Loisay, L. | bioRxiv Science

bioRxiv2024

Subchondral bone marrow adipose tissue lipolysis regulates bone formation in hand osteoarthritis

ObjectiveBone marrow adipose tissue (BMAT) is emerging as an important regulator of bone formation and energy metabolism. Lipolysis of BMAT releases glycerol and fatty acid substrates that are catabolized by osteoblasts. Here, we investigated whether BMAT lipolysis is involved in subchondral bone formation in hand osteoarthritis (OA). MethodsSubchondral BMAT lipolysis and bone marrow adipocyte (BMAd) morphology were studied in clinical specimens of carpo-metacarpal (CMC1) ans distal interphalangeal joint (DIP) OA. BMAd size, osteoblast numbers and expression of lipolysis enzymes (ATGL, phospho-HSL, MGLL) were compared between regions of low and high bone formation. Free fatty acids, glycerol and bone biomarkers were measured in osteochondral explants. ResultsSubchondral BMAd size was positively correlated with BMI and reduced in regions of high bone formation. Osteoblast numbers were negatively correlated with BMAd size. ATGL, phoshpo-HSL and MGLL were expressed in both in BMAds and activated osteoblasts and increased in regions of high bone formation. Secreted glycerol levels, but not free fatty acids, were correlated with bone formation markers pro-collagen type I and alkaline phosphatase. ConclusionOur findings reveal a previously unrecognized role of BMAT lipolysis in regulating bone formation in hand OA, which may be modulated by BMI.

pathology↗

bioRxiv2020

The phosphatase inhibitor LB-100 acts synergistically with the NPR2 agonist BMN-111 to improve bone growth

Activating mutations in fibroblast growth factor receptor 3 (FGFR3) and inactivating mutations in the natriuretic peptide receptor 2 (NPR2) guanylyl cyclase both result in decreased production of cyclic GMP (cGMP) in chondrocytes and severe short stature, causing achondroplasia (ACH) and acrosomelic dysplasia type Maroteaux, respectively. Previously we showed that an NPR2 agonist BMN-111 (vosoritide) increases bone growth in mice mimicking ACH (Fgfr3Y367C/+), and that in control growth plate chondrocytes, FGFR3 signaling decreases NPR2 activity by dephosphorylating the NPR2 protein. Here we tested whether a phosphatase inhibitor (LB-100) could enhance bone growth in ACH. In ex vivo imaging experiments using a FRET sensor to measure cGMP production in chondrocytes of living tibias from newborn mice, LB-100 counteracts the FGF-induced dephosphorylation and inactivation of NPR2. In ex vivo experiments with Fgfr3Y367C/+ mice, LB-100 in combination with BMN-111 increases the rate of femur growth by [~]25% vs BMN-111 alone, restores chondrocyte terminal differentiation, increases the proliferative growth plate area of the femur, and reduces the activity of the MAP kinase pathway. Our results provide a proof of concept that a phosphatase inhibitor could be used together with an NPR2 agonist to enhance cGMP production as a therapy for ACH. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=193 HEIGHT=200 SRC="FIGDIR/small/288589v1_ufig1.gif" ALT="Figure 1"> View larger version (21K): org.highwire.dtl.DTLVardef@1d0f5d3org.highwire.dtl.DTLVardef@1bb0724org.highwire.dtl.DTLVardef@1d206d1org.highwire.dtl.DTLVardef@1bd9ad7_HPS_FORMAT_FIGEXP M_FIG C_FIG

developmental biology↗