Pak. J. Pharm. Sci., Vol.27, No.2, March 2014, pp.321-333 321 Bone Marrow Stromal Cell (BMSC) and skeletal aging: Role of telomerase enzyme Hamid Saeed 1* and Mehwish Iqtedar 2 1 Department of Endocrinology, School of Medicine, Stanford University, CA, United States 2 Department of Bio-technology & Microbiology, Lahore College for Women University, Lahore, Pakistan Abstract: Telomere shortening and telomerase deficiency have been linked with several age related degenerative diseases. Moreover, degenerative changes in various tissues/organs have been attributed to derangement of stem cell functions causing regenerative tragedy. Bone marrow stromal cells (BMSCs) are considered the ideal candidates for regenerative approaches owing to their beneficial effects in numerous clinical applications. Thus, the effect of telomerase deficiency in perpetrating age related changes in BMSC functions during in vitro culture; their morphology, proliferation and differentiation, that can be extrapolated and reasoned for skeletal aging is conversed in this review. Besides, information regarding pertinent molecular and biochemical markers that can be employed to examine the earliest events, during the course of BMSC aging, is also provided. Additionally, impact of telomerase deficiency in enacting skeletal aging phenotype and its associated microenvironment is also discussed. In the end, further studies, using tissue specific models of telomerase deficiency, are recommended as a future research strategy to advance our understanding of tissue specific telomerase regulation. Keywords: Telomeres, telomerase, bone marrow stromal cells, aging. INTRODUCTION Regenerative medicine holds a promise for future therapies, for patients with chronic degenerative diseases and severe injuries such as, Osteoporosis, Alzheimer´s and Parkinson´s disease and spinal cord injuries, respectively (Abdallah and Kassem, 2009; Sugaya et al., 2007; Vidaltamayo et al., 2010). Regenerative capacity of our body decreases with aging. Regeneration of tissues and organs with aging depend upon resident tissue/organ specific stem cells (Wagner et al., 2009). Bone marrow stromal cells (BMSCs), because of their ease of culture, adaptable growth and multi-lineage differentiation potential (Peister et al., 2004; Pittenger et al., 1999), are ideal candidates for regenerative approaches and are currently being employed in clinical trials (Abdallah and Kassem, 2008; Abdallah and Kassem, 2009). Plausible regenerative applications of BMSCs include stem cell transplantation (Devine and Hoffman, 2000), stem cell based strategies for the repair of damaged organs (Bruder et al., 1998) and gene therapy (Fukuda et al., 2000). Moreover, beneficial effects of BMSCs, alone or in combination, in regenerative approaches have been reported in humans and mice studies, i-e., they can enhance the engraftment of hematopoietic stem cells after co-transplantation (Anklesaria et al., 1987), regenerate the marrow environment after myelo-ablative therapy(Koc et al., 2000) and as immuno-modulators (Lu et al., 2009; Yagi et al., 2010). BMSCs have been considered as the primary source of osteoblasts for skeletal repair (Fibbe, 2002). However with aging, owing to number of factors, including telomerase deficiency, functional and numerical decline of BMSCs resulted in the compromised ability of BMSCs to repair the skeleton and maintain skeletal homeostasis (Bergman et al., 1996; D'Ippolito et al., 1999; Saeed et al., 2011). Skeletal homeostasis is maintained by a highly precise and intricate process termed as bone re-modeling, which allows a unique micro-environment to facilitate coupled osteoclast reosption and osteoblast bone formation, a process termed as coupling (Andersen et al., 2009). Disruption in the coupling process with aging initiates a bone related pathological condition termed as osteoporosis most prevalent pathological condition in humans with advanced age (Ahlborg et al., 2010; Khosla, 2010; Manolagas, 2000; Reginster and Burlet, 2006). One of the primary patho-physiological mechanisms of osteoporosis is the impairment of osteoblastic bone formation during bone remodeling with aging (Cohen- Solal et al., 1991). Number of studies have shown that age/osteoporosis-related impairment of bone formation is caused by accumulation of senescent osteogenic stem cells, which not only impair bone regeneration capacity but also create a “senescent microenvironment” that inhibits osteogenic stem cell differentiation (Justesen et al., 2002; Kveiborg et al., 2000; Stenderup et al., 2003). Telomere shortening owing to telomerase deficiency is one of the factors contributing to senescence associated replicative arrest in cultured stem cells (Simonsen et al., 2002; Stenderup et al., 2003; Kassem et al., 1997). While telomerase over-expression in human bone marrow stromal stem cells (hBMSC-TERT) resulted in long telomeres and improved self-renewal capacity. Importantly, telomerase not only inhibited the cellular *Corresponding author: e-mail: dkstemham@yahoo.com