Insights on Biology and Pathology of HIF-1α/-2α, TGFβ/BMP, Wnt/β-Catenin, and NF-κB Pathways in Osteoarthritis

Abstract

Osteoarthritis (OA) constitutes a major health problem. Different signaling pathways are involved that impair homeostasis, but the cross-talk between them (although well investigated and partly understood), remains unclear. HIF-1α promotes chondrocyte differentiation and survival, while HIF-2α coactivates with β-catenin and NF-κB pathways to promote chondrocyte apoptosis and endochondral ossification. Depending on the ALK1/ALK5 ratio in chondrocytes, the TGFβ pathway can play an anabolic or catabolic role. TGFβ1 can activate the β-catenin signaling pathway via ALK5, Smad3, PI3K, and PKA pathways. The mediator Axins balance TGF-β and Wnt/β-catenin signaling during chondrocyte proliferation and maturation. However, the biological functions of Wnt/β-catenin signaling are still controversial. Both excessive and insufficient β-catenin levels may impair the homeostasis of articular chondrocytes by enhancing pathological maturation and apoptosis, respectively; loss- and gain-of-functions of β-catenin cause apoptosis at the center of the joint and chondrocyte maturation at the periphery, depending on the vascularity. The NF-κB transcription factor can be triggered by a host of stress-related stimuli including pro-inflammatory cytokines. The recent discovery of functional cross-regulation between these pathways has shown complex roles for HIF-1α/HIF-2α, TGFβ/BMP, Wnt/β-catenin, and NF-κB signaling pathways in the pathogenesis of OA. This has important implications for potential therapeutic agents directed at these pathways. This review attempts to cover the literature of the past three years dealing with the biology and pathology of the HIF-1α/-2α, TGFβ/BMP, Wnt/β-catenin, and NF-κB/cytokines signaling pathways in OA.

Bone Age and Serum Osteocalcin Levels in Children With Obstructive Sleep Apnea Hypopnea Syndrome Before and After Adenotonsillectomy

“…Hypoxic condition in OSAHS is implicated in reduced osteocalcin levels and abnormal bone growth. 32 However, we found significant difference between bone age and actual age.…”

Monotropein exerts protective effects against IL-1β-induced apoptosis and catabolic responses on osteoarthritis chondrocytes

“…It has been elucidated that the signaling pathways are the key molecular players [5], which include, but not limited to, the p38, JNK and ERK MAP kinases, the PI-3 kinase-Akt pathway, HIF-1α/-2α, TGFβ/BMP, Wnt/β-catenin and nuclear factor-κB (NF-κB)/ cytokines pathway [5][6][7][8]. Activity modulation of any of these pathways has been associated with various pathological states in cartilage.…”

Interaction of HIF1α and β-catenin inhibits matrix metalloproteinase 13 expression and prevents cartilage damage in mice

“…HIF1α is a major HIF that regulates chondrocyte metabolism (17). We first assessed the role of hypoxia in the metabolic effects of Wnt signaling in primary chondrocytes.…”