Inactivation of Lrp5 in osteocytes reduces Young's modulus and responsiveness to the mechanical loading

Abstract

Low-density-lipoprotein receptor-related protein 5 (Lrp5) is a co-receptor in Wnt signaling, which plays a critical role in development and maintenance of bone. Osteoporosis-pseudoglioma syndrome, for instance, arises from loss-of- function mutations in Lrp5, and global deletion of Lrp5 in mice results in significantly lower bone mineral density. Since osteocytes are proposed to act as a mechanosensor in bone, we addressed a question whether a conditional loss-of-function mutation of Lrp5 selective to osteocytes (Dmp1-Cre; Lrp5f/f) would alter responses to ulna loading. Loading was applied to the right ulna for 3 min (360 cycles at 2 Hz) at a peak force of 2.65 N for 3 consecutive days, and the contralateral ulna was used as a non-loaded control. Young’s modulus was determined using a midshaft section of the femur. The results showed that compared to age-matched littermate controls, mice lacking Lrp5 in osteocytes exhibited smaller skeletal size with reduced bone mineral density and content. Compared to controls, Lrp5 deletion in osteocytes also led to a 4.6-fold reduction in Young’s modulus. In response to ulna loading, mineralizing surface, mineral apposition rate, and bone formation rate were diminished in mice lacking Lrp5 in osteocytes by 52%, 85%, and 69%, respectively. Collectively, the results support the notion that the loss-of-function mutation of Lrp5 in osteocytes causes suppression of mechanoresponsiveness and reduces bone mass and Young’s modulus. In summary, Lrp5-mediated Wnt signaling significantly contributes to maintenance of mechanical properties and bone mass.

Impaired Bone Homeostasis in Amyotrophic Lateral Sclerosis Mice with Muscle Atrophy

“…Conversely, skeletal unloading results in significant bone loss (12)(13)(14). Mechanical signals exert important influences on bone cells (12,(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25). Osteocytes embedded in the bone matrix are thought to coordinate osteoblast and osteoclast activity in response to mechanical stimuli, translating mechanical strain into biochemical signals that ultimately regulate bone remodeling (i.e.…”

“…bone resorption and formation) (9, 17-21, 25, 26). Accumulative evidence suggests that Wnt/␤-catenin signaling plays a critical role in mediation of the mechanical regulation of bone homeostasis (17)(18)(19)(20)(21)25). Osteocyte-derived sclerostin, which is encoded by the Sost gene (27), can be induced by mechanical unloading and inhibits Wnt/␤-catenin signaling in osteoblasts (12,28,29).…”

P2X7 nucleotide receptor signaling potentiates the Wnt/β-catenin pathway in cells of the osteoblast lineage

“…Homozygous deletion of either P2X7 or canonical Wnt signaling components in mice reduces anabolic responses of the skeleton to mechanical load [11,40,41]. The cross talk identified between these two pathways in the present study may help to explain how each increases osteoblast differentiation and bone formation during mechanotransduction.…”

Osteoporosis-pseudoglioma syndrome in South Africa

“…[12] These findings have been further confirmed by the demonstration that inactivation of LRP5 in osteocytes results in impaired bone size and mass in response to mechanical loading. [18] Although in the majority of cases of OPPG there is loss of function of the LRP5 gene, no mutation has been detected in a significant number of cases. Concepts have evolved and OPPG is now regarded as a member of an overlapping disorder, spondylo-ocular syndrome (SOS), which is also associated with eye abnormalities and vertebral compression fractures.…”

“…[20] More recently, Arantes et al [7] provided therapeutic insight into the management of OPPG and supported the rationale for using an osteoanabolic agent. Zhao et al [18] suggested that increasing LRP5-induced signalling in osteoblasts of persons with OPPG may be beneficial to the treatment of osteopaenia and osteoporosis.…”