Mesenchymal stromal cell-derived septoclasts resorb cartilage during developmental ossification and fracture healing

Abstract

Developmental osteogenesis, physiological bone remodelling and fracture healing require removal of matrix and cellular debris. Osteoclasts generated by the fusion of circulating monocytes degrade bone, whereas the identity of the cells responsible for cartilage resorption is a long-standing and controversial question. Here we show that matrix degradation and chondrocyte phagocytosis are mediated by fatty acid binding protein 5-expressing cells representing septoclasts, which have a mesenchymal origin and are not derived from haematopoietic cells. The Notch ligand Delta-like 4, provided by endothelial cells, is necessary for septoclast specification and developmental bone growth. Consistent with the termination of growth, septoclasts disappear in adult and ageing bone, but re-emerge in association with growing vessels during fracture healing. We propose that cartilage degradation is mediated by rare, specialized cells distinct from osteoclasts. Our findings have implications for fracture healing, which is frequently impaired in aging humans.

Sugar transporter Slc37a2 regulates bone metabolism via a dynamic tubular lysosomal network in osteoclasts

“…Alternatively, it may point to disturbances in a population of matrix-degrading cells specific to the periosteal-bone niche that are distinct from osteoclasts but are functionally dependent on Slc37a2. For example, septoclasts, a rare but specialized mesenchymal stromal-derived cell type, have recently been shown to resorb cartilage during endochondral ossification and fracture healing and express high levels of MMP9, 13 and 14 (Sivaraj et al, 2022), in keeping with the increased MMP9/13/14 expression within Slc37a2 KO femurs observed here (Fig. s 4H, 5K&P).…”

“…Alternatively, it may point to disturbances in a population of matrix-degrading cells specific to the periosteal-bone niche that are distinct from osteoclasts but are functionally dependent on Slc37a2. For example, septoclasts, a rare but specialized mesenchymal stromal-derived cell type, have recently been shown to resorb cartilage during endochondral ossification and fracture healing and express high levels of MMP9, 13 and 14 (Sivaraj et al, 2022), in keeping with the increased MMP9/13/14 expression within Slc37a2 KO femurs observed here ( Fig.s 4H, 5K&P ). Whether septoclasts, reversal cells, or an as yet undefined Runx2/MMP13 + matrix-degrading periosteal cell type contribute directly to the Slc37a2 KO bone phenotype requires the future generation and detailed characterization of several cell-specific conditional Slc37a2 knockout mouse lines, which forms the basis of our ongoing investigations.…”

Osteoclasts and Macrophages—Their Role in Bone Marrow Cavity Formation During Mouse Embryonic Development

“…While this work was submitted, Sivaraj and colleagues published that septoclasts are derived from Pdgfrb-expressing mesenchymal stromal cells and not from cells of the hematopoietic lineage, as septoclasts were not labeled by the Vav1-Cre line. (71) Likewise, Bando and colleagues proposed that septoclasts are pericytederived cells using Pdgfrb and Fabp5 as markers. (58,(72)(73)(74) Yet, our results suggest that septoclasts are derived from Pu.1-expressing precursor cells, most likely myeloid progenitors, which are absent in Pu.1-deficient specimens.…”

Could BMPs Therapy Be Improved if BMPs Were Used in Composition Acting during Bone Formation in Endochondral Ossification?

“…Septoclasts also displayed the presence of PDGF receptor beta (PDGFRβ) [ 94 ] as well as PDGF-BB [ 95 ]. Septoclasts have a mesenchymal origin arising from pericytes accompanying capillary vessels and, contrary to osteoclasts, do not arise from haematopoietic cells [ 94 , 96 ]. Septoclast specification requires the presence of the Notch ligand Delta-like 4, produced by endothelial cells, [ 96 ].…”

“…Septoclasts develop a ruffled border extending into the non-calcified cartilage and degrading the last transverse septum of the rows of chondrocytes in the growth plate [ 92 , 93 ]. They express lysosomal-associated membrane protein 1 (LAMP1) and proteolytic enzymes MMP9 and MMP14 [ 96 ]. Thus, it seems possible that septoclasts can liberate growth factors from the non-calcified matrix.…”