preproenkephalin and Osteoarthritis

Joint pain is a major clinical problem mainly associated to osteoarthritis, and characterized by articular cartilage degradation resulting in a complex chronic pain state that includes nociceptive, emotional and cognitive manifestations. Memory impairment, depressive- and anxiety-like symptoms have been reported to be associated with chronic pain, leading to a decrease of life quality. In this study, we evaluated the involvement of the endogenous dynorphin/kappa opioid receptor (KOR) system on the nociceptive, emotional, cognitive, neurochemical and epigenetic manifestations of joint pain. The murine model of monosodium iodoacetate (MIA) was used to induce joint pain in knockout mice for KOR (KOR-KO), prodynorphin (PDYN-KO) and their wild-type (WT) littermates. KOR-KO and PDYN-KO mice developed mechanical allodynia after intra-articular injection of MIA. This allodynia was significantly increased in both KOR-KO and PDYN-KO when compared to WT mice. Accordingly, both mutants showed increased microglial activation on the lumbar section of the spinal cord after MIA. The emotional responses were evaluated by measuring anxiety-like behaviour in the elevated plus maze and anhedonia as depressive-like behaviour, and cognitive alterations in the object recognition paradigm. Emotional and cognitive impairments after joint pain were differently modified in KOR-KO and PDYN-KO mice. Alterations of corticotropin-releasing factor (CRF) on the amygdala and hippocampus and down regulation of histone 3 acetylation on the amygdala suggest a possible mechanism to explain these emotional and cognitive manifestations. Our results reveal a specific involvement of the dynorphin/KOR system on joint pain manifestations that are usually associated to osteoarthritis.

Topics: Acetylation; Amygdala; Animals; Arthralgia; Chronic Pain; Cognition; Corticotropin-Releasing Hormone; Disease Models, Animal; Emotions; Enkephalins; Epigenesis, Genetic; Hippocampus; Histones; Hyperalgesia; Mice, Inbred C57BL; Mice, Knockout; Microglia; Osteoarthritis; Protein Precursors; Receptors, Opioid, kappa; Spinal Cord

The aim of this study was to identify genes responsible for the formation and maintenance of cartilage tissue. For this purpose, gene expression patterns were compared between differentiating and dedifferentiating chondrocytes by cDNA macroarray analysis. A total of 1,186 genes were examined, and at least 7 genes were identified as candidate genes having critical roles in cartilages. Three of them encode well-known cartilage matrix molecules: aggrecan, decorin and type IX collagen, and others were preproenkephalin A, Early Growth Response-1, Early Growth Response-3, and basigin. All these genes were expressed at high level in mature cartilage, but their expressions were suppressed in response to dedifferentiation of chondrocytes. Meanwhile, transcription factor ALY, variant in the kinase (vik), and syndecan 2 genes were newly activated during the process of chondrocyte dedifferentiation. A similar process is somewhat observed in osteoarthritis. Therefore, activation of these genes might be closely related to the progression of osteoarthritis and would be a useful marker for it.

Topics: Aggrecans; Animals; Antigens, CD; Antigens, Neoplasm; Antigens, Surface; Avian Proteins; Basigin; Biomarkers; Blood Proteins; Cartilage; Cell Differentiation; Cells, Cultured; Chondrocytes; Collagen Type II; Enkephalins; Extracellular Matrix Proteins; Gene Expression Regulation; Gene Expression Regulation, Developmental; Lectins, C-Type; Membrane Glycoproteins; Mice; Mice, Inbred C57BL; Oligonucleotide Array Sequence Analysis; Osteoarthritis; Osteogenesis; Protein Precursors; Proteoglycans; Transcription Factors