Our lab has had a long-term interest in the mechanisms whereby cytokines, hormones and growth factors regulate the formation, activation and survival of osteoclasts. In particular, we have studied the mechanisms whereby IL-1, TNF, PTHrP, RANKL, and TGFb affect these functions of osteoclasts using in vitro and in vivo models of bone resorption and common bone diseases, such as osteoporosis, metastatic bone disease, and inflammatory arthritis in collaboration with Lianping Xing and other members of the Center for Musculoskeletal Research at URMC. These studies have included exploring the roles of Src tyrosine kinase and NF-kB signaling in osteoclast activation and formation and demonstrating the requirement for Src in ruffled border formation, of TGFb in estrogen-induced osteoclast apoptosis, and of NF-kB p50 and p52 expression in osteoclast formation. Recent studies are focused on the role of NF-kB canonical and non-canonical signaling in TNF- and RANKL- induced osteoclast formation and activation. Both of these cytokines activate NF-kB RelA and p50 in the canonical pathway to induce osteoclastogenesis, but they also induce expression of the NF-kB p100, an inhibitory protein that retains RelB in an inactive state in the cytoplasm and restricts signaling in the non-canonical pathway. We have found that unlike RANKL, TNF does not efficiently process p100 to p52 because it does not efficiently induce degradation RANK-associated TRAF3 to facilitate NIK-induced processing of p100. We have generated p100/RelB double knockout mice to explore the role of non-canonical NF-kB signaling in bone cell function and in hematopoietic stem cell functions. The RelB-/- and p100/RelB double knockout mice have increased bone mass and reduced HSC functions. The mechanisms involved are the subject of ongoing NIH-funded research.
- Xing L, Boyce BF. Regulation of Apoptosis in Osteoclasts and Osteoblastic Cells. Biochem Biophys. Res. Comm. 2005; 328(3):709-720.
- Ito H, Koefoed M, Tiyapatanaputi P, Gromov K, Goater JJ, Carmouche J, Zhang X, Rubery PT, Rabinowitz J, Samulski RJ, Nakamura T, Soballe K, Boyce BF, O’Keefe RJ, Schwarz EM. Remodeling of Cortical Bone Allografts Mediated by Adherent rAAV-RANKL and VEGF Gene Therapy. Nat. Med. 2005; 11(3):291-297. PMCID: PMC1364464.
- Zhang Q, Badell IR, Schwarz EM, Boulukos KE, Yao Z, Boyce BF; Xing L. TNF prevents alendronate-induced osteoclast apoptosis in vivo by stimulating Bcl-xL expression through Ets-2. Arth. Rheum. 2005; 52(9):2708-2718.
- Boyce BF, Xing L, Chen D. Osteoprotegerin, the Bone Protector, is a Surprising Target for β-Catenin Signaling. Cell Metab. 2005; 2(6):344-345. PMCID: PMC2647984.
- Kaneki H, Gao R, Chen D, Yao Z, Schwarz EM, Zhang YE, Boyce BF, Xing L. TNF Promotes Runx2 Degradation through up-Regulation of Smurf1 and Smurf2 in Osteoblasts. J. Biol. Chem. 2006; 281(7):4326-4333. PMCID: PMC2647592.
- Morello R, Bertin T, Chen Y, Hicks J, Tonachini L, Monticone M, Castagnola P, Rauch F, Glorieux FH, Vranka J, Bachinger HP, Weis MA, Fernandes R, Eyre DR, Yao Z, Boyce BF, Lee B. CRTAP is required for collagen 3-prolyl-hydroxylation and loss of its function causes recessive Osteogenesis Imperfecta. Cell. 2006; 127(2):291-304.
- Boyce BF, Xing L. Osteoclasts, no longer osteoblast slaves. Nat. Med. 2006; 12(12):1356-1358.
- Yamashita T, Yao Z, Li F, Zhang Q, Badell IR, Schwarz EM, Nishimura R, Takeshita S, Wagner EF, Noda M, Matsuo K, Xing L, Boyce BF. NF-κB p50 and p52 regulate RANKL- and TNF-induced osteoclast precursor differentiation by activating c-Fos and NFATc1. J. Biol. Chem. 2007; 282 (25):18245-18253.
- Boyce BF, Yao Z, Zhang Q, Guo R, Lu Y, Xing L. New roles for osteoclasts in bone. Ann. NY Acad. Sci. 2007; 1116:245-254.
- Engin F, Yang T, Zhou G, Bertin T, Jiang MM, Chen Y, Wang L, Zheng H, Yao Z, Sutton RE, Boyce BF, Lee B. Dimorphic effects of Notch signaling in bone homeostasis. Nat. Med. 2008; 14(3):299-305. PMCID: PMC2671578.
- Usui M, Xing L, Drissi H, Zuscik M, O’Keefe R, Chen D, Boyce BF. Murine and chicken chondrocytes regulate osteoclastogenesis by producing RANKL in response to BMP2. J. Bone Miner Res. 2008; 23(3):314-325. PMCID: PMC2636701.
- Yao Z, Xing L, Qin C, Schwarz EM, Boyce BF. Osteoclast precursor interaction with bone matrix induces osteoclast formation directly by an IL-1-mediated autocrine mechanism. J. Biol. Chem. 2008; 283(15):9917-9924. PMCID: PMC2442286.
- Boyce BF, Xing L. Functions of RANKL/RANK/OPG in bone modeling and remodeling. Arch. Biochem. Biophys. 2008; 473(2):139-146. PMCID: PMC2413418.
- Zhang Q, Guo R, Lu Y, Zhao L, Zhou Q, Schwarz EM, Huang J, Chen D, Jin Z, Boyce BF, Xing L. VEGF-C, a lymphatic growth factor, is a RANKL target gene in osteoclasts that enhances bone resorption through an autocrine mechanism. J. Biol. Chem. 2008; 283(19):13491-13499. PMCID: PMC2442315.
- Zhang Q, Guo R, Schwarz EM, Boyce BF, Xing L. TNF inhibits production of stromal cell-derived factor 1 by bone stromal cells and increases osteoclast precursor mobilization from bone marrow to peripheral blood. Arthr. Res. Ther. 2008; 10(2):R37. PMCID: PMC2453755.
- Guo R, Yamashita M, Zhang Q, Zhou Q, Chen D, Reynolds DG, Awad HA, Yanoso L, Zhao L, Schwarz EM, Zhang YE, Boyce BF, Xing L. Ubiquitin ligase Smurf1 mediates TNF-induced systemic bone loss by promoting proteasomal BMP signaling proteins. J. Biol. Chem. 2008; 283(34):23084-23092. PMCID: PMC2517001.
- Boyce BF. Sphingosine-1 Phosphate: a new player in osteoimmunology. Dev. Cell 2009; 16(3):323-324.
- Boyce BF. Stomaching calcium for bone health. Nat. Med. 2009; 15(6):610-612.
- Boyce BF, Yao Z, Xing L. Osteoclasts have multiple roles in bone in addition to bone resorption. Crit. Rev. Eukaryot. Gene Expr. 2009; 19(3):171-180. PMCID: PMC2856465.
- Yao Z, Xing L, Boyce BF. NF-?B p100 limits TNF-induced bone resorption in mice by a TRAF3-dependent mechanism. J. Clin. Invest. 2009; 119(10):3024-3034. PMCID: PMC2752069.
- Yao Z, Li P, Zhang Q, Guo R, Schwarz EM, Boyce BF, Xing L. Disruption of Rankl/Rank Signaling Reduces TNF-Induced Joint Inflammation In Vivo. Open Arth. J. 2009; 2:7-13.
- Boyce BF, Yao Z, Xing L. Functions of NF-κB in Bone. Ann. NY Acad. Sci. 2010; 1192(1):367-375. PMCID: PMC3013362.
- Camacho N, Krakow D, Johnykutty S, Katzman, PJ, Pepkowitz S, Boyce BF Cohn DH. Dominant TRPV4 mutations in non-lethal and lethal metatropic dysplasia. Am. J. Med. Genet. Part A. 2010; 152A(5):1169-1177.
Graduate Program Affiliations
Brendan F. Boyce, M.D.
University of Rochester
601 Elmwood Ave., Box 626
Rochester, NY 14642
Phone: (585) 275-5837
Zhenqiang Yao, M.D.; Research Assistant Professor
Yan Xiu, MD, PhD, Postdoctoral Research Associate
Yanyun Li; Laboratory Technician