BMP-2 Long-Term Stimulation of Human Pre-Osteoblasts Induces Osteogenic Differentiation and Promotes Transdifferentiation and Bone Remodeling Processes

Abstract

Bone morphogenic protein (BMP-) 2 plays an important role in the regeneration of bone defects by promoting osteogenic differentiation. However, several animal studies have reported adverse side effects of BMP-2, including osteoclast activation, induction of peroxisome proliferator- activated receptor gamma (PPARG)expression, and inflammation. High BMP-2 concentrations are thought to be responsible for these side effects. For this reason, primary pre-osteoblasts were exposed to lower BMP-2 concentrations (1 and 2 µg/mL). Long-term exposure (up to 28 days) was performed to investigate whether this stimulation protocol may promote osteogenic differentiation without causing the side effects mentioned above. The results showed that BMP-2 treatment for 14 or 28 days resulted in increased osteogenesis, through an increase in runt-related transcription factor 2, osterix, alkaline phosphatase, and integrin-binding sialoprotein expression. However, an increase in tumor necrosis factor alpha and receptor activator of nuclear factor kappa-Β ligand protein levels was observed after BMP-2 exposure, indicating also an increased potential for osteoclast activation by osteoblasts. Additionally, morphological changes like intracellular, filled vacuoles could be detected. Enhanced PPARG and perilipin 1 mRNA transcripts and lipid droplets indicated an induced adipogenic differentiation. Overall, the data demonstrate that long-term BMP-2 exposure promotes not only osteogenic differentiation but also adipogenesis and regulates mediators involved in osteoclast activation in vitro.

Cellular response of advanced triple cultures of human osteocytes, osteoblasts and osteoclasts to high sulfated hyaluronan (sHA3)

“…As described before, the active metabolite of vitamin D3: 1,25 (OH)2-vitamin D3 significantly increased BGLAP production in OBs [ 27 ] and BGLAP expression in induced pluripotent stem cell derived osteoprogenitors [ 28 ], making vitamin D3 a potent promoter of OB-OCy-transition. Induction of osteogenic differentiation with upregulated RANKL expression in response to BMP-2 was also reported by Ingwersen et al [ 29 ]. In addition, SOST expression is known to be stimulated by BMPs in MLO-A5 osteocytes [ 30 ] as well as in Saos-2 cells [ 31 ].…”

Influence of Chinese Herbal Formula on Bone Characteristics of Cobb Broiler Chickens

“…TNF-α can reduce the special markers of osteoblast differentiation, and can also regulate the expression of BMP-2 , and finally inhibit the differentiation of osteoblasts. It also promotes the mitosis of osteoclast precursor cells and the differentiation and maturation of osteoclast progenitor cells, and can also inhibit the apoptosis of osteoclasts and inhibit bone remodeling, ultimately leading to bone loss [ 50 , 51 ]. In this experiment: in the thoracic vertebrae and leg cartilage tissues, the relative expression levels of TNF-α mRNA in the 30- and 60-day-old CHF group and BPs group were lower than those in the NC group.…”

Traditional Chinese medicine in osteoporosis: from pathogenesis to potential activity

“…In bone, BMP signals were also mediated by their receptors and formed complex bodies with them, further regulating the transcription of related genes involved in the differentiation of osteoblast and formation of bone ( Wu et al, 2016 ). Among BMPs, BMP-2 could promote osteogenesis by regulating the expression of Runx2, ALP, and integrin-binding sialoprotein and activate osteoclast through the upregulation of TNF-α and NF-κB ligands ( Ingwersen et al, 2022 ). Moreover, BMP/Smad1 could regulate the activity of atonal homolog 8 and inhibit the expression ratio of RANKL/OPG, thereby regulating the osteoclast number negatively and promoting bone resorption and loss ( Yahiro et al, 2020 ) ( Figure 4 ).…”