TNF receptor-associated factors: promising targets of natural products for the treatment of osteoporosis

Abstract

Tumor necrosis factor receptor-associated factors (TRAFs) are crucial intracellular signaling proteins in bone homeostasis. TRAFs mediate pathways associated with bone remodeling, particularly in response to inflammatory stimuli, influencing osteoclast differentiation and function. Dysregulation of TRAF-mediated signaling contributes significantly to osteoporosis, a condition marked by increased bone resorption and fragility. Natural products, with their anti-inflammatory and antioxidant properties, offer promising therapeutic potential by targeting TRAF-associated pathways to inhibit excessive osteoclast activity and promote bone formation. This review explores the mechanisms by which natural compounds modulate TRAF signaling in osteoclastogenesis and osteoblastogenesis, providing insights into their potential for osteoporosis treatment.

Keywords: ABCA2; AQP4; CD14; CD163; KCND3; SV2B; common genes; such as SNAP25.

FIGURE 1

Comparison of healthy and osteoporotic bone tissue highlights the cellular interactions and signaling pathways involved in bone remodeling. Osteoblasts (bone-forming cells), osteocytes (mature bone cells), and osteoclast precursors are in balance in healthy tissue. However, an increase in RANKL in osteoporosis promotes osteoclast activation, leading to excessive bone resorption. Osteoprotegerin (OPG) acts as a decoy receptor to regulate RANKL activity, but its diminished function in osteoporosis results in bone deterioration.

FIGURE 2

Key factors influencing osteoporosis development. Hormonal factors, such as estrogen deficiency, play a crucial role in bone loss by enhancing osteoclast activity and reducing bone density, particularly in postmenopausal women. Genetic factors, through specific gene mutations and inherited traits, contribute to susceptibility by influencing bone mineral density (BMD) and osteoblast function. Nutritional factors, including calcium, vitamin D, protein, and other micronutrients, support bone health, while deficiencies elevate osteoporosis risk. Age-related changes and oxidative stress also contribute by disrupting bone remodeling and cellular function, with oxidative stress promoting osteoclast activity and cell senescence. Understanding these interconnected mechanisms can guide targeted therapies for osteoporosis prevention and management.

FIGURE 3

Schematic representation of the signaling pathways involved in osteoclast differentiation and osteoporosis activity highlights molecular targets for potential therapeutic intervention by natural products. The illustration shows the interaction between RANKL (receptor activator of nuclear factor kappa-Β ligand) and its receptor RANK, which activates downstream signaling cascades, including TRAF-mediated pathways (TRAF2, TRAF3, and TRAF6) and essential kinases (TAK1, MAPK, JNK, ERK, and p38). Natural compounds and their extracts influence these pathways, with effects on regulators such as NF-κB, Nrf2, and various microRNAs (e.g., miR-423-3p, miR-181a-5p, and miR-214-3p), ultimately modulating expressions of genes and proteins associated with osteoclastogenesis and bone resorption.