Abstract
BackgroundTargeting new molecular pathways leading to Osteoporosis (OP) and Osteoarthritis (OA) is a hot topic for drug discovery. Clusterin (CLU) is a glycoprotein involved in inflammation, proliferation, cell death, neoplastic disease, Alzheimer disease and aging. The present study focuses on the expression and the role of CLU in influencing the decrease of muscle mass and fiber senescence in OP-OA condition.MethodsVastus lateralis muscle biopsies were collected from 20 women with OP undergoing surgery for fragility hip fracture and 20 women undergoing arthroplasty for hip osteoarthritis.ResultsWe found an overexpression of CLU in degenerated fibers in OP closely correlated with interleukin 6 (IL6) and histone H4 acetylation level. Conversely, in OA muscle tissues we observed a weak expression of CLU but no nuclear histone H4 acetylation. Ex vivo studies on isolated human myoblasts confirmed CLU overexpression in OP as compared to OA (p < 0.001). CLU treatment of isolated OP and OA myoblasts showed: modulation of proliferation, morphological changes, increase of histone H4 acetylation and induction of myogenin (MYOG) activation in OP myoblast only. In OP condition, functional knockdown of CLU by siRNA restores proliferative myoblasts capability and tissue damage repair, carried out by an evident upregulation of Transglutaminase 2 (TGM2). We also observed downmodulation of CX3CR1 expression with consequent impairing of the inflammatory infiltrate recruitment.ConclusionsResults obtained suggest a potential role of CLU in OP by influencing myoblasts terminal differentiation, epigenetic regulation of muscle cell differentiation and senescence. Moreover, CLU silencing points out its role in the modulation of tissue damage repair and inflammation, proposing it as a new diagnostic marker for muscle degeneration and a potential target for specific therapeutic intervention in OP related sarcopenia.
Highlights
Targeting new molecular pathways leading to Osteoporosis (OP) and Osteoarthritis (OA) is a hot topic for drug discovery
We focused on the role of CLU, which is involved in calcium metabolism [21], to clarify its function in these pathologies and its potential action in reduction of muscular mass leading to sarcopenia and its possible involvement in the inflammatory process that characterizes OP and OA condition [22]
In order to define the role of CLU in the activation of nuclear factors involved in proliferation, we evaluated the potential activation of nuclear factor kappalight-chain-enhancer of activated B cells (NFKB) in myoblast conditioned for 6 days with CLU, in order to clarify the long lasting CLU conditioning effect on OP and OA myoblasts (Fig. 3b)
Summary
Targeting new molecular pathways leading to Osteoporosis (OP) and Osteoarthritis (OA) is a hot topic for drug discovery. Aging and the subsequent atrophy of muscle fibers lead to a reduction of mechanical bone stimuli exercised through the tendons, which regulate bone development and remodelling, bringing to a degenerative process such as OA and OP [4]. In this context, Clusterin (CLU) is a new pleiotropic factor potentially involved in the stimulation of inflammatory cytokines such as IL6 and lipid metabolism, cell differentiation, tissue remodeling and neoplastic diseases [5,6,7]. We characterized the effect of CLU silencing by siRNA on: proliferation, expression of genes and proteins involved in tissue damage repair and in the initiation of the inflammatory process
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