Connexin37 deficiency alters organic bone matrix, cortical bone geometry, and increases Wnt/beta-catenin signaling
Pacheco-Costa, Rafael [UNIFESP]
Kadakia, Jay R.
Atkinson, Emily G.
Wallace, Joseph M.
Plotkin, Lilian I.
Reginato, Rejane D. [UNIFESP]
Is part ofBone
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Deletion of connexin (Cx) 37 in mice leads to increased cancellous bone mass due to defective osteoclast differentiation. Paradoxicallyhowever, Cx37-deficient mice exhibit reduced cortical thickness accompanied by higher bone strength, suggesting a contribution of Cx37 to bone matrix composition. Thus, we investigated whether global deletion of Cx37 alters the composition of organic bone extracellular matrix. Five-month-old Cx37(-/-) mice exhibited increased marrow cavity area, and periosteal and endocortical bone surface resulting in higher total area in tibia compared to Cx37(+/+) control mice. Deletion of Cx37 increased genes involved in collagen maturation (loxl3 and loxl4) and glycosaminoglycans- (chsyl, chpf and has3) proteoglycans- associated genes (biglycan and decorin). In addition, expression of type II collagen assessed by immunostaining was increased by 82% whereas collagen maturity by picrosirius-polarizarion tended to be reduced (p = 0.071). Expression of glycosaminoglycans by histochemistry was decreased, whereas immunostaining revealed that biglycan was unchanged and decorin was slightly increased in Cx37(-/-) bone sections. Consistent with these in vivo findings, MLO-Y4 osteocytic cells silenced for Cx37 gene exhibited increased mRNA levels for collagen synthesis (col1a1 and col3a1) and collagen maturation (lox, loxl1 and loxl2 genes). Furthermore, mechanistic studies showed Wnt/beta-catenin activation in MLO-Y4 osteocytic cells, L5 vertebra, and authentic calvaria-derived osteocytes isolated by fluorescent-activated cell sorter. Our findings demonstrate that altered profile of the bone matrix components in Cx37-deficient mice acts in favor of higher resistance to fracture in long bones. (C) 2017 Elsevier Inc. All rights reserved.
CitationBone. New York, v. 97, p. 105-113, 2017.
SponsorshipClinical and Transitional Sciences Institute Project Development Team (PDT) from Indiana University
Coordination of Improvement of Higher Level Personnel (CAPES), Brazil
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