transforming-growth-factor-beta and Peripheral-Nervous-System-Diseases

Transforming growth factors-beta (TGF-betas) signal through type I and type II serine-threonine kinase receptor complexes. During ligand binding, type II receptors recruit and phosphorylate type I receptors, triggering downstream signaling. BAMBI [bone morphogenetic protein (BMP) and activin membrane-bound inhibitor] is a transmembrane pseudoreceptor structurally similar to type I receptors but lacks the intracellular kinase domain. BAMBI modulates negatively pan-TGF-beta family signaling; therefore, it can be used as an instrument for unraveling the roles of these cytokines in the adult CNS. BAMBI is expressed in regions of the CNS involved in pain transmission and modulation. The lack of BAMBI in mutant mice resulted in increased levels of TGF-beta signaling activity, which was associated with attenuation of acute pain behaviors, regardless of the modality of the stimuli (thermal, mechanical, chemical/inflammatory). The nociceptive hyposensitivity exhibited by BAMBI(-/-) mice was reversed by the opioid antagonist naloxone. Moreover, in a model of chronic neuropathic pain, the allodynic responses of BAMBI(-/-) mice also appeared attenuated through a mechanism involving delta-opioid receptor signaling. Basal mRNA and protein levels of precursor proteins of the endogenous opioid peptides proopiomelanocortin (POMC) and proenkephalin (PENK) appeared increased in the spinal cords of BAMBI(-/-). Transcript levels of TGF-betas and their intracellular effectors correlated directly with genes encoding opioid peptides, whereas BAMBI correlated inversely. Furthermore, incubation of spinal cord explants with activin A or BMP-7 increased POMC and/or PENK mRNA levels. Our findings identify TGF-beta family members as modulators of acute and chronic pain perception through the transcriptional regulation of genes encoding the endogenous opioids.

Topics: Activins; Afferent Pathways; Animals; Bone Morphogenetic Protein 7; Cells, Cultured; Disease Models, Animal; Enkephalins; Hyperalgesia; Male; Membrane Proteins; Mice; Mice, Knockout; Narcotic Antagonists; Nociceptors; Pain Measurement; Pain Threshold; Peripheral Nerves; Peripheral Nervous System Diseases; Pro-Opiomelanocortin; Protein Precursors; Receptors, Opioid, delta; Sciatic Neuropathy; Signal Transduction; Spinal Cord; Transforming Growth Factor beta; Up-Regulation

To characterize muscle and nerve pathology in Dunnigan familial partial lipodystrophy (FPLD).. We used conventional histology, immunohistochemistry, messenger RNA (mRNA) expression, gene sequencing, and clinical studies of 13 patients with neuromuscular involvement.. The clinical findings consisted of muscle hypertrophy (12/13), severe myalgias (9/13), and multiple nerve entrapment syndromes (8/13). Skeletal muscle histology demonstrated marked Type 1 and 2 muscle fiber hypertrophy and nonspecific myopathic changes, whereas numerous paranodal myelin swellings (tomacula) were found in sural nerve biopsies. We found that myostatin mRNA expression was reduced in patients with FPLD vs controls. We sequenced the myostatin gene in our subjects, but found no mutations. We then investigated whether or not SMAD, the intracellular mediator of myostatin signaling, might be impaired in patients with FPLD. We found that in FPLD muscle, a large number of SMAD molecules adhered to the nuclear membrane and were not found within the nucleus, compared with normal muscle or muscle from a patient with a non-FPLD lamin A/C disease.. The myopathy and neuropathy associated with Dunnigan familial partial lipodystrophy are distinct from other lamin A/C disorders. We hypothesize that the lipodystrophy-associated mutation interferes with SMAD signaling, linking this type of lipodystrophy to the phenotypically similar myostatin deficiency.

Topics: Adult; Female; Humans; Lipodystrophy, Familial Partial; Male; Muscle, Skeletal; Muscular Diseases; Myostatin; Peripheral Nervous System Diseases; Smad Proteins; Sural Nerve; Transforming Growth Factor beta

Topics: Clusterin; Humans; Immunologic Factors; Immunosuppression Therapy; Myelin Sheath; Nerve Regeneration; Neuritis; Peripheral Nervous System Diseases; Schwann Cells; Transforming Growth Factor beta