The involvement of signaling pathways in the pathogenesis of osteoarthritis: An update

Abstract

Osteoarthritis (OA) is one of the most common disabling pathologies, characterized by joint pain and reduced function, significantly worsening the quality of life. Even if important progresses have been made in OA research, little is yet known about the precise cellular and molecular mechanisms underlying OA. Understanding dysregulated signaling networks and their crosstalk in OA may offer a strong opportunity for the development of combined targeted therapies. Hence, this review highlights the recent findings on the main pathways involved in OA development, including Wnt, Notch, Hedgehog, MAPK, AMPK, and JAK/STAT, providing insights on current targeted therapies in OA patients' management.

The translational potential of this article: The identification of key signaling pathways involved in OA development and the investigation of their signaling crosstalk could pave the way for more effective treatments and improved management of OA patients in the future.

Keywords: Osteoarthritis; Signaling crosstalk; Signaling pathways; Targeted therapy.

Figure 1

Comparison of articular cartilage composition, structure, and signaling pathways in healthy and osteoarthritic condition. The upper side (green) depicts a physiological joint, while the lower side (red) shows an altered OA joint. A. Anatomy of a healthy and an osteoarthritic hip. B. Extracellular matrix changes in healthy and osteoarthritic joint. MMP, metalloproteinases; IL-1β, interleukin 1β; TNF, tumor necrosis factor. C. Collagen type II fibers orientation in healthy and osteoarthritic samples. D. Chondrocytes in healthy patients compared to hypertrophic and apoptotic osteoarthritic chondrocytes. E. Dysregulated signaling pathways in healthy and osteoarthritic cells. ERK 1/2, extracellular signal-regulated kinase; JNK, Jun N-terminal kinase; JAK, Janus kinase; Hh, Hedgehog.(For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)

Figure 2

Most common signaling pathways involved in OA and the related crosstalk. ADAM10, A Disintegrin and metalloproteinase domain-containing protein; AMPK, AMP-activated protein kinase; APC, Adenomatous Polyposis Coli; β-cat, β-catenin; CAMKK, Calcium/calmodulin-dependent protein kinase kinase; DLL, Delta like ligand; DSH, Dishevelled; ERK, extracellular-signal-regulated kinase; FRZ, Frizzled; GSK3, Glycogen synthase kinase 3; Hh, Hedgehog; IL-6, Interleukin-6; Jag, Jagged; JAK, Janus kinase; JNK, Jun N-terminal kinase; LKB1, Liver Kinase B1; LRP, lipoprotein receptor-related protein; MAPKKK, mitogen-activated protein kinase kinase kinase, MKK, Mitogen-activated protein kinase kinase; PTCH, Patched; RTK, receptor tyrosine kinase; SMO, Smoothened; STAT, signal transducers and activators of transcription; SUFU, suppressor of fused; TAK1, Transforming growth factor beta-activated kinase 1.