CD109 deficiency induces osteopenia with an osteoporosis‐like phenotype in vivo

Abstract

Osteoporosis is a global public health problem that is increasing along with an aging population. A major determinant of osteoporosis is high bone turnover, which results from osteoclast activation. CD109 is a glycosylphosphatidylinositol-anchored glycoprotein, a deficiency that leads to a psoriasis-like skin inflammation in mice. Although the expression of CD109 has been reported in mouse pre-osteoclast cells, its function in osteoclasts in vivo remains largely unknown. To investigate the physiological role of CD109 in bone metabolism, we analyzed bones from wild-type and CD109-deficient adult mice. Micro-computed tomography analysis of the femur (thigh bone) showed that bone volume was lower in CD109-deficient mice than in wild-type mice. Bone histomorphometric analysis showed not only a reduction in bone volume but also an increase in bone turnover in CD109-deficient mice as compared with wild-type mice. Additionally, we measured serum levels of several markers of bone turnover and found a significant increase in the N-terminal telopeptide of type I collagen, a bone resorption marker, as well as alkaline phosphatase, a bone formation marker, in CD109-deficient mice. These results indicate that CD109 deficiency induces a high-turnover, osteoporosis-like phenotype, which suggests that CD109 plays a role in bone metabolism in vivo.

CD109: a multifunctional GPI‐anchored protein with key roles in tumor progression and physiological homeostasis

“…These findings suggest that CD109‐deficient mice exhibit a “high‐turnover osteoporosis” phenotype (Fig. b) . Paradoxically, CD109 deficiency reduced osteoclast formation in pre‐osteoclast cells in vitro .…”

“…Additionally, CD109‐deficient mice exhibited an osteopenia phenotype that was verified by reduced bone/tissue volume, decreased trabecular number, and increased trabecular separation according to microcomputed tomography (micro‐CT) scans (Fig. a) . IHC analysis showed that CD109 is expressed in both osteoblasts and osteoclasts, and serum analyses revealed that CD109 deficiency increases their activities in mice .…”

“…b) . Paradoxically, CD109 deficiency reduced osteoclast formation in pre‐osteoclast cells in vitro . These phenotypes indicated that CD109 plays a regulatory role in skin and bone homeostasis.…”

“…Although CD109 expression is significantly higher in lower‐grade SCCs or urothelial carcinomas of the urinary bladder relative to that in higher‐grade SCCs or urothelial carcinomas, respectively, its expression is significantly higher in higher‐grade glioma, ductal carcinoma of the breast, non‐small cell carcinomas of the lung, hepatocellular carcinoma, epithelioid sarcoma, and myxofibrosarcoma as compared with that in lower‐grade tumors, respectively . Additionally, CD109 expression in normal tissues is strictly controlled and specifically occurs in myoepithelial cells of the mammary, lacrimal, salivary, and bronchial glands, basal cells of the prostate and bronchial epithelia and epidermis, seminiferous tubules of testis, and osteoblasts and osteoclasts in bone . These findings suggest that CD109 expression is controlled in normal tissues and associated with tumor development.…”

“…As noted, studies using cultured tumor cells and clinicopathologic analyses revealed a role for CD109 in modulating TGF‐β signaling by binding to its cognate receptors, and that CD109 expression correlates with the outcomes of various human malignant tumors. Additionally, in vivo CD109 functions have also been studied using several mouse models (Table ) . Among these studies, we compared the phenotype of CD109‐deficient mice with that of their wild‐type (WT) counterparts, with macroscopic analyses revealing transient impairment of hair growth in CD109‐deficient mice (Fig.…”