International Journal of Molecular Sciences Review Senile Osteoporosis: The Involvement of Differentiation and Senescence of Bone Marrow Stromal Cells Abdul Qadir 1,2,3, Shujing Liang 1,2,3, Zixiang Wu 1,2,3, Zhihao Chen 1,2,3, Lifang Hu 1,2,3,* and Airong Qian 1,2,3,* 1 Laboratory for Bone Metabolism, Key Laboratory for Space Biosciences and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi’an 710072, China; [email protected] (A.Q.); [email protected] (S.L.); [email protected] (Z.W.); [email protected] (Z.C.) 2 Research Center for Special Medicine and Health Systems Engineering, School of Life Sciences, Northwestern Polytechnical University, Xi’an 710072, China 3 NPU-UAB Joint Laboratory for Bone Metabolism, School of Life Sciences, Northwestern Polytechnical University, Xi’an 710072, China * Correspondence: [email protected] (L.H.); [email protected] (A.Q.); Tel.: +86-29-88491840 (A.Q.) Received: 13 December 2019; Accepted: 31 December 2019; Published: 5 January 2020 Abstract: Senile osteoporosis has become a worldwide bone disease with the aging of the world population. It increases the risk of bone fracture and seriously affects human health. Unlike postmenopausal osteoporosis which is linked to menopause in women, senile osteoporosis is due to aging, hence, affecting both men and women. It is commonly found in people with more than their 70s. Evidence has shown that with age increase, bone marrow stromal cells (BMSCs) differentiate into more adipocytes rather than osteoblasts and undergo senescence, which leads to decreased bone formation and contributes to senile osteoporosis. Therefore, it is necessary to uncover the molecular mechanisms underlying the functional changes of BMSCs. It will benefit not only for understanding the senile osteoporosis development, but also for finding new therapies to treat senile osteoporosis. Here, we review the recent advances of the functional alterations of BMSCs and the related mechanisms during senile osteoporosis development. Moreover, the treatment of senile osteoporosis by aiming at BMSCs is introduced. Keywords: senile osteoporosis; bone marrow stromal cells; differentiation; senescence; treatment 1. Introduction The word “osteoporosis” means “porous bone”, which is actually a worldwide metabolic bone disorder with high incidence. It is characterized by decreased bone mass, increased bone fragility and deteriorated microstructural bone tissues [1]. It occurs due to the imbalance between bone formation and bone resorption [2]. Although it has been observed in all races, gender and age groups, but more commonly found in women and older people [3]. It remains hidden until being revealed as a disorder through bone fractures, due to minor strokes [4]. It is considered amongst the most common human diseases associated with bone fractures and other severe secondary major health problems. According to the recent report of National Osteoporosis Foundation (NOF), every second woman and fourth man worldwide over the age of 50 years will encounter bone fracture, due to osteoporosis in their remaining lives. Osteoporosis is generally divided into two forms, primary osteoporosis and secondary osteoporosis. The primary osteoporosis mainly contains three categories, juvenile, postmenopausal, and senile Int. J. Mol. Sci. 2020, 21, 349; doi:10.3390/ijms21010349 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2020, 21, 349 2 of 23 osteoporosis, while the secondary osteoporosis is mainly caused by a large number of diseases and medications [5]. The primary osteoporosis is more common than the second one, and the senile osteoporosis has become one significant health concern of the world as it is an age-related disorder that occursInt. J. Mol. in Sci. people’s 2019, 20, x 70s,FOR PEER leading REVIEW to the attenuation of both the cortical and trabecular bones2 of 22 [6 ]. Besidesthe senile the osteoporosis imbalance has between become boneone significant formation health conducted concern of by the osteoblasts world as it and is an bone age-related resorption conducteddisorder by that osteoclasts, occurs in evidence people’s demonstrates70s, leading to thatthe changesattenuation in numberof both the and cortical function and of trabecular bone marrow stromalbones cells [6]. (BMSCs) are also one key cause for senile osteoporosis [7]. Study shows that BMSCs normallyBesides differentiate the imbalance in a proper between manner bone into formation osteoblast, conducted chondrocytes by osteoblasts and and adipocytes, bone resorption but during old ages,conducted there isby comparatively osteoclasts, evidence less di ffdemonstrateserentiation ofthat BMSCs changes into in osteoblast number and than function adipocytes. of bone Such a shift inmarrow cell di stromalfferentiation cells (BMSCs) of BMSCs are also results one inkey reduced cause for bone senile formation, osteoporosis which [7]. Study contributes shows that to senile osteoporosisBMSCs normally (Figure 1differentiate)[ 8]. The underlyingin a proper manner mechanism into osteoblast, behind this chondrocytes abnormal and decision adipocytes, in old but ages is during old ages, there is comparatively less differentiation of BMSCs into osteoblast than adipocytes. still under investigation. However, some achievements have been made in the form of identification Such a shift in cell differentiation of BMSCs results in reduced bone formation, which contributes to of peroxisome proliferator-activated receptor γ (PPARγ) and core binding factor α1 (CEBPα/β/δ) as senile osteoporosis (Figure 1) [8]. The underlying mechanism behind this abnormal decision in old masterages regulators is still under of di ffinvestigation.erentiation toward However, adipogenesis, some achievements while Osterix have been and runt-relatedmade in the transcriptionform of factoridentification 2 (Runx2) toward of peroxisome osteogenesis proliferator-activated [9]. In addition, receptor recent evidence γ (PPARγ demonstrates) and core binding that the factor senescence α1 of BMSCs(CEBP isα/ alsoβ/δ) oneas master important regulators cause of of differentiation senile osteoporosis toward adipogenesis, (Figure1). Cellular while Osterix senescence and runt- was first discoveredrelated bytranscription Hayflick in factor the 1960s, 2 (Runx2) which istoward a phenomenon osteogenesis where [9]. theIn cellsaddition, halt torecent divide evidence in response to variousdemonstrates stresses that causing the senescence DNA damage, of BMSCs and is begin also one to secreteimportant chemokines, cause of senile cytokines, osteoporosis and extracellular (Figure matrix1). proteins,Cellular senescence creating a was toxic first microenvironment discovered by Hayflick called in senescence-associatedthe 1960s, which is a phenomenon secretory phenotypewhere (SASP)the [ 10cells]. Suchhalt to toxicity divide ofin SASPresponse affects to various neighboring stresses normal causing cells, DNA resulting damage, inand further begin senescentto secrete cells chemokines, cytokines, and extracellular matrix proteins, creating a toxic microenvironment called accumulation, and thus, damage the residing tissue [11]. The expression of senescence biomarker senescence-associated secretory phenotype (SASP) [10]. Such toxicity of SASP affects neighboring p16Ink4anormal is cells, also resulting enhanced in [further12]. Cellular senescent senescence cells accumulation, has been and demonstrated thus, damage the to playresiding a crucial tissue role in age-related[11]. The expression pathologies, of senescence such as biomarker atherosclerosis, p16Ink4a type is also II diabetes,enhanced Alzheimer’s,[12]. Cellular senescence and Parkinson’s has diseasesbeen [ 13demonstrated]. Like the to senescence play a crucial of otherrole in cells age-related associated pathologies, with age-related such as atherosclerosis, pathologies, type the II exact mechanismdiabetes, behind Alzheimer’s, BMSCs and senescence Parkinson’s during diseases senile [13]. osteoporosis Like the senescence is still unclear.of other However,cells associated telomere shortening,with age-related oxidative stresspathologies, and some the geneticexact mechan and epigeneticism behind regulations BMSCs havesenescence been foundduring to senile contribute to BMSCsosteoporosis senescence is still during unclear. senile However, osteoporosis telomere shortening, [14]. Therefore, oxidative both stress abnormal and some diff erentiationgenetic and and senescenceepigenetic of BMSCs regulations lead have to the been reduced found to number contribute of osteoblaststo BMSCs senescence in old ages, during which senile result osteoporosis in decreased bone[14]. formation, Therefore, thus, both cause abnormal senile differentiation osteoporosis. and senescence of BMSCs lead to the reduced number of osteoblasts in old ages, which result in decreased bone formation, thus, cause senile osteoporosis. Figure 1. Schematic diagram of differentiation and senescence of bone marrow stromal cells (BMSCs) Figure 1. Schematic diagram of differentiation and senescence of bone marrow stromal cells (BMSCs) during senile osteoporosis. during senile osteoporosis. Int. J. Mol. Sci. 2020, 21, 349 3 of 23 To date, numerous medicines have been used to treat senile osteoporosis, but there are still some limitations, due to their side effects [15–19]. Therefore, in order to find out proper treatments, it is the focus of new era cell-based therapy research to uncover the molecular mechanisms behind the differentiation and senescence of BMSCs. Here, we