Mucin 1 (Muc1) Deficiency in Female Mice Leads to Temporal Skeletal Changes During Aging

Abstract

Mucin1 (MUC1) encodes a glycoprotein that has been demonstrated to have important roles in cell‐cell interactions, cell‐matrix interactions, cell signaling, modulating tumor progression and metastasis, and providing physical protection to cells against pathogens. In this study, we investigated the bone phenotype in female C57BL/6 Muc1 null mice and the impact of the loss of Muc1 on osteoblasts and osteoclasts. We found that deletion of Muc1 results in reduced trabecular bone volume in 8‐week‐old mice compared with wild‐type controls, but the trabecular bone volume fraction normalizes with increasing age. In mature female mice (16 weeks old), Muc1 deletion results in stiffer femoral bones with fewer osteoblasts lining the trabecular surface but increased endosteal mineralized surface and bone formation rate. The latter remains higher compared with wild‐type females at age 52 weeks. No difference was found in osteoclast numbers in vivo and in bone marrow osteoblast or osteoclast differentiation capacity or activity in vitro. Taken together, these results suggest that Muc1 depletion causes a transiently reduced trabecular bone mass phenotype in young mice, and later in life reduced numbers of osteoblasts with increased endocortical mineralization activity coincides with unaffected total bone mass and increased stiffness. In conclusion, our results show, for the first time to our knowledge, a role for Muc1 in bone mass and mineralization in mice in a time‐dependent manner. © 2018 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

Influence of MUC1 on trafficking of TRPV5 and TRPV6 andin vivoCa2+homeostasis

“…Given the robust difference in TRP channel localization observed in vivo in kidney and duodenum, it is surprising that the measured parameters of Ca homeostasis – blood Ca 2+ , urine Ca excretion, PTH, and 1,25 (OH)2 vitamin D, are not more dramatically altered. Even the decrement in bone mineralization previously observed in Muc1 -/- mice is relatively minor compared to the decrease in bone density observed in TRPV5 -/- or TRPV6 -/- mice (20,21,25). All this suggests compensatory measures independent of these Ca 2+ -selective channels.…”

“…This could reflect a state of Ca homeostasis, albeit with lower systemic Ca stores. 3) A previous study found mild reduction in bone density in Muc1 -/- mice (25). Osteoblast and osteoclast function appeared normal in Muc1 -/- mice, and no compelling mechanism for the bone phenotype was described.…”

Polymer–Protein Hybrid Network Involving Mucin: A Mineralized Biomimetic Template for Bone Tissue Engineering

“…[ 6 ] Mucin 1 (Muc1) expression increases during osteoblast differentiation when compared with undifferentiated human mesenchymal stromal cells, indicating a potential role for Mucin 1 in the dynamic bone formation and remodeling process. [ 7,8 ] Due to mucoadhesive properties of various polymers, [ 9,10 ] it is usually thought that mucin‐attractive polymers are capable of forming a large number of hydrogen bonds with mucin. [ 11 ] This might be because mucins contain hydroxyl groups in the branched sugar chains and carboxylic acid and sulfate groups in the terminal segments of branched chains., [ 12,13 ] Mucins typically contain 70–90 wt% carbohydrate, and the protein backbone accounts for most of the remaining part.…”

Inhibition of hypoxia‐induced Mucin 1 alters the proteomic composition of human osteoblast‐produced extracellular matrix, leading to reduced osteogenic and angiogenic potential

“…Mucin 1 (MUC1) is a transmembrane heterodimeric glycoprotein expressed on the surface of secretory epithelial, mucosal, and hematopoietic cells (Nath & Mukherjee, 2014). We previously found that MUC1 is upregulated in differentiating osteoblasts derived from human MSC and that Muc1 plays an age-dependent role in murine bone development (Brum et al, 2018). The extracellular domain of MUC1 (N-terminal) is composed of a variable number of 20 amino acid tandem repeats with extensive O-glycans (Dhar & McAuley, 2019).…”

“…Despite the previously generated knowledge regarding the role of MUC1 in bone in vivo (Brum et al, 2018 ), there is a large knowledge gap as to how and what physiological changes in the ECM are modulated by MUC1 in human osteoblasts? Considering the upregulation of MUC1 under hypoxia and the oxygen concentration is a major modulating factor for ECM and its mineralization, we assessed the role of MUC1 and hypoxia on the proteomic composition of human osteoblast‐produced ECM and its consequences for osteogenesis and angiogenesis.…”