectomy (OVX) mouse model, BMP9 attenuated bone loss and improved bone biomechanical properties in vivo by increasing bone-forming activity and suppressing bone resorption activity. Accordingly, our current work highlights the dual regulatory effects that BMP9 exerts on bone remodeling by promoting bone anabolic activity and inhibiting osteoclast differentiation in OVX mice.

LGRs in Skeletal Tissues: An Emerging Role for Wnt‐Associated Adult Stem Cell Markers in Bone

“…(66) A recent study has demonstrated that LGR6 acts to potentiate Wnt/β-catenin signaling in MC3T3-E1 cells downstream of BMP signaling, leading to transcription of osteogenic genes. (67) LGR4 is expressed within BMSCs undergoing osteogenic differentiation; however, the expression levels of LGR4 do not appear to be correlated with osteogenic genes or in vitro osteoblastic differentiation of BMSCs. (65) Although LGR4 may not serve as a marker for osteoblast precursors in the same manner as LGR6, others have demonstrated a necessary role for LGR4 in osteogenic differentiation in vitro.…”

“…Mouse Promotes osteogenesis via RSPO2 binding; becomes upregulated upon BMP2 exposure Luo et al (48) ; Zhu et al (68) ; Pawaputanon na Mahasarakham et al (71) ; Zhou et al (67) LGR4 Preosteoclasts, osteoclasts…”

“…Mouse Upregulated during early in vitro osteogenic differentiation, promotes osteogenesis via stabilization of β-catenin; may act downstream of the BMP pathway to upregulate osteogenic genes Liu et al (66) ; Zhou et al (67) LGRs are also expressed in compartment-specific locations in incisors. In the labial cervical loop, LGR4 and LGR5 label distinct areas of the epithelial portion of the enamel organ, whereas LGR6 is confined to the mesenchyme and additionally labels enamel-producing ameloblasts.…”

Hepcidin-induced reduction in iron content and PGC-1β expression negatively regulates osteoclast differentiation to play a protective role in postmenopausal osteoporosis

“…The method of ALP and TRAP staining were similar as performed before. The osteoblast surface/bone surface (Ob.S/BS) was the ratio of the ALP-stained area to total bone area and the osteoclast surface/bone surface (Oc.S/BS) was the ratio of the TRAP-stained area to the total bone area [ 43 ], which were quantified using Imagej software.…”

Lysyl Oxidase Down-Regulates The Osteoblastic Potential of BMP9 Through Inhibiting HIF-1α/Wnt/β-Catenin Axis in Mesenchymal Stem Cells

“…Bone morphogenetic proteins (BMPs) is a serial of factors belong to TGF-β super-family, and several member of BMP possess excellent potential to commit progenitor cells to osteoblastic lineage, such as BMP2, BMP7 and BMP9 (2,3). To date, expanding evidences support that BMP9 is one of most effective factors to induce osteoblastic commitment, and may be a potent alternative for bone tissue engineering (4,5). However, adipocytes are also presented in the bone masses induced by BMP9 obviously (6).…”