Prostate transmembrane protein androgen induced 1 is induced by activation of osteoclasts and regulates bone resorption

Abstract

Osteoclasts derived from hematopoietic cells are activated on bone surface. To resorb bone, osteoclasts release acid and lysosome acid hydrolase via membrane transport. Prostate transmembrane protein androgen induced 1 (Pmepa1) is a type I transmembrane protein that regulates proliferation, migration, and metastasis of cancer cells. Because recent reports showed that Pmepa1 is involved in membrane transport in cancer cells, we investigated the role of Pmepa1 in osteoclast function. Pmepa1 expression was barely detected in osteoclasts formed on plastic surfaces in vitro, but was markedly increased in activated osteoclasts formed on calcified matrix. Inhibitors of bone resorption, such as alendronate, bafilomycin A1, and the PI3K inhibitor LY294002, suppressed the expression of Pmepa1 in osteoclasts. Knockdown of Pmepa1 expression impaired bone resorption activity and inhibited formation of a ring‐like, actin‐rich podosome belt that is essential for osteoclast function. Pmepa1 protein localized to lysosomes in osteoclasts. In addition, in sites of bone destruction observed in rats with adjuvant‐induced arthritis, a marked high level of Pmepa1 expression was associated with the osteoclasts' resorbing bone. Our results suggest that Pmepa1 is a critical regulator of bone resorption and is a promising marker for activated osteoclasts and a potential therapeutic target in pathologic bone destruction.—Xu, X., Hirata, H., Shiraki, M., Kamohara, A., Nishioka, K., Miyamoto, H., Kukita, T., Kukita, A. Prostate transmembrane protein androgen induced 1 is induced by activation of osteoclasts and regulates bone resorption. FASEB J. 33, 4365–4375 (2019). http://www.fasebj.org

Study on the cellular internalization mechanisms and in vivo anti-bone metastasis prostate cancer efficiency of the peptide T7-modified polypeptide nanoparticles

“…Furthermore, clinical statistics revealed that low expression of PMEPA1 led to bone metastases and dropped survival. In BMPCa patients, PMEPA1 was decreased that regulates the tumor cells invasion, proliferation, and metastasis (Fournier et al, 2015;Xu et al, 2019). 20-25% of metastatic PCa harbor defects in DNA repair genes (Athie et al, 2019).…”

Overexpression of c‐Fos reverses osteoprotegerin‐mediated suppression of osteoclastogenesis by increasing the Beclin1‐induced autophagy

“…LY294002 (LY), the PI3K inhibitor, which can block the formation of phagophore in the early stage of autophagy 27,28 . There are no different on the number of TRAP‐positive multinucleated cells treatment with LY + OPG group compared with OPG‐only group (Figure 3A).…”

Hdac3 deletion in myeloid progenitor cells enhances bone healing in females and limits osteoclast fusion via Pmepa1

“…Pmepa1 localizes to intracellular organelle membranes, and to cathepsin-K positive vesicle membranes in osteoclast progenitor cells 66 . Xu et al showed that knockdown of Pmepa1 suppressed osteoclast activity and that Pmepa1 is associated with the actin ring of osteoclasts during adjuvant-induced bone resorption 67 . In our study, we find that knockdown of Pmepa1 after 24 h of RANKL exposure enhances osteoclast fusion, but represses osteoclast activity.…”