Abstract
Several studies have indicated that PAPSS2 (3′-phosphoadenosine-5′-phosphosulfate synthetase 2) activity is important to normal skeletal development. Mouse PAPSS2 is predominantly expressed during the formation of the skeleton and cartilaginous elements of the mouse embryo and in newborn mice. However, the role and mechanism of PAPSS2 in bone formation remains largely unidentified. By analyzing the expression pattern of the PAPSS2 gene, we have found that PAPSS2 is expressed in bone tissue and bone formation. PAPSS2 transcripts increase during osteoblast differentiation and are in less level in RANKL-induced osteoclast like cells. By using lentivirus-mediated RNA interference (RNAi) technology, we knocked down PAPSS2 expression in MC3T3-E1 osteoblast. Silencing of PAPSS2 expression significantly decreases ALP activity and cell mineralization, inhibits expression of osteoblast marker osteopontin (OPN) and collagen I. Conversely, overexpression of PAPSS2 promotes the MC3T3-E1 to differentiate into osteoblast and mineralization. Moreover, compared to that in the control cells, the mRNA level and protein expression of phosphorylated Smad 2/3, which is a key transcriptional factor in the Smad osteoblast differentiation pathway, showed significant decreases in PAPSS2-silenced cells and increases in PAPSS2-overexpression cells. These results suggest that PAPSS2 might regulate osteoblast ALP activity and cell mineralization, probably through Smads signal pathways.
Highlights
Bone is a mineralized tissue that underlies multiple mechanical and metabolic functions of the skeleton [1,2]
We found that the expression of PAPSS2 was very high in the bones, liver, and lungs and moderate in the heart
Our results showed that PAPSS2 was prominently expressed in authentic mouse osteoblasts exposed to OS media at both the mRNA and protein levels
Summary
Bone is a mineralized tissue that underlies multiple mechanical and metabolic functions of the skeleton [1,2]. Formation and maintenance of bone tissue are regulated in a sophisticated fashion by bone-forming osteoblasts and bone-resorbing osteoclasts Many skeletal diseases, such as osteoporosis, Kashin-Beck disease, Paget’s disease of the bone, rheumatoid arthritis, and bone metastases all arise from an imbalance in the relative activities of osteoblasts and osteoclasts [3]. A homozygous PAPSS2 mutation (S475X) was identified in another large Pakistani family affected by SEMD, Pakistani type [8,9]. This manifested as disproportionately short stature with short, bowed lower limbs, enlarged knee joints, kyphoscoliosis, and generalized brachydactyly [7]. Humans lacking normal PAPSS2 activity exhibit long bone shortening and bowing, and show degenerative joint disease, including evidence of knee joint arthrosis. Given the premature development of degenerative knee joint disease in the mutant mice and other similarities between SEMD mice and human lacking normal PAPSS2 activity, it has been proposed that this mutant represents a model of human PAPSS2 deficiency-associated arthrosis [11]
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