Perlecan/Hspg2 deficiency impairs bone's calcium signaling and associated transcriptome in response to mechanical loading.

ABSTRACT: Perlecan, a heparan sulfate proteoglycan, acts as a mechanical sensor for bone to detect external loading. Deficiency of perlecan increases the risk of osteoporosis in patients with Schwartz-Jampel Syndrome (SJS) and attenuates loading-induced bone formation in perlecan deficient mice (Hypo). Considering that intracellular calcium [Ca²⁺]_i is an ubiquitous messenger controlling numerous cellular processes including mechanotransduction, we hypothesized that perlecan deficiency impairs bone's calcium signaling in response to loading. To test this, we performed real-time [Ca²⁺]_i imaging on in situ osteocytes of adult murine tibiae under cyclic loading (8N). Relative to wild type (WT), Hypo osteocytes showed decreases in the overall [Ca²⁺]_i response rate (-58%), calcium peaks (-33%), cells with multiple peaks (-53%), peak magnitude (-6.8%), and recovery speed to baseline (-23%). RNA sequencing and pathway analysis of tibiae from mice subjected to one or seven days of unilateral loading demonstrated that perlecan deficiency significantly suppressed the calcium signaling, ECM-receptor interaction, and focal adhesion pathways following repetitive loading. Defects in the endoplasmic reticulum (ER) calcium cycling regulators such as Ryr1/ryanodine receptors and Atp2a1/Serca1 calcium pumps were identified in Hypo bones. Taken together, impaired calcium signaling may contribute to bone's reduced anabolic response to loading, underlying the osteoporosis risk for the SJS patients.

SUBMITTER: Pei S 

PROVIDER: S-EPMC6945981 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature