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.

High-Energy, Whole-Body Proton Irradiation Differentially Alters Long-Term Brain Pathology and Behavior Dependent on Sex and Alzheimer’s Disease Mutations

AUTHORS

Robert G. Hinshaw, Maren K. Schroeder, Jason Ciola, Curran Varma, Brianna Colletti, Bin Liu, Grace Geyu Liu, Qiaoqiao Shi, Jacqueline P. Williams, M. Kerry O’Banion, Barbara J. Caldarone and Cynthia A. Lemere

ABSTRACT

Whole-body exposure to high-energy particle radiation remains an unmitigated hazard to human health in space. Ongoing experiments at the NASA Space Radiation Laboratory and elsewhere repeatedly show persistent changes in brain function long after exposure to simulations of this unique radiation environment, although, as is also the case with proton radiotherapy sequelae, how this occurs and especially how it interacts with common comorbidities is not well-understood. Here, we report modest differential changes in behavior and brain pathology between male and female Alzheimer’s-like and wildtype littermate mice 7–8 months after exposure to 0, 0.5, or 2 Gy of 1 GeV proton radiation. The mice were examined with a battery of behavior tests and assayed for amyloid beta pathology, synaptic markers, microbleeds, microglial reactivity, and plasma cytokines. In general, the Alzheimer’s model mice were more prone than their wildtype littermates to radiation-induced behavior changes, and hippocampal staining for amyloid beta pathology and microglial activation in these mice revealed a dose-dependent reduction in males but not in females. In summary, radiation-induced, long-term changes in behavior and pathology, although modest, appear specific to both sex and the underlying disease state.

Mitochondrial fragmentation and donut formation enhance mitochondrial secretion to promote osteogenesis

AUTHORS

Joonho Suh, Na-Kyung Kim, Wonn Shim, Jae Hyuck Jang, Jung-Eun Kim, Yun-Sil Lee

ABSTRACT

Mitochondrial components have been abundantly detected in bone matrix, implying that they are somehow transported extracellularly to regulate osteogenesis. Here, we demonstrate that mitochondria and mitochondrial-derived vesicles (MDVs) are secreted from mature osteoblasts to promote differentiation of osteoprogenitors. We show that osteogenic induction stimulates mitochondrial fragmentation, donut formation, and secretion of mitochondria through CD38/cADPR signaling. Enhancing mitochondrial fission and donut formation through Opa1 knockdown or Fis1 overexpression increases mitochondrial secretion and accelerates osteogenesis. We also show that mitochondrial fusion promoter M1, which induces Opa1 expression, impedes osteogenesis, whereas osteoblast-specific Opa1 deletion increases bone mass. We further demonstrate that secreted mitochondria and MDVs enhance bone regeneration in vivo. Our findings suggest that mitochondrial morphology in mature osteoblasts is adapted for extracellular secretion, and secreted mitochondria and MDVs are critical promoters of osteogenesis.

Ablation of myeloid discoidin domain receptor 2 exacerbates arthritis and high fat diet induced inflammation

AUTHORS

Qingyun Liu, Xiaolong Wang, Yazhuo Chen, Xiao Ma, Xiaomin Kang, Fang He, Dongxu Feng, Yan Zhang

ABSTRACT

Chronic systemic inflammation leads to sever disorders and diseases. It is of great importance to explore novel target for effective treatment. Discoidin domain receptor 2 (Ddr2) is a member of receptor tyrosine kinase (RTK) family and is implicated in skeletal and fat hemostasis. However, the role of Ddr2 in myeloid cells remains obscure. In this study, we conditionally deleted Ddr2 in myeloid lineage cells to generate cKO mice to investigate the role of Ddr2 in myeloid lineage cells. We found that cKO mice exhibited more severe inflammation both in collagen antibody-induced arthritis (CAIA) and high-fat diet (HFD)-induced obesity, indicating the protective role of Ddr2 against inflammation. Mechanistically, Ddr2 promotes macrophage repolarization from the M1 to M2 phenotype, and protect against systemic inflammation. Our study reveals for the first time that Ddr2 modulates macrophage repolarization and plays critical roles in macrophage-mediated inflammation, providing potential target for the intervention of inflammation and related diseases.

Peroxiredoxin 5 regulates osteogenic differentiation through interaction with hnRNPK during bone regeneration

AUTHORS

Eunjin Cho, Xiangguo Che, Mary Jasmin Ang, Seongmin Cheon, Jinkyung Lee, Kwang Soo Kim, Chang Hoon Lee, Sang-Yeop Lee, Hee-Young Yang, Changjong Moon, Chungoo Park, Je-Yong Choi, Tae-Hoon Lee

ABSTRACT

Peroxiredoxin 5 (Prdx5) is involved in pathophysiological regulation via the stress-induced cellular response. However, its function in the bone remains largely unknown. Here, we show that Prdx5 is involved in osteoclast and osteoblast differentiation, resulting in osteoporotic phenotypes in Prdx5 knockout (Prdx5Ko) male mice. To investigate the function of Prdx5 in the bone, osteoblasts were analyzed through immunoprecipitation (IP) and liquid chromatography combined with tandem mass spectrometry (LC–MS/MS) methods, while osteoclasts were analyzed through RNA-sequencing. Heterogeneous nuclear ribonucleoprotein K (hnRNPK) was identified as a potential binding partner of Prdx5 during osteoblast differentiation in vitro. Prdx5 acts as a negative regulator of hnRNPK-mediated osteocalcin (Bglap) expression. In addition, transcriptomic analysis revealed that in vitro differentiated osteoclasts from the bone marrow-derived macrophages of Prdx5Ko mice showed enhanced expression of several osteoclast-related genes. These findings indicate that Prdx5 might contribute to the maintenance of bone homeostasis by regulating osteoblast differentiation. This study proposes a new function of Prdx5 in bone remodeling that may be used in developing therapeutic strategies for bone diseases.

USP53 regulates bone homeostasis by controlling Rankl expression in osteoblasts and bone marrow adipocytes

AUTHORS

Hadla Hariri, Orhun Kose, Aren Bezdjian, Sam J Daniel, René St-Arnaud

ABSTRACT

In the skeleton, osteoblasts and osteoclasts synchronize their activities to maintain bone homeostasis and integrity. Investigating the molecular mechanisms governing bone remodeling is critical and helps understand the underlying biology of bone disorders. Initially, we have identified the ubiquitin-specific peptidase gene (Usp53) as a target of the parathyroid hormone in osteoblasts and a regulator of mesenchymal stem cell differentiation. Mutations in USP53 have been linked to a constellation of developmental pathologies. However, the role of Usp53 in bone has never been visited. Here we show that Usp53 null mice have a low bone mass phenotype in vivo. Usp53 null mice exhibit a pronounced decrease in trabecular bone indices including trabecular bone volume (36%) and trabecular number (26%) along with an increase in trabecular separation (13%). Cortical bone parameters are also impacted showing a reduction in cortical bone volume (12%) and cortical bone thickness (15%). As a result, the strength and mechanical bone properties of Usp53 null mice have been compromised. At the cellular level, the ablation of Usp53 perturbs bone remodeling, augments osteoblast-dependent osteoclastogenesis, and increases osteoclast numbers. Bone marrow adipose tissue volume increased significantly with age in Usp53-deficient mice. Usp53 null mice displayed increased serum RANKL levels and Usp53 deficient osteoblasts and bone marrow adipocytes have increased expression of Rankl. Mechanistically, USP53 regulates RANKL expression by enhancing the interaction between VDR and SMAD3. This is the first report describing the function of Usp53 during skeletal development. Our results put Usp53 in display as a novel regulator of osteoblast–osteoclast coupling and open the door for investigating the involvement of USP53 in pathologies.