Bone Remodeling and the Role of TRAF3 in Osteoclastic Bone Resorption

Abstract

Skeletal health is maintained by bone remodeling, a process in which microscopic sites of effete or damaged bone are degraded on bone surfaces by osteoclasts and subsequently replaced by new bone, which is laid down by osteoblasts. This normal process can be disturbed in a variety of pathologic processes, including localized or generalized inflammation, metabolic and endocrine disorders, primary and metastatic cancers, and during aging as a result of low-grade chronic inflammation. Osteoclast formation and activity are promoted by factors, including cytokines, hormones, growth factors, and free radicals, and require expression of macrophage-colony stimulating factor (M-CSF) and receptor activator of NF-κB ligand (RANKL) by accessory cells in the bone marrow, including osteoblastic and immune cells. Expression of TNF receptor-associated factor 6 (TRAF6) is required in osteoclast precursors to mediate RANKL-induced activation of NF-κB, which is also necessary for osteoclast formation and activity. TRAF3, in contrast is not required for osteoclast formation, but it limits RANKL-induced osteoclast formation by promoting proteasomal degradation of NF-κB-inducing kinase in a complex with TRAF2 and cellular inhibitor of apoptosis proteins (cIAP). TRAF3 also limits osteoclast formation induced by TNF, which mediates inflammation and joint destruction in inflammatory diseases, including rheumatoid arthritis. Chloroquine and hydroxychloroquine, anti-inflammatory drugs used to treat rheumatoid arthritis, prevent TRAF3 degradation in osteoclast precursors and inhibit osteoclast formation in vitro. Chloroquine also inhibits bone destruction induced by ovariectomy and parathyroid hormone in mice in vivo. Mice genetically engineered to have TRAF3 deleted in osteoclast precursors and macrophages develop early onset osteoporosis, inflammation in multiple tissues, infections, and tumors, indicating that TRAF3 suppresses inflammation and tumors in myeloid cells. Mice with TRAF3 conditionally deleted in mesenchymal cells also develop early onset osteoporosis due to a combination of increased osteoclast formation and reduced osteoblast formation. TRAF3 protein levels decrease in bone and bone marrow during aging in mice and humans. Development of drugs to prevent TRAF3 degradation in immune and bone cells could be a novel therapeutic approach to prevent or reduce bone loss and the incidence of several common diseases associated with aging.

Malt1 deficient mice develop osteoporosis independent of osteoclast-intrinsic effects of Malt1 deficiency

“…Osteoporosis is a bone disease characterized by reduced bone strength and increased risk of bone fractures . In homeostasis, bone is constantly remodeled at a microscopic level; damaged or ineffete bone is resorbed by osteoclasts and new bone is laid down by osteoblasts . Osteoblasts are derived from mesenchymal cells whereas osteoclasts are hematopoietic in origin .…”

“…In homeostasis, bone is constantly remodeled at a microscopic level; damaged or ineffete bone is resorbed by osteoclasts and new bone is laid down by osteoblasts . Osteoblasts are derived from mesenchymal cells whereas osteoclasts are hematopoietic in origin . In osteoporosis, dysregulation of osteoblast or osteoclast number or activity causes bone resorption to overtake bone formation and net bone mass decreases.…”

miR‐506‐3p alleviates uncontrolled osteoclastogenesis via repression of RANKL/NFATc1 signaling pathway

“…Bone remodeling is an intricate cellular process that essentially sustains the formation of bone and maintains the skeletal architecture (Brylka & Schinke, 2019; Ragipoglu et al, 2020). Nonetheless, this process gets altered during bone degenerative autoimmune disorders including rheumatoid arthritis (RA), ankylosing spondylitis, and osteoarthritis (Boyce, Li, Xing, & Yao, 2018; Mohammadi et al, 2018; Pourakbari, Khodadadi, Aghebati‐Maleki, Aghebati‐Maleki, & Yousefi, 2019). In clinical perspectives, these deformities deal with uncontrolled bone erosion leading to dysfunction and diminished locomotion (Hardy & Fernandez‐Patron, 2020; Vlot et al, 2018).…”

Bif‐1/Endophilin B1/SH3GLB1 regulates bone homeostasis

“…In particular, bone controls calcium levels in the tissues and blood to regulate cellular functions. Despite its hard structure, bone occurs constantly dynamic turnover, named as “bone remodeling,” to maintain the calcium homeostasis and bone volume throughout life …”

“…Despite its hard structure, bone occurs constantly dynamic turnover, named as "bone remodeling," to maintain the calcium homeostasis and bone volume throughout life. [1][2][3] Bone remodeling starts to remove old bones by osteoclasts involving bone resorption. [4][5][6] Osteoclasts are differentiated from hematopoietic cells, in particular, a macrophagemonocyte lineage.…”