PubMed · 14856042
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G HOLLER. 1951-04-28. [Ulcerative colitis].. https://pubmed.ncbi.nlm.nih.gov/14856042/
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siRNA oligonucleotides for protein phosphatase 5 (PP5) were designed and transfected into mouse corticotroph AtT20 cells to induce lower PP5 expression levels. PP5-siRNA transfections (at 3 days) produced a approximately 50% down-regulation in targeted protein levels. PP5-underexpressing cells released significantly more ir-ACTH (10-12-fold) relative to baseline levels and promoted POMC release into the media. Neither CRF-mediated ACTH release nor dexamethasone-induced ACTH repression were affected in PP5-siRNA transfected cells. In summary, our observations suggest that endogenous PP5 can exert a negative modulatory effect on basal ACTH release in neurosecretion-competent AtT20 cells through a mechanism as yet unknown but which does not directly involve regulated CRF or glucocorticoid receptor-dependent pathways. However, PP5 may cause mis-sorting of POMC and POMC-derived peptides at the constitutive-like secretory pathway level in an unregulated manner. Such a missorting could lead to impaired processing of POMC.
Melanocortin receptors belong to the seven transmembrane domain, G-protein coupled family of receptors. There are five members of this receptor family labeled MC1R-MC5R. These receptors are activated by fragments derived from a larger molecule, proopiomelanocortin (POMC) and include ACTH, alpha beta and gamma-MSH and beta-endorphin. Because of in vitro and in vivo data suggesting direct effects of these POMC molecules on bone and bone turnover, we examined bone and bone derived cells for the presence of the various members of the melanocortin receptor family. We report that the five known melanocortin receptors are expressed to varying degrees in osteoblast-like and osteoclastic cells. POMC fragments increased proliferation and expression of a variety of genes in osteoblastic cells. Furthermore, POMC mRNA was detected in osteoclastic cells. These data demonstrate that POMC-derived peptide hormones acting through high affinity melanocortin receptors have specific effects on bone cells. Thus, in addition to the indirect effects of POMC-derived hormones on bone turnover through their modulation of steroid hormone secretion, POMC fragments may have direct and specific effects on bone cell subpopulations.
Both clinical and in vitro evidence points to the involvement of the melanocortin peptide, ACTH, in the terminal differentiation of chondrocytes. Terminal differentiation along the endochondral pathway is responsible for linear growth, but also plays a role in osteoarthritic cartilage degeneration. Chondrocyte terminal differentiation is associated with an incremental increase in chondrocyte basal intracellular free calcium ([Ca(2+)](i)), and ACTH agonism of melanocortin receptors is known to mobilize [Ca(2+)](i.) Using differentiated resting chondrocytes highly expressing type II collagen and aggrecan, we examined the influence of both ACTH and dexamethasone treatment on matrix gene transcription and [Ca(2+)](i). Resting chondrocytes treated concurrently with dexamethasone and ACTH expressed matrix gene transcripts in a pattern consistent with that of rapid terminal differentiation. Using the fluorescent Ca(2+) indicator, fura-2, we determined that ACTH evokes transient increases in [Ca(2+)](i) and elevates basal Ca(2+) levels in resting chondrocytes. The transient increases were initiated intracellularly, were abrogated by the phospholipase C-specific inhibitor, U73122, and were partly attenuated by myo-inositol 1,4,5-triphosphate receptor inhibition via 10 mm caffeine. The initial intracellular release also resulted in store-operated calcium entry, presumably through store-operated channels. Dexamethasone priming increased both the initial ACTH-evoked [Ca(2+)](i) release and the subsequent store-operated calcium entry. These data demonstrate roles for ACTH and glucocorticoid in the regulation of chondrocyte terminal differentiation. Because the actions of ACTH are mediated through known G protein-coupled receptors, the melanocortin receptors, these data may provide a new therapeutic target in the treatment of growth deficiencies and cartilage degeneration.