Tumor Necrosis Factor Family Receptors Regulating Bone Turnover

While the tumor necrosis factor (TNF) family members RANKL and TNF-alpha are critical regulators of osteoclast formation, functions of other TNFs in bone are poorly understood. Here we consider the roles in regulating bone turnover of TNF receptors (TNF-R) also expressed by osteoblasts and osteoblast precursors. TNF receptors in osteoblasts and preosteoblasts include TNFR1 (p55), DR3 (TNFR25), DR5 (TRAIL-R2) and Fas, and possibly FN14 and DR4 (TRAIL-R1). Osteoblasts also produce soluble TNF receptors, DcR2, osteoprotegerin, and sDR3; these bind the TNFs TRAIL, RANKL, TL1A, and Apo3L and block ligand effects on cell surface receptors. Activation of DR3 regulates osteoblast maturation and may control the decision to exit the pool of differentiation-competent preosteoblasts. A major natural ligand for DR3, TL1A, is produced by vascular cells adjacent to differentiating osteoblasts and possibly by Fcgamma-stimulated osteoclast precursors. The activity of DR3 is regulated by osteoblast production of its soluble DR3 splice variant. Activation of TNFR1 or DR5 by TNF-alpha or TRAIL may regulate osteoblast connectivity, which is important to bone turnover. When there is a source for Fas ligand, such as an inflammatory infiltrate, activation of Fas may lead to apoptosis of any bone cell. TNF receptors are thus implicated in multiple aspects of bone turnover.