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Hox11 genes are required for regional patterning and integration of muscle, tendon and bone.

ABSTRACT: Development of the musculoskeletal system requires precise integration of muscles, tendons and bones. The molecular mechanisms involved in the differentiation of each of these tissues have been the focus of significant research; however, much less is known about how these tissues are integrated into a functional unit appropriate for each body position and role. Previous reports have demonstrated crucial roles for Hox genes in patterning the axial and limb skeleton. Loss of Hox11 paralogous gene function results in dramatic malformation of limb zeugopod skeletal elements, the radius/ulna and tibia/fibula, as well as transformation of the sacral region to a lumbar phenotype. Utilizing a Hoxa11eGFP knock-in allele, we show that Hox11 genes are expressed in the connective tissue fibroblasts of the outer perichondrium, tendons and muscle connective tissue of the zeugopod region throughout all stages of development. Hox11 genes are not expressed in differentiated cartilage or bone, or in vascular or muscle cells in these regions. Loss of Hox11 genes disrupts regional muscle and tendon patterning of the limb in addition to affecting skeletal patterning. The tendon and muscle defects in Hox11 mutants are independent of skeletal patterning events as disruption of tendon and muscle patterning is observed in Hox11 compound mutants that do not have a skeletal phenotype. Thus, Hox genes are not simply regulators of skeletal morphology as previously thought, but are key factors that regulate regional patterning and integration of the musculoskeletal system.

SUBMITTER: Swinehart IT

PROVIDER: S-EPMC3817943 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:IntroductionSuccessful graft ingrowth following reconstruction of the anterior cruciate ligament is governed by complex biological processes at the tendon-bone interface. The aim of this study was to investigate in an in vitro study the effects of bone morphogenetic protein 7 (BMP-7) on tendon-bone integration.Materials and methodsTo study the biological effects of BMP-7 on the process of tendon-bone-integration, two independent in vitro models were used. The first model involved the mono- and coculture of bovine tendon specimens and primary bovine osteoblasts with and without BMP-7 exposure. The second model comprised the mono- and coculture of primary bovine osteoblasts and fibroblasts. Alkaline phosphatase (ALP), lactate dehydrogenase (LDH), lactate and osteocalcin (OCN) were analyzed by ELISA. Histological analysis and electron microscopy of the tendon specimens were performed.ResultsIn both models, positive effects of BMP-7 on ALP enzyme activity were observed (p<0.001). Additionally, similar results were noted for LDH activity and lactate concentration. BMP-7 stimulation led to a significant increase in OCN expression. Whereas the effects of BMP-7 on tendon monoculture peaked during an early phase of the experiment (p<0.001), the cocultures showed a maximal increase during the later stages (p<0.001). The histological analysis showed a stimulating effect of BMP-7 on extracellular matrix formation. Organized ossification zones and calcium carbonate-like structures were only observed in the BMP-stimulated cell cultures.DiscussionThis study showed the positive effects of BMP-7 on the biological process of tendon-bone integration in vitro. Histological signs of improved mineralization were paralleled by increased rates of osteoblast-specific protein levels in primary bovine osteoblasts and fibroblasts.ConclusionOur findings indicated a role for BMP-7 as an adjuvant therapeutic agent in the treatment of ligamentous injuries, and they emphasized the importance of the transdifferentiation process of tendinous fibroblasts at the tendon-bone interface.

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Hox11 genes are required for regional patterning and integration of muscle, tendon and bone.

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