BACKGROUND/AIMS: The pathogenesis of Lumbar disc degeneration (LDD) has been extensively studied in the past. In particular, a role of matrix metalloproteinase 3 (MMP3) in the disease initiation and progression has been recently reported. However, an involvement of Insulin-like growth factor 1 (IGF-I)-stimulated phosphatidylinositol-3 kinase (PI3k) / Akt signaling pathway-mediated control of MMP3 in LDD has not been acknowledged. METHODS: We examined the serum IGF-1 levels and activation of the receptor for IGF-1 (IGF-1R) in resected discs in patients with LDD, compared to the fractured discs from traumatized, non-LDD subjects as a control. We analyzed the effects of IGF-1 on the activation of IGF-1R, Akt and MMP3 in a human nucleus pulposus SV40 cell line (HNPSV). We transfected HNPSV cells with a constitutive nuclear FoxO1, and analyzed its effect on the activation of IGF-1R, Akt and MMP3. RESULTS: LDD patients had significantly lower levels of serum IGF-1, and LDD discs had significantly lower levels of activated IGF-1R. IGF-1 induced phosphorylation of IGF-1R, and then phosphorylation of its downstream factor Akt in the HNPSV cells, resulting in significantly inhibition of MMP3. Further, FoxO1 nuclear retention completely abolished the inhibitory effects of IGF-1 on MMP3 in HNPSV cells. CONCLUSION: Together, IGF-1/Akt/FoxO1/MMP3 regulatory machinery may control the development of LDD.
BACKGROUND/AIMS: The pathogenesis of Lumbar disc degeneration (LDD) has been extensively studied in the past. In particular, a role of matrix metalloproteinase 3 (MMP3) in the disease initiation and progression has been recently reported. However, an involvement of Insulin-like growth factor 1 (IGF-I)-stimulated phosphatidylinositol-3 kinase (PI3k) / Akt signaling pathway-mediated control of MMP3 in LDD has not been acknowledged. METHODS: We examined the serum IGF-1 levels and activation of the receptor for IGF-1 (IGF-1R) in resected discs in patients with LDD, compared to the fractured discs from traumatized, non-LDD subjects as a control. We analyzed the effects of IGF-1 on the activation of IGF-1R, Akt and MMP3 in a human nucleus pulposus SV40 cell line (HNPSV). We transfected HNPSV cells with a constitutive nuclear FoxO1, and analyzed its effect on the activation of IGF-1R, Akt and MMP3. RESULTS:LDDpatients had significantly lower levels of serum IGF-1, and LDD discs had significantly lower levels of activated IGF-1R. IGF-1 induced phosphorylation of IGF-1R, and then phosphorylation of its downstream factor Akt in the HNPSV cells, resulting in significantly inhibition of MMP3. Further, FoxO1 nuclear retention completely abolished the inhibitory effects of IGF-1 on MMP3 in HNPSV cells. CONCLUSION: Together, IGF-1/Akt/FoxO1/MMP3 regulatory machinery may control the development of LDD.
Authors: Christopher L Mendias; Elizabeth R Sibilsky Enselman; Adam M Olszewski; Jonathan P Gumucio; Daniel L Edon; Maxwell A Konnaris; James E Carpenter; Tariq M Awan; Jon A Jacobson; Joel J Gagnier; Ariel L Barkan; Asheesh Bedi Journal: Am J Sports Med Date: 2020-05-26 Impact factor: 6.202
Authors: Olga Krupkova; Junichi Handa; Marian Hlavna; Juergen Klasen; Caroline Ospelt; Stephen John Ferguson; Karin Wuertz-Kozak Journal: Oxid Med Cell Longev Date: 2016-03-28 Impact factor: 6.543
Authors: Olalekan M Ogundele; Joaquin Pardo; Joseph Francis; Rodolfo G Goya; Charles C Lee Journal: Front Neuroanat Date: 2018-05-14 Impact factor: 3.856