Abstract
Lysyl oxidase is a multifunctional enzyme required for collagen biosynthesis. Various growth factors regulate lysyl oxidase during osteoblast differentiation, subject to modulation by cytokines such as TNF-α in inflammatory osteopenic disorders including diabetic bone disease. Canonical Wnt signaling promotes osteoblast development. Here we investigated the effect of Wnt3a and TNF-α on lysyl oxidase expression in pluripotent C3H10T1/2 cells, bone marrow stromal cells, and committed osteoblasts. Lysyl oxidase was up-regulated by a transcriptional mechanism 3-fold in C3H10T1/2 cells, and 2.5-fold in bone marrow stromal cells. A putative functional TCF/LEF element was identified in the lysyl oxidase promoter. Interestingly, lysyl oxidase was not up-regulated in committed primary rat calvarial- or MC3T3-E1 osteoblasts. TNF-α down-regulated lysyl oxidase both in Wnt3a-treated and in non-treated C3H10T1/2 cells by a post-transcriptional mechanism mediated by miR203. Non-differentiated cells do not produce a collagen matrix; thus, a novel biological role for lysyl oxidase in pluripotent cells was investigated. Lysyl oxidase shRNAs effectively silenced lysyl oxidase expression, and suppressed the growth of C3H10T1/2 cells by 50%, and blocked osteoblast differentiation. We propose that interference with lysyl oxidase expression under excess inflammatory conditions such as those that occur in diabetes, osteoporosis, or rheumatoid arthritis can result in a diminished pool of pluripotent cells which ultimately contributes to osteopenia.
Highlights
Ostepenia can be caused by a variety of systemic conditions among which are osteoporosis, rheumatoid osteoarthritis and diabetes [1]
Diabetic osteopenia is characterized by reduced osteoblast bone synthetic activity, while osteoporosis and osteoarthritis are characterized by a greater proportion of bone resorption [1,2]
TNF-a signaling initiates formation of intermediates including increased levels of reactive oxygen species, which can inhibit aspects of canonical Wnt signaling in osteoblasts [12]
Summary
Ostepenia can be caused by a variety of systemic conditions among which are osteoporosis, rheumatoid osteoarthritis and diabetes [1]. Diabetic osteopenia leads to elevated incidences of foot fractures, and poor bone healing after orthopedic and dental procedures. Diabetic osteopenia is characterized by reduced osteoblast bone synthetic activity, while osteoporosis and osteoarthritis are characterized by a greater proportion of bone resorption [1,2]. The canonical Wnt pathway contributes to bone formation and activates b-catenin-dependent transcription. The canonical Wnt signaling pathway is mediated by the frizzled receptors and low-density lipoprotein receptor-related protein (LRP5/6) co-receptors, culminating in the nuclear accumulation of b-catenin and its co-activation of TCF/LEF transcription factors [10]. A mutation in the Wnt co-receptor LRP5 leads to diminished Wnt-signaling and reduced bone mass in osteoporosis-pseudoglioma syndrome (OPPG) [11]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
