Perlecan/Hspg2 deficiency impairs bone's calcium signaling and associated transcriptome in response to mechanical loading.
Bone
; 131: 115078, 2020 02.
Article
em En
| MEDLINE
| ID: mdl-31715337
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.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Proteoglicanas de Heparan Sulfato
/
Sinalização do Cálcio
Tipo de estudo:
Risk_factors_studies
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Bone
Ano de publicação:
2020
Tipo de documento:
Article