ABSTRACT
This review presents an overview of myopathies and inherited connective tissue disorders that are caused by defects in or deficiencies of molecules within the extracellular matrix (ECM). We will cover the myopathies caused by defects in transmembrane protein complexes (dystroglycan, sarcoglycan, and integrins), laminin, and collagens (collagens VI, XIII, and XV). Clinical characteristics of several of these myopathies imply skin and joint features. We subsequently describe the inherited connective tissue disorders that are characterized by mild to moderate muscle involvement in addition to the dermal, vascular, or articular symptoms. These disorders are caused by defects of matrix-embedded ECM molecules that are also present within muscle (collagens I, III, V, IX, lysylhydroxylase, tenascin, fibrillin, fibulin, elastin, and perlecan). By focussing on the structure and function of these ECM molecules, we aim to point out the clinical and molecular overlap between the groups of disorders. We argue that clinicians and researchers dealing with myopathies and inherited connective tissue disorders should be aware of this overlap. Only a multi-disciplinary approach will allow full recognition of the wide variety of symptoms present in the spectrum of ECM defects, which has important implications for scientific research, diagnosis, and for the treatment of these disorders.
Subject(s)
Connective Tissue Diseases/metabolism , Connective Tissue Diseases/pathology , Muscular Diseases/metabolism , Muscular Diseases/pathology , Animals , Connective Tissue Diseases/genetics , Diagnosis, Differential , Extracellular Matrix/metabolism , Extracellular Matrix Proteins/metabolism , Humans , Muscle Proteins/metabolism , Muscle Weakness/metabolism , Muscle Weakness/pathologyABSTRACT
In the present study, phage display-derived antibodies were used to investigate the topology of glycosaminoglycan epitopes in the diaphragm of chronic obstructive pulmonary disease (COPD) and non-COPD patients. Furthermore, the potential physiological significance of changes in the occurrence of glycosaminoglycan epitopes in the diaphragm of COPD patients was studied by determining the overlap in epitope recognition of glycosaminoglycan antibodies and growth factors. Diaphragm cryosections from non-COPD (n = 5) and COPD patients (Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage I/II; n = 9) were incubated with antibodies directed against heparan sulphate, chondroitin sulphate and dermatan sulphate epitopes. Antibodies were visualised immunofluorescently. In addition, interference of antibody and growth factor binding with heparan sulphate epitopes was tested. Specific glycosaminoglycan epitopes showed increased expression in the diaphragm of COPD patients, whereas other epitopes were decreased or unaffected. Interestingly, the anti-heparan sulphate antibody HS4C3, which is directed against a downregulated epitope, interfered with the binding of hepatocyte growth factor. Three patients with the most severe airway obstruction also demonstrated interference of heparan sulphate antibody A04B08 with hepatocyte growth factor binding. Results indicate changes in glycosaminoglycan composition in the diaphragm of patients with chronic obstructive pulmonary disease. This may affect cellular physiology via alterations in growth factor handling and might be related to reduced levels of contractile protein in the diaphragm of these patients.
Subject(s)
Diaphragm/pathology , Heparitin Sulfate/metabolism , Pulmonary Disease, Chronic Obstructive/complications , Pulmonary Disease, Chronic Obstructive/pathology , Aged , Epitopes/chemistry , Female , Glycosaminoglycans/chemistry , Heparitin Sulfate/chemistry , Hepatocyte Growth Factor/metabolism , Humans , Intercellular Signaling Peptides and Proteins/chemistry , Lung Diseases/pathology , Male , Microscopy, Fluorescence , Middle Aged , Muscle Contraction , Peptide LibrarySubject(s)
Antibodies/genetics , Antibodies/isolation & purification , Heparitin Sulfate/immunology , Peptide Library , Animals , Antibody Specificity , DNA Fingerprinting , Enzyme-Linked Immunosorbent Assay , Fluorescent Antibody Technique , Immunoblotting , Kidney/metabolism , Mice , Polymerase Chain Reaction , RatsABSTRACT
The basal lamina (BL) enveloping skeletal muscle fibers contains different glycoproteins, including proteoglycans. To obtain more information on the glycosaminoglycan moiety of proteoglycans, we have selected a panel of anti-heparan sulfate (HS) antibodies from a semisynthetic antibody phage display library by panning against glycosaminoglycan preparations derived from skeletal muscle. Epitope recognition by the antibodies is strongly dependent on O- and N-sulfation of the heparan sulfate. Immunostaining with these antibodies showed a distinct distribution of heparan sulfate epitopes in muscle basal lamina of various species. Clear differences in staining intensity were observed between neural, synaptic, and extrasynaptic basal laminae. Moreover, temporal and regional changes in abundancy of heparan sulfate epitopes were observed during muscle development both in vitro and in vivo. Taken together, these data suggest a role for specific heparan sulfate domains/species in myogenesis and synaptogenesis. Detailed analysis of the functions of heparan sulfate epitopes in muscle morphogenesis has now become feasible with the isolation of antibodies specific for distinct heparan sulfate epitopes.
