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The destruction of the myelin sheath that encircles axons leads to impairments of nerve conduction and neuronal dysfunctions. A major demyelinating disorder is multiple sclerosis (MS), a progressively disabling disease in which immune cells attack the myelin. To date, there are no therapies to target selectively myelin lesions, repair the myelin or stop MS progression. Small peptides recognizing epitopes selectively exposed at sites of injury show promise for targeting therapeutics in various pathologies. Here we show the selective homing of the four amino acid peptide, cysteine-alanine-lysine glutamine (CAQK), to sites of demyelinating injuries in three different mouse models. Homing was assessed by administering fluorescein amine (FAM)-labeled peptides into the bloodstream of mice and analyzing sites of demyelination in comparison with healthy brain or spinal cord tissue. FAM-CAQK selectively targeted demyelinating areas in all three models and was absent from healthy tissue. At lesion sites, the peptide was primarily associated with the fibrous extracellular matrix (ECM) deposited in interstitial spaces proximal to reactive astrocytes. Association of FAM-CAQK was detected with tenascin-C although tenascin depositions made up only a minor portion of the examined lesion sites. In mice on a 6-week cuprizone diet, FAM-CAQK peptide crossed the nearly intact blood-brain barrier and homed to demyelinating fiber tracts. These results demonstrate the selective targeting of CAQK to demyelinating injuries under multiple conditions and confirm the previously reported association with the ECM. This work sets the stage for further developing CAQK peptide targeting for diagnostic and therapeutic applications aimed at localized myelin repair. [ABSTRACT FROM AUTHOR]

Although the roles of acids in bone metabolism are well characterized, the function of proton-sensing receptors in bone metabolism remains to be explored. In this study, we evaluated the role of proton-sensing receptor T-cell death-associated gene 8 (TDAG8) in osteoclastic activity during bone loss after ovariectomy. Through observations of bone mineral content, we found that pathological bone resorption was significantly exacerbated in mice homozygous for a gene trap mutation in the Tdag8 gene. Furthermore, osteoclasts from the homozygous mutant mice resorbed calcium in vitro more than the osteoclasts from the heterozygous mice did. Impaired osteoclast formation under acidic conditions was ameliorated in cultures of bone marrow cells by Tdag8 gene mutation. Extracellular acidification changed the cell morphology of osteoclasts via die TDAG8-Rho signaling pathway. These results suggest that the enhancement of TDAG8 function represents a new strategy for preventing bone resorption diseases, such as osteoporosis. [ABSTRACT FROM AUTHOR]