GPR177

Gpr177, a novel locus for bone-mineral-density and osteoporosis, regulates osteogenesis and chondrogenesis in skeletal development.

"Gpr177 exhibits an ability to modulate the trafficking of Wnt similar to the Drosophila Wls/Evi/Srt.  To overcome the early lethality associated with the inactivation of Gpr177 in mice, conditional gene deletion is utilized to assess its functionality. Here we report the generation of four different mouse models with Gpr177 deficiency in various skeletogenic cell types. The loss of Gpr177 severely impairs development of the craniofacial and body skeletons, demonstrating its requirement for intramembranous and endochondral ossifications, respectively. Defects in the expansion of skeletal precursors and their differentiation into osteoblasts and chondrocytes suggest that Wnt production and signaling mediated by Gpr177 cannot be substituted. Because the Gpr177 ablation impairs the secretion of Wnt proteins, we therefore identify their sources essential for osteogenesis and chondrogenesis. The intercross of Wnt signaling between distinct cell types is carefully orchestrated and necessary for skeletogenesis.  Gpr177 controls skeletal development through modulation of autocrine and paracrine Wnt signals in a lineage-specific fashion"

"formation of the calvarial, maxillary and mandibular bones mediated by intramembranous ossification is defective or completely missing in the Gpr177Dermo1 embryos"

Loss of GPR177 delays chondrocyte hypertrophy.

"The chondrogenic deletion of Gpr177 significantly reduced bone mineralization, and interfered with chondrocyte maturation"

"The number of cells undergoing mitotic division is significantly reduced in the columnar zone, but not epiphyses of the Gpr177Dermo1 and Gpr177Col2 humeruses, suggesting that expansion of the proliferating and prehypertrophic but not the resting chondrocytes was affected by the loss of Gpr177"

"disruption of endochondral ossification starts at chondrocyte maturation, and the subsequent events, including ECM remodeling, vascular invasion and osteoblastogenesis, are impaired in the Gpr177Dermo1 mutants."  Chondrocyte maturation is where Beta Catenin begins to take over for Sox9.

"Gpr177 is dispensable in the osteoblasts during intramembranous and endochondral ossifications. Our findings suggest that the impairment of osteoblast differentiation in the Gpr177Dermo1 and Gpr177Col2 limbs is attributed to delay in chondrocyte maturation but not intrinsic defects of the osteoblasts."