Low-Bone-Mass Phenotype of Deficient Mice for the Cluster of Differentiation 36 (CD36)

Abstract

Bone tissue is continuously remodeled by bone cells and maintenance of its mass relies on the balance between the processes of resorption and formation. We have reported the expression of numerous scavenger receptors, namely scavenger receptor (SR) class B type I and II (SR-BI and SR-BII), and CD36, in bone-forming osteoblasts but their physiological roles in bone metabolism are still unknown. To unravel the role of CD36 in bone metabolism, we determined the bone phenotype of CD36 knockout (CD36KO) mice and characterized the cell functions of osteoblasts lacking CD36. Weights of CD36KO mice were significantly lower than corresponding wild-type (WT) mice, yet no significant difference was found in femoral nor tibial length between CD36KO and WT mice. Analysis of bone architecture by micro-computed tomography revealed a low bone mass phenotype in CD36KO mice of both genders. Femoral trabecular bone from 1 to 6 month-old CD36KO mice showed lower bone volume, higher trabecular separation and reduced trabeculae number compared to WT mice; similar alterations were noticed for lumbar vertebrae. Plasma levels of osteocalcin (OCN) and N-terminal propeptide of type I procollagen (PINP), two known markers of bone formation, were significantly lower in CD36KO mice than in WT mice, whereas plasma levels of bone resorption markers were similar. Accordingly, histology highlighted lower osteoblast perimeter and reduced bone formation rate. In vitro functional characterization of bone marrow stromal cells and osteoblasts isolated from CD36KO mice showed reduced cell culture expansion and survival, lower gene expression of osteoblastic Runt-related transcription factor 2 (Runx2) and osterix (Osx), as well as bone sialoprotein (BSP) and osteocalcin (OCN). Our results indicate that CD36 is mandatory for adequate bone metabolism, playing a role in osteoblast functions ensuring adequate bone formation.

Thrombospondin-1 Regulates Bone Homeostasis Through Effects on Bone Matrix Integrity and Nitric Oxide Signaling in Osteoclasts

“…C, D ). This dramatic increase in trabecular bone volume is in contrast to the modest bone volume phenotypes of TSP1‐receptor deficient mice (CD47, CD36, β3 integrin−/−) and is consistent with TSP1 binding to multiple receptors. TSP1−/− mice also had significantly increased cortical bone thickness at 8‐, 16‐, and 32‐weeks of age and increased total cortical area at 32 weeks (Supplementary Table 1), indicating a geometrically larger bone and increased periosteal expansion in TSP1−/− compared to WT mice.…”

“…TSP1 is expressed by OBs and is present in osteoid and mineralized bone matrix, where it is directly deposited by bone‐forming OBs . TSP1 is involved in OB differentiation in part through activation of latent TGF‐β, and TSP1 receptors CD47 and CD36 also regulate OB . TSP1 is a regulator of NO in endothelial cells, platelets, and vascular smooth muscle cells, but only receptors CD36 and CD47 have been implicated in NO regulation .…”

“…(19,20) TSP1 is involved in OB differentiation in part through activation of latent TGF-b, (21,22) and TSP1 receptors CD47 and CD36 also regulate OB. (9,10) TSP1 is a regulator of NO in endothelial cells, platelets, and vascular smooth muscle cells, (23,24) but only receptors CD36 and CD47 have been implicated in NO regulation. (24)(25)(26) TSP1 has been implicated in OC activity, but its mechanism of action remains unknown.…”

Bone and the Innate Immune System

“…Mice deficient in the scavenger receptor type A locus show increased bone mass, increased femur length and decreased osteoclasts (30, 31). In contrast a low bone mass phenotype is seen in Cd36 −/− mice with diminished osteoblast differentiation (32). Thus, it is likely that defects in removal of apoptotic cells effects bone homeostasis but the roles of specific receptors remains to be established.…”

Network based subcellular proteomics in monocyte membrane revealed novel candidate genes involved in osteoporosis

“…CD36 binding factors may stimulate bone resorption by osteoclasts [40]. CD36 knockout experiments in mouse model revealed that CD36KO mice tend to have low bone mass compare with wild type mouse [41]. ITGB1 is also a key gene in the leukocyte transendothelial migration pathway.…”