Targeting sulfation-dependent mechanoreciprocity between matrix and osteoblasts to mitigate bone loss

Sulfation is a widespread modification for biomolecules so far poorly explored. Through cross phenotype meta-analysis for human bone mineral density up to 426824 participants and phenotypic characterization of multiple mutant mouse lines, we identified a causative role of the sulfate transporter SLC26A2 deficiency in osteoporosis. Ablation of SLC26A2 in osteoblasts caused severe bone loss and accumulation of immature bone cells and elicited a peculiar pericellular matrix (PCM) outcome, undersulfation coupled with decreased stiffness. Consequently, such altered chemophysical properties of PCM disrupted focal adhesion formation of osteoblasts. Based on bulk RNA sequencing and functional assays, we held a mechano-reciprocal tandem inhibition of FAK and YAP/TAZ responsible for impinged osteoblast maturation by SLC26A2 deficiency, where sulfation and stiffness of PCM were compromised by defective sulfate uptake and thus to exert an outside-in impediment to FAK-dependent YAP/TAZ activity required for osteoblast maturation. Moreover, pharmacological abrogation of the Hippo kinases and forced wheel-running concordantly ameliorated SLC26A2-deficient osteoporosis via enforcement of YAP/TAZ activity. Intriguingly, “guilt by association” analysis of single-cell sequencing data suggested coordination between sulfate metabolism, focal adhesion and YAP/TAZ activity during osteoblast-to-osteocyte transition. As seen in ovariectomized mice and patients with osteoporosis, tandem inhibition of FAK and YAP/TAZ apparently engaged in pathology of broader types of osteoporosis beyond SLC26A2 context. Collectively, these data unveil an unanticipated role of sulfation in developmental mechanoreciprocity between matrix and osteoblasts, which could be leveraged to prevent bone loss. To better understand molecular mechanisms underlying disrupted osteoblast maturation caused by SLC26A2 deficiency, we applied bulk RNA sequencing (bulk-seq) to Col2.3kb-Cre; Slc26a2 fl/fl (CKO) and Col2.3kb-Cre; Slc26a2 fl/+ (Control) femoral cortical bone shafts at post natal day 7 (P7).