In this study, to explore the potential correlation between human plasma proteins and BMD across different life courses, we conducted a large-scale LDSC analysis using two independent cohorts. We identified multiple plasma proteins correlated with BMD, such as PARK7, SCGF-beta, POSTN, GAPDS and RANTES.
PARK7 (Parkinson disease protein 7, also known as Protein deglycase DJ-1) belongs to the peptidase C56 family. According to the view of a previous study, PARK7/DJ-1 protein level was increased up to 3 times in MLO-Y4 osteocytic cells, which were treated by N-BPs (Nitrogen-containing bisphosphonates), a kind of osteoporosis drug . And this change was demonstrated to be involved with a pathway which plays a role in the effect of N-BPs on osteocytes . As a result of a study, short stature and brachydactyly are two characteristics observed in the parkinsonism patients without PARK7 region in the DJ-1 gene [26, 27]. The authors indicated that the PARK7 region may contain a modifier gene for bone growth .
SCGF-beta (Stem Cell Growth Factor-beta), also named as Osteolectin or CLEC11A, was recognized as an osteogenic growth factor [28, 29]. Researchers have found that this protein promotes Leptin Receptor+ (LepR+) skeletal stem cells and other osteogenic progenitors in bone marrow to differentiate into osteoblasts and to maintain the adult skeletal bone mass . Andriani GA et al. indicated that CLEC11A is a component of SASP (senescence-associated secretory phenotype) . They also suggested that aneuploid cells which accumulate during aging in some mammalian tissues potentially play key roles in age-related pathologies via SASP secretion .
Periostin is a secreted extracellular matrix protein in human, which is encoded by POSTN gene. It was expressed in many tissues including skeleton and originally identified in periosteum and bone . A previous study indicated that periostin participates in the early stages of osteoblast differentiation and bone formation . It stimulates osteoblast functions and bone formation via integrin receptors and Wnt-beta-catenin pathways . Experimental mice without periostin proportionately suffered from severe periodontal disease and bone density reduction . Pepe J et al. suggested that Serum periostin levels were associated with radial cortical porosity, even after adjusted by age . Moreover, periostin expression declines with the skeletal growth, but it could re-express in the process of fracture healing and bone repair . It also has been demonstrated that it plays a key role in postmenopausal osteoporosis for that serum levels could be measured to predict BMD and the risk of fracture .
GAPDS (Glyceraldehyde-3-phosphate dehydrogenase, testis-specific) is a member of GAPDH (glyceraldehyde-3-phosphate dehydrogenase) family that play an important role in carbohydrate metabolism. GAP was recognized as an osteoblast marker enzyme with high mRNA expression in periosteal cells from young rats . Vitamin K2, a homologue to GAPDH, confirmed by the observations of Biochem Pharmacol et al, play a crucial role in bone metabolism . It is able to post-translationally modify the osteocalcin, induce osteoclast apoptosis and imped the osteoclast formation and resorption activity .
RANTES, also known as CCL5 (C-C Motif Chemokine Ligand 5), is a member of chemokine genes clustered on the q-arm of chromosome 17, which are involved in immunoregulatory and inflammatory processes. By sharing common signaling pathways and regulatory mechanisms, the bone systems are closely related to the immune systems . According to the previous studies, CCL5 is directly associated with disturbed bone metabolism in nonpainful rheumatoid arthritis . Additionally, the chemokine CCL5 is overexpressed in the FDOJ (fatty oxide osteoporosis/osteolysis in the jawbone) cases . More, in the knowledge that hyperhomocysteinemia is a risk factor for osteoporotic fractures, another previous study indicated that protein CCL5 could be generated in the osteobalsts after homocysteine induces serum amyloid A3 . In summary, CCL5 may play an important role in the bone metabolism, which needs more confirmative evidence.
It is well known that bone remodeling is a dynamic process and BMD varies at different human life stages . Because of bone reformation, BMD increases dramatically during childhood and adolescent periods, peaking at the third decade of life approximately. Around the age of over 50, the process of bone resorption gradually overwhelms the process of bone reformation, which results in a decrease of BMD, particularly for postmenopausal women. In this study, we identified several plasma proteins showing age specific effects on BMD. For instance, coagulation Factor X showed negative genetic correlation with BMD in the subjects aged more than 60 years. Coagulation Factor X is a vitamin K-dependent enzyme of blood coagulation cascade and plays a critical role in blood coagulation . Gigi R et al. demonstrated that Rivaroxaban, an anticoagulant against factor Xa, could significantly induce the reduction in osteoblastic cell growth and energy metabolism, and the inhibition of alkaline phosphatase, which was a kind of osteoblastic marker . Coagulation Factor X may contribute to the decrease of BMD of the subjects aged more than 60 years through activating osteoblast. Additionally, MYBPC1 appeared to be correlated with BMD in the subjects aged 45–60 years in this study. MYBPC1 encodes myosin binding protein c (slow type), which plays an important role in muscle contraction. MYBPC1 mutation has been linked to skeletal muscle atrophy related disorder . Furthermore, previous studies have demonstrated the positive association between body lean mass and BMD . It is well known that adult body lean mass trend to decrease with age, especially after 40 years. Based on previous studies and our study results, we may infer that MYBPC1 contributed to the variation of BMD through affecting skeletal muscle loss in the subjects aged 45–60 years.
There are some limitations that should be noted in this study. Firstly, we used the GWAS data driven from European, American, Australian and multiethnic populations, in which most of the subjects were European. Because of the different genetic background of different populations, it should be careful to apply our study results to other populations. Especially for the group [0–15], there’s more subjects of not-european ancestry in the group [0–15] comparing to other groups. Secondly, the stability of LDSC result could be influenced by the small sample size of the study, which is worth noted. Thirdly, among the two datasets of BMD in our study, different body parts and different method was used to measure BMD, which may have some effect on our results. Further efforts are still need to confirm our results and clarify the potential biological mechanism underlying the observed genetic correlations between plasma proteins and BMD.