Paget's disease of bone (PDB) is a chronic focal skeletal disorder that affects 2-3% of the population over 55 years of age with genetic heterogeneity. PDB is characterized by high bone turnover with increased abnormal osteoclast (OCL) formation/bone resorption activity followed exaggerated osteoblasts response at focal lesions. Pagetic OCL contains paramyxoviral nuclear inclusions and nucleocapsid transcripts. We have previously shown that measles virus nucleocapsid protein (MVNP) induces pagetic phenotype in OCL. Also, we identified high levels of RANK ligand (RANKL), a critical osteoclastogenic factor expression in bone marrow stromal/preosteoblast cells from patients with PDB. However, the mechanisms of elevated RANKL and OCL activity in PDB are unclear. In preliminary studies, microarray analysis revealed that MVNP significantly increased expression of CXCL5 (72 fold) in normal human bone marrow monocytes. Bone marrow monocytes in paget's patients also demonstrated high levels of CXCL5 mRNA expression and increased serum levels of CXCL5 compared to normal subjects. CXCL5 stimulation significantly increased RANKL expression in normal human bone marrow stromal/preosteoblasts. We further show that CXCL5 increased the levels of p-ERK1/2, p-p38 and p-CREB which modulate RANKL expression in these cells. Interestingly, anti-CXCL5 antibody suppresses MVNP induced pagetic osteoclast differentiation. We hypothesize that MVNP induction of CXCL5 controls RANKL expression and contribute to enhanced osteoclast development/bone resorption activity in PDB. To test this hypothesis, we will pursue the specific aims: (1) Determine the potential of MVNP induced CXCL5 to stimulate RANKL expression in stromal/preosteoblasts and pagetic osteoclast development. (2) Delineate the molecular mechanisms underlying CXCL5 modulation of RANKL expression in stromal/preosteoblast cells and pagetic OCL development. (3) Determine the contribution of CXCL5 in RANKL expression and pagetic osteoclast (OCL) development using MVNP transgenic mice in vivo. The long-term goal is to identify small molecular therapeutic compounds targeting CXCL5/CXCR1 axis to control high bone turnover in PDB.
Paget's disease of bone (PDB) is a chronic focal skeletal disorder that affects 2-3% of the population over 55 years of age. We identified elevated levels of CXC chemokine ligand, CXCL5 which induces RANKL, a critical bone resorbing osteoclastogenic factor expression in PDB. We hypothesize that MVNP induction of CXCL5 controls RANKL expression and contribute to enhanced osteoclast development/bone resorption activity in PDB and the studies may identify potential novel therapeutic targets to control excess RANKL expression and high bone turnover in PDB.
|Sambandam, Yuvaraj; Sundaram, Kumaran; Saigusa, Takamitsu et al. (2017) NFAM1 signaling enhances osteoclast formation and bone resorption activity in Paget's disease of bone. Bone 101:236-244|