The Inflammatory Contribution of B-Lymphocytes and Neutrophils in Progression to Osteoporosis

Abstract

Osteoporosis is a bone disease characterized by structural deterioration and low bone mass, leading to fractures and significant health complications. In this review, we summarize the mechanisms by which B-lymphocytes and neutrophils contribute to the development of osteoporosis and potential therapeutics targeting these immune mediators to reduce the proinflammatory milieu. B-lymphocytes-typically appreciated for their canonical role in adaptive, humoral immunity-have emerged as critical regulators of bone remodeling. B-lymphocytes communicate with osteoclasts and osteoblasts through various cytokines, including IL-7, RANK, and OPG. In inflammatory conditions, B-lymphocytes promote osteoclast activation and differentiation. However, B-lymphocytes also possess immunomodulatory properties, with regulatory B-lymphocytes (Bregs) secreting TGF-β1 to restrain pathogenic osteoclastogenesis. Neutrophils, the body's most prevalent leukocyte, also contribute to the proinflammatory environment that leads to osteoporotic bone remodeling. In aged individuals, neutrophils display reduced chemotaxis, phagocytosis, and apoptosis. Understanding the delicate interplay between B-lymphocytes and neutrophils in the context of impaired bone metabolism is crucial for targeted therapies for osteoporosis.

Keywords: B-lymphocytes; Bregs; IL-10; TGF-β1; aging; bone remodeling; inflammation; neutrophils; osteoimmunology; osteoporosis.

Figure 1

The effects of B-lymphocytes on bone homeostasis. B-lymphocytes (BC) and osteogenic precursors develop together in the bone marrow niche. In (a), osteoblasts (OB) can secrete RANKL, which binds RANK on the surfaces of monocyte-like progenitor cells (MpC) and stimulates differentiation and fusion into multinucleated osteoclasts (OC). RANKL also binds RANK on osteoclasts to promote survival and proliferation. In healthy bone, pro-osteoclastogenic RANKL is regulated by the osteoprotegerin (OPG) decoy receptor, as well as various soluble mediators secreted by OBs, BCs, and B-regulatory lymphocytes (Bregs). Thus, normal B-lymphocyte and osteogenic signaling generates an anti-inflammatory environment that maintains bone mineral density (BMD). In osteoporotic tissue, seen in (b), proinflammatory mediators drive osteoclastogenesis through increased expression of RANK-L, shifting the balance of bone metabolism toward catabolism and ultimately bone loss. Created with BioRender.com, accessed on 3 June 2023.

Figure 2

Impaired tissue apoptosis in aged neutrophils triggers excessive neutrophil mobilization. (a) Normal neutrophils (polymorphonuclear, PMN) extravasate at the endothelial lining into the tissue, release a burst of bleach (HOCl•) to fight bacterial infection, and eventually undergo apoptosis. Macrophages (Mp) phagocytose apoptotic neutrophils and deactivate IL-23 secretion, which decreases IL-17 and granulocyte colony-stimulating factor (G-CSF) signaling and pauses neutrophil mobilization from the bone marrow. Thus, the neutrophil-to-lymphocyte ratio (NLR) is maintained with normal neutrophil function. In aged individuals with greater systemic inflammation and ROS, shown in (b), neutrophils have impaired chemotaxis, extravasation, and apoptosis. Macrophages are then free to secrete IL-23, which increases IL-17 expression from TH17 T-lymphocytes (TC) and G-CSF from fibroblasts (fb). Increased G-CSF leads to increased neutrophil release from the bone marrow and a high NLR ratio. Created with BioRender.com, accessed on 3 June 2023.