A Neutralizing Antibody Targeting Oxidized Phospholipids Promotes Bone Anabolism in Chow‐Fed Young Adult Mice

Autor: Robert L. Jilka, Ha-Neui Kim, Horacio Gomez-Acevedo, Stavros C. Manolagas, Joseph L. Witztum, Elena Ambrogini, Sotirios Tsimikas, Xuchu Que, Michela Palmieri
Rok vydání: 2020
Předmět:
Male
0301 basic medicine
CELLS OF BONE
Aging
medicine.medical_specialty
Anabolism
ANABOLICS
Knockout
Endocrinology
Diabetes and Metabolism
Transgene
Osteoporosis
030209 endocrinology & metabolism
Medical and Health Sciences
Article
Antibodies
Mice
03 medical and health sciences
Engineering
0302 clinical medicine
Osteogenesis
OSTEOBLASTS
Internal medicine
medicine
Animals
Orthopedics and Sports Medicine
Scavenger receptor
Receptor
MOLECULAR PATHWAYS—REMODELING
Neutralizing
Phospholipids
Mice
Knockout
Chemistry
BONE MODELING AND REMODELING
Osteoblast
Biological Sciences
Anatomy & Morphology
medicine.disease
Antibodies
Neutralizing
SCARB1
030104 developmental biology
medicine.anatomical_structure
Endocrinology
THERAPEUTICS
MOLECULAR PATHWAYS-REMODELING
Female
Cortical bone
Oxidation-Reduction
Zdroj: Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research, vol 36, iss 1
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research
ISSN: 1523-4681
0884-0431
Popis: Oxidized phospholipids containing phosphocholine (OxPL) are pro-inflammatory lipid peroxidation products that bind to scavenger receptors (SRs), such as Scarb1, and toll-like receptors (TLRs). Excessive OxPL, as found in oxidized low-density lipoprotein (OxLDL), overwhelm these defense mechanisms and become pathogenic in atherosclerosis, nonalcoholic steatohepatitis (NASH), and osteoporosis. We previously reported that the innate IgM natural antibody E06 binds to OxPL and neutralizes their deleterious effects; expression of the single-chain (scFv) form of the antigen-binding domain of E06 (E06-scFv) as a transgene increases trabecular bone in male mice. We show herein that E06-scFv increases trabecular and cortical bone in female and male mice by increasing bone formation and decreasing osteoblast apoptosis in vivo. Homozygous E06-scFv mice have higher bone mass than hemizygous, showing a dose effect of the transgene. To investigate how OxPL restrain bone formation under physiologic conditions, we measured the levels of SRs and TLRs that bind OxPL. We found that osteoblastic cells primarily express Scarb1. Moreover, OxLDL-induced apoptosis and reduced differentiation were prevented in bone marrow-derived or calvaria-derived osteoblasts from Scarb1 knockout mice. Because Scarb1-deficient mice are reported to have high bone mass, our results suggest that E06 may promote bone anabolism in healthy young mice, at least in part, by neutralizing OxPL, which in turn promote Scarb1-mediated apoptosis of osteoblasts or osteoblast precursors. © 2020 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR)..
Databáze: OpenAIRE
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