The Rho-GEF Kalirin regulates bone mass and the function of osteoblasts and osteoclasts

Abstract

Bone homeostasis is maintained by the balance between bone resorption by osteoclasts and bone formation by osteoblasts. Dysregulation in the activity of the bone cells can lead to osteoporosis, a disease characterized by low bone mass and an increase in bone fragility and risk of fracture. Kalirin is a novel GTP-exchange factor protein that has been shown to play a role in cytoskeletal remodeling and dendritic spine formation in neurons. We examined Kalirin expression in skeletal tissue and found that it was expressed in osteoclasts and osteoblasts. Furthermore, micro-CT analyses of the distal femur of global Kalirin knockout (Kal-KO) mice revealed significantly reduced trabecular and cortical bone parameters in Kal-KO mice, compared to WT mice, with significantly reduced bone mass in 8, 14 and 36 week-old female Kal-KO mice. Male mice also exhibited a decrease in bone parameters but not to the level seen in female mice. Histomorphometric analyses also revealed decreased bone formation rate in 14 week-old female Kal-KO mice, as well as decreased osteoblast number/bone surface and increased osteoclast surface/bone surface. Consistent with our in vivo findings, the bone resorbing activity and differentiation of Kal-KO osteoclasts was increased in vitro. Although alkaline phosphatase activity by Kal-KO osteoblasts was increased in vitro, Kal-KO osteoblasts showed decreased mineralizing activity, as well as decreased secretion of OPG, which was inversely correlated with ERK activity. Taken together, our findings suggest that deletion of Kalirin directly affects osteoclast and osteoblast activity, leading to decreased OPG secretion by osteoblasts which is likely to alter the RANKL/OPG ratio and promote osteoclastogenesis. Therefore, Kalirin may play a role in paracrine and/or endocrine signaling events that control skeletal bone remodeling and the maintenance of bone mass.

MMP14 is a novel target of PTH signaling in osteocytes that controls resorption by regulating soluble RANKL production

“…Medium was refreshed every 2 d for 6–8 d. Osteoclast differentiation in the presence of vehicle or KD014 (0.6 µg/ml) was evaluated after staining for tartrate‐resistant acid phosphatase (TRAP) using a commercial kit (Sigma‐Aldrich, St. Louis, MO, USA). The resorption activity of osteoclasts cultured in the absence or presence of KD014 (0.6 µg/ml) was evaluated, as previously described (31). Conditioned medium was collected, and CTX was measured as described above.…”

Role of endoplasmic reticulum stress in disuse osteoporosis

“…The ratio between length of TRAP-positive cells and total circumference of bone trabecula were calculated. MacNeal's staining was used for identifying osteoblasts as described previously [26,27]. The osteoblast number was normalized using the trabecular bone surface.…”

Exposure to excess phenobarbital negatively influences the osteogenesis of chick embryos

“…Bone ossification requires a delicate balance between bone formation of osteoblasts and bone resorption of osteoclasts (Huang et al, 2014). Being devoid of walking and bearing weight, the number of osteoclasts during embryogenesis is considerably less than that after birth (Cheng et al, 2016).…”