Uterine Dysfunction in Biglycan and Decorin Deficient Mice Leads to Dystocia during Parturition

Abstract

Cesarean birth rates are rising. Uterine dysfunction, the exact mechanism of which is unknown, is a common indication for Cesarean delivery. Biglycan and decorin are two small leucine-rich proteoglycans expressed in the extracellular matrix of reproductive tissues and muscle. Mice deficient in biglycan display a mild muscular dystrophy, and, along with mice deficient in decorin, are models of Ehlers-Danlos Syndrome, a connective tissue anomaly associated with uterine rupture. As a variant of Ehlers-Danlos Syndrome is caused by a genetic mutation resulting in abnormal biglycan and decorin secretion, we hypothesized that biglycan and decorin play a role in uterine function. Thus, we assessed wild-type, biglycan, decorin and double knockout pregnancies for timing of birth and uterine function. Uteri were harvested at embryonic days 12, 15 and 18. Nonpregnant uterine samples of the same genotypes were assessed for tissue failure rate and spontaneous and oxytocin-induced contractility. We discovered that biglycan/decorin mixed double-knockout dams displayed dystocia, were at increased risk of delayed labor onset, and showed increased tissue failure in a predominantly decorin-dependent manner. In vitro spontaneous uterine contractile amplitude and oxytocin-induced contractile force were decreased in all biglycan and decorin knockout genotypes compared to wild-type. Notably, we found no significant compensation between biglycan and decorin using quantitative real time PCR or immunohistochemistry. We conclude that the biglycan/decorin mixed double knockout mouse is a model of dystocia and delayed labor onset. Moreover, decorin is necessary for uterine function in a dose-dependent manner, while biglycan exhibits partial compensatory mechanisms in vivo. Thus, this model is poised for use as a model for testing novel targets for preventive or therapeutic manipulation of uterine dysfunction.

Decorin and biglycan are necessary for maintaining collagen fibril structure, fiber realignment, and mechanical properties of mature tendons

“…While this is the first study to characterize the mechanical properties of tendons null for both decorin and biglycan, it is interesting to note that the reduced failure loads seen here were similar to those of decorin-null and compound decorin and biglycan-null uteri [32]. Mature decorin-null tendons also have been noted to have decreased maximum load, stiffness, and modulus [3].…”

The regulatory roles of small leucine‐rich proteoglycans in extracellular matrix assembly

“…SLRP‐deficient mice exhibit phenotypes that are consistent with dysfunctional matrix assembly in connective tissues such as skin, bone, cartilage and teeth , as well as non‐connective tissues such as liver and the pregnant uterus . These phenotypes resemble those observed in many human diseases.…”

“…Decorindeficient mice not only exhibit disrupted collagen fibril structure, but also altered viscoelastic properties, indicating that decorin regulates inter-fibril organization [130]. SLRP-deficient mice exhibit phenotypes that are consistent with dysfunctional matrix assembly in connective tissues such as skin, bone, cartilage and teeth [131], as well as non-connective tissues such as liver [132] and the pregnant uterus [133,134]. These phenotypes resemble those observed in many human diseases.…”

Insights from physiology into myometrial function and dysfunction

“…Less easy to understand is how mutations in Atp11c, a P4-type ATPase, produce the expected cholestasis, hence hyperbilirubinaenia in mice, but also B-cell lymphopenia and dystocia (Siggs et al 2011). Wu et al (2012) studied mice deficient in biglycan and decorin. These two small leucine-rich proteoglycan components of the extracellular matrix have 55% sequence homology.…”

“…Wu et al . () studied mice deficient in biglycan and decorin. These two small leucine‐rich proteoglycan components of the extracellular matrix have 55% sequence homology.…”