Fratzl-Zelman, N. | bioRxiv Science

bioRxiv2026

Mitochondrial dysfunction plays a key role in premature musculoskeletal aging in hypochondroplasia mouse model

Hypochondroplasia (HCH) is a mild form of chondrodysplasia, caused by variants in fibroblast growth factor receptor 3 (FGFR3). Today, the biological mechanism underlying musculoskeletal aging in HCH remains largely unknown. In this study, we show that Hch mice exhibit phenotypic traits of bone fragility and accelerated age-dependent articular cartilage and subchondral bone changes. Hch mice also presented decreased muscle strength and reduction in muscle fibers size. Furthermore, proteomics analyses of the cortical bone revealed that Hch mice follow a different aging trajectory than control. FGFR3 mutation leads to a premature boost of the mitochondrial processes forcing the mutant to reach a physiological state much earlier than the control. Together, these findings demonstrate that aging in Hch mice is accompanied by bone fragility and osteoarthritis-like changes. Proteomics analyses highlighted the key role for mitochondria in the cortical bone of Hch mice, providing insight into the mechanisms underlying premature aging in HCH.

genetics↗

bioRxiv2023

3D osteocyte lacunar morphometry of human bone biopsies with high resolution microCT: from monoclonal gammopathy to newly diagnosed multiple myeloma

Osteocytes are mechanosensitive, bone-embedded cells which are connected via dendrites in a lacuno-canalicular network and regulate bone resorption and formation balance. Alterations in osteocyte lacunar volume, shape and density have been identified in conditions of aging, osteoporosis and osteolytic bone metastasis, indicating patterns of impaired bone remodeling, osteolysis and disease progression. Osteolytic bone disease is a hallmark of the hematologic malignancy multiple myeloma (MM), in which monoclonal plasma cells in the bone marrow disrupt the bone homeostasis and induce excessive resorption at local and distant sites. Qualitative and quantitative changes in the 3D osteocyte lacunar morphometry have not yet been evaluated in MM, nor in the precursor conditions monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM). In this study, we characterized the osteocyte lacunar morphology in trabecular bone of the iliac crest at the ultrastructural level using high resolution microCT in human bone biopsy samples of three MGUS, two SMM and six newly diagnosed MM. In MGUS, SMM and MM we found a trend for lower lacunar density and a shift towards larger lacunae with disease progression (higher 50% cutoff of the lacunar volume cumulative distribution) in the small osteocyte lacunae 20-900 m3 range compared to control samples. In the larger lacunae 900-3000 m3 range, we detected significantly higher lacunar density and microporosity in the MM group compared to the MGUS/SMM group. Regarding the shape distribution, the MGUS/SMM group showed a trend for flatter, more elongated and anisotropic osteocyte lacunae compared to the control group. Altogether, our findings suggest that osteocytes in human MM bone disease undergo changes in their lacunae density, volume and shape, which could be an indicator for osteolysis and disease progression. Future studies are needed to understand whether alterations of the lacunae architecture affect the mechanoresponsiveness of osteocytes and ultimately bone adaptation and fracture resistance in MM and its precursors conditions.

bioengineering↗