Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2013 Sep 25;527(2):440-7.
doi: 10.1016/j.gene.2013.05.069. Epub 2013 Jul 2.

A current review of molecular mechanisms regarding osteoarthritis and pain

Andrew S Lee  1 , Michael B Ellman, Dongyao Yan, Jeffrey S Kroin, Brian J Cole, Andre J van Wijnen, Hee-Jeong Im
Affiliations
Review

A current review of molecular mechanisms regarding osteoarthritis and pain

Andrew S Lee et al. Gene. .

Abstract

Osteoarthritis afflicts millions of individuals across the world resulting in impaired quality of life and increased health costs. To understand this disease, physicians have been studying risk factors, such as genetic predisposition, aging, obesity, and joint malalignment; however have been unable to conclusively determine the direct etiology. Current treatment options are short-term or ineffective and fail to address pathophysiological and biochemical mechanisms involved with cartilage degeneration and the induction of pain in arthritic joints. OA pain involves a complex integration of sensory, affective, and cognitive processes that integrate a variety of abnormal cellular mechanisms at both peripheral and central (spinal and supraspinal) levels of the nervous system Through studies examined by investigators, the role of growth factors and cytokines has increasingly become more relevant in examining their effects on articular cartilage homeostasis and the development of osteoarthritis and osteoarthritis-associated pain. Catabolic factors involved in both cartilage degradation in vitro and nociceptive stimulation include IL-1, IL-6, TNF-α, PGE2, FGF-2 and PKCδ, and pharmacologic inhibitors to these mediators, as well as compounds such as RSV and LfcinB, may potentially be used as biological treatments in the future. This review explores several biochemical mediators involved in OA and pain, and provides a framework for the understanding of potential biologic therapies in the treatment of degenerative joint disease in the future.

Keywords: ADAMTS-4; Anti-IL-1; BMP-7; Biochemical mediators; COX; Cartilage; DRG; E prostanoid receptor; ECM; EP; ERK; FGF-2; FGFR1-Ras; Fn-f; IGF-1; IL; IL-1ra; IL-1β; IVD; JNK; LIF; Lf; LfcinB; MAPKs; MMP; NFκB; NSAIDS; OA; Osteoarthritic pain; Osteoarthritis; PG; PGD2; PGE synthase; PGE2; PGES; PGF2Fa; PGI2; PKCδ; RA; RNA; ROS; RSV; SP; TNF-α; TNFR; a disintergrin and metalloproteinase with thrombospondin motifs; anti-interleukin 1; bone morphogenetic protein 7; bovine lactoferrin; c-Jun N-terminal kinase; cAMP; cyclic adenosine monophosphate; cyclooxygenase; dorsal root ganglion; extracellular matrix; extracellular signal-regulated kinase; fibroblast growth factor 2; fibroblast growth factor receptor 1-Ras; fibronectin fragment; iNOS; inducible nitric oxide synthase; insulin-like growth factor 1; interleukin; interleukin-1 beta; interleukin-1 receptor antagonist; intervertebral disk; lactoferrin; leukemia inducing factor; mPGES-1; mRNA; matrix metalloproteinase; messenger ribonucleic acid; microsomal prostaglandin E synthase-1; mitogen-activated protein kinase; nonsteroidal anti-inflammatory drugs; nuclear factor kappa-light-chain-enhancer of activated B cells; osteoarthritis; prostaglandin D2; prostaglandin E2; prostaglandin I2; prostaglandin fibroblast growth factor alpha; protein kinase C alpha; proteoglycan; reactive oxygen species; resveratrol; rheumatoid arthritis; ribonucleic acid; substance P; tumor necrosis factor alpha; tumor necrosis factor receptor.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Complex cellular interplay in synovial joint. In osteoarthritic state, aberrantly activated chondrocytes produce ECM-degrading proteases (MMPs, aggrecanases), pro-inflammatory cytokines (eg. IL-1), and catabolic growth factors (eg. FGF-2). These proteins can be secreted into synovial fluid, and subsequently act upon synoviocytes. Fragments derived from ECM degradation (eg. Fn-f) are also present in the synovial fluid as catabolic inducers. In OA, a subpopulation of chondrocytes undergoes hypertrophic changes, as manifested by their expression of type X collagen. Chondrocytes may also upregulate apoptosis, resulting in diminished local cellularity. In response to cartilage loss, pathological remodeling of subchondral bone gives rise to sclerosis and osteophyte formation. Synoviocytes (fibroblasts and macrophages) also actively synthesize proteases and cytokines which can negatively effect on the articular cartilage and synovium. Pathophysiological changes in synoviocytes pave the way for angiogenesis and innervations, which may account for OA pain [adapted from S. B. Abramson & M. Attur, Arthritis Res Ther 2009;11(3):227].
Figure 2
Figure 2
Notable mediators in OA.
Figure 3
Figure 3
Pathophysiological status of each component in synovial joint is linked to joint degeneration and related pain perception. Local homeostasis inside the joint can be perturbed by various factors, such as aging, injury, and genetic predisposition. Low grade chronic inflammation in the joint not only contributes to accelerated cartilage damage and synovitis, but also renders the joint susceptible to peripheral sensitization and, in some cases, central sensitization.
Figure 4
Figure 4
Schematic model of FGF-2 signaling in articular chondrocytes. FGF-2 binds to FGFR1, which in turn activates both Ras and PKCδ. The signaling inputs then converge on the Raf1-MEK1/2-ERK1/2 axis. Activated ERK1/2 elicits transcription or repression of target genes mediated by a subset of transcription factors, including Elk-1 [adapted from D. Yan & H. J. Im et al., J Cell Biochem 2012].
Figure 5
Figure 5
PKCδ functions as the signaling node of multiple pathways. Input from each illustrated ligand-receptor complex triggers PKCδ activation. PKCδ in turn activates MAP kinases (ERK1/2, p38, and JNK) and NFκB, leading to inhibition of anabolic signaling (eg. IGF-1 and BMP7), suppression of PG production, and upregulation of catabolic proteases.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Buckwalter JA, Saltzman C, Brown T. The impact of osteoarthritis: implications for research. Clin Orthop Relat Res. 2004 Oct.(no. 427):S6–15. doi:10.1097/01.blo.0000143938.30681.9d. - PubMed
    1. Kotlarz H, Gunnarsson CL, Fang H, Rizzo JA. Insurer and out-of-pocket costs of osteoarthritis in the US: evidence from national survey data. Arthritis Rheum. 2009 Dec.vol. 60(no. 12):3546–3553. doi:10.1002/art.24984. - PubMed
    1. Pereira D, Peleteiro B, Araújo J, Branco J, Santos RA, Ramos E. The effect of osteoarthritis definition on prevalence and incidence estimates: a systematic review. Osteoarthritis and Cartilage. 2011 Nov.vol. 19(no. 11):1270–1285. doi:10.1016/j.joca.2011.08.009. - PubMed
    1. Issa SN, Sharma L. Epidemiology of osteoarthritis: an update. Curr Rheumatol Rep. 2006 Feb.vol. 8(no. 1):7–15. doi:10.1007/s11926-006-0019-1. - PubMed
    1. Buckwalter JA, Saltzman C, Brown T. The Impact of Osteoarthritis. Clin Orthop Relat Res. 2004 Oct.vol. 427:S6–S15. doi:10.1097/01.blo.0000143938.30681.9d. - PubMed

Publication types