3′-Sialyllactose alleviates bone loss by regulating bone homeostasis

AUTHORS

Ahreum Baek, Dawoon Baek, Yoonhee Cho, Seongmoon Jo, Jinyoung Kim, Yoontaik Hong, Seunghee Cho, Sung Hoon Kim & Sung-Rae Cho

ABSTRACT

Osteoporosis is a common skeletal disease that results in an increased risk of fractures. However, there is no definitive cure, warranting the development of potential therapeutic agents. 3′-Sialyllactose (3′-SL) in human milk regulates many biological functions. However, its effect on bone metabolism remains unknown. This study aimed to investigate the molecular mechanisms underlying the effect of 3′-SL on bone homeostasis. Treatment of human bone marrow stromal cells (hBMSCs) with 3′-SL enhanced osteogenic differentiation and inhibited adipogenic differentiation of hBMSCs. RNA sequencing showed that 3′-SL enhanced laminin subunit gamma-2 expression and promoted osteogenic differentiation via the phosphatidylinositol 3‑kinase/protein kinase B signaling pathway. Furthermore, 3′-SL inhibited the receptor activator of nuclear factor κB ligand-induced osteoclast differentiation of bone marrow-derived macrophages through the nuclear factor κB and mitogen‑activated protein kinase signaling pathway, ameliorated osteoporosis in ovariectomized mice, and positively regulated bone remodeling. Our findings suggest 3′-SL as a potential drug for osteoporosis.

Sugar transporter Slc37a2 regulates bone metabolism in mice via a tubular lysosomal network in osteoclasts

AUTHORS

Pei Ying Ng, Amy B. P. Ribet, Qiang Guo, Benjamin H. Mullin, Jamie W. Y. Tan, Euphemie Landao-Bassonga, Sébastien Stephens, Kai Chen, Jinbo Yuan, Laila Abudulai, Maike Bollen, Edward T. T. T. Nguyen, Jasreen Kular, John M. Papadimitriou, Kent Søe, Rohan D. Teasdale, Jiake Xu, Robert G. Parton, Hiroshi Takayanagi & Nathan J. Pavlos

ABSTRACT

Osteoclasts are giant bone-digesting cells that harbor specialized lysosome-related organelles termed secretory lysosomes (SLs). SLs store cathepsin K and serve as a membrane precursor to the ruffled border, the osteoclast’s ‘resorptive apparatus’. Yet, the molecular composition and spatiotemporal organization of SLs remains incompletely understood. Here, using organelle-resolution proteomics, we identify member a2 of the solute carrier 37 family (Slc37a2) as a SL sugar transporter. We demonstrate in mice that Slc37a2 localizes to the SL limiting membrane and that these organelles adopt a hitherto unnoticed but dynamic tubular network in living osteoclasts that is required for bone digestion. Accordingly, mice lacking Slc37a2 accrue high bone mass owing to uncoupled bone metabolism and disturbances in SL export of monosaccharide sugars, a prerequisite for SL delivery to the bone-lining osteoclast plasma membrane. Thus, Slc37a2 is a physiological component of the osteoclast’s unique secretory organelle and a potential therapeutic target for metabolic bone diseases.