10 IntroductionSkeletogenesis is an interesting area for research in the pool of

1.0 IntroductionSkeletogenesis is an interesting area for research in the pool of various organ developmental studies, where bone is derived from the mesoderm. During embryonic and fetal development, growing fetus gets nourishment in the form of calcium and nutrients from maternal sources which can affect either the calcium metabolism or skeletal mass in pregnant women. Calcium is needed from mother to fetus via placenta which nurtures the developing fetus and helps in osteogenesis and postnatal bone development. In this process continuous transfer of calcium through breast feeding (milk) where the transport of calcium from mother to baby takes place which causes mother’s bones weak and calcium deficient over time [1-6]. Lactation and weaning are two physiological processes in females after pregnancy for successful mammalian reproduction, and they are tightly regulated by a number of proteins. Vertebrate progenies are dependent on their mothers for calcium requirement to assist the initial growth of their skeletons. During the lactation process, maternal skeleton serves as one of the main sources of the calcium used for milk production. In humans, on an average a nursing woman secretes 300–400 mg of calcium into milk on a daily basis, and transports more than 80 g of calcium to her child in this manner over a 9-month period of lactation [4-7]. The requirement of calcium supply for milk production exhibits a substantial stress on maternal calcium as well as skeletal homeostasis. The maternal transformations during lactation for calcium demands have been examined currently in detail [1-6]. One common transformation shown by all mammals is the transfer of skeletal calcium storage, followed by bone loss [1, 4, 5]. Overall, calcium is an essential nutrient during pregnancy and lactation that assists the fetal and postnatal skeletal growth and development, especially because of maternal-fetal or mother-baby transfer of calcium.Bone is considered as mineral storage organ which reserves 99% of calcium into bone [8, 9]. Many studies report that the released calcium of bones plays an important role during lactation period [10-12]. The loss of calcium through milk is compensated by the skeleton and results in ~6–10% of their loss from bone mass (bone mineral content) over a lactation period of 6 months [1, 5, 13, 14]. The degree of bone loss is related, in part, to suckling intensity and the amount of milk produced. In case of rodents, which nurse many more offspring than humans show up to 35% of loss from their skeletal mass (bone mineral content) over 3 weeks of lactation [7, 15, 16]. Not only trabecular bone is most critically altered during lactation, but cortical bone is also affected. Not shockingly, lactation is also related with decline in the biomechanical strength of bone by deteriorating the bone mass [15, 17]. Lactation bone loss is completely recovered once the offspring are weaned and milk production is halted [4-6]. The process is so remarkable and drastic that within 6-12 months the BMD is restored in human to baseline at a rate of approximately 0.5–2%/month [5, 13, 18, 19]. Various histomorphometric studies on rat trabecular bone micro-architecture revealed increase in trabecular number, thickness, and connectivity by 2 weeks after lactation had ended, and this was accompanied by a substantial increase (800%) in the rate of bone formation resulting in recovery of bone mass within 4–8 week after the end of lactation [20]. To overcome the loss of calcium during lactation, mother could need increased intestinal absorption of calcium, and decreased renal calcium loss [21, 22]. Thus, lactation is considered as temporary demineralization phase of skeleton in which lactating women release calcium from bones, and after weaning when lactation stops this metabolism is reversed [23]. The process of demineralization is commonly modulated by estrogen hormone and parathyroid hormone related peptide (PTHrP) [16, 24, 25]. In context of physiology during breast-feeding, ovarian cycle ceases and there is low secretion of estrogen hormone from ovarian follicular cells. Estrogen is the principal hormone in females that sustains bone strength and enhances bone micro-architecture. During lactation, when estrogen level becomes low, then there is also less trabecular bone and bone strength which enhances the chances of fracture in women. If women are not able to get proper nutritional support during this time, then the likelihood of women becoming osteopenic is very high, and this stage is assumed as temporary osteoporosis [26-30]. Surprisingly, there have been relatively few studies addressing the mechanisms that underlie this dramatic burst of anabolic bone growth. There has been great interest in comprehension of the potential roles of microRNAs during lactation and weaning physiology as well as in embryonic and postnatal skeletogenesis, modeling, and remodeling of bone. For example, the conditional deletion of the miRNA-processing Dicer in osteoblast lineage cells reveals a direct need of miRNAs in embryonic skeletogenesis, postnatal bone growth, modeling, as well as remodeling [31], and miRNA-874-3p shows skeletal anabolic effects epigenetically during weaning [32]. In lactating women if correction for calcium does not take place then they are prone to osteoporotic conditions. Despite the wealth of genetic tools, very few studies have examined systemic or local regulation, or the molecular mechanisms of miRNAs involved in lactation and weaning physiology. Human body organization is represented as the percentage of bone, muscle and fat in a person, and they are nearly interconnected to each other owing to the fact that variation in one leads to alteration in the other. These changes create pivotal part of aging where alterations can be phenotypically noticed. Although, many other metabolic abnormalities which include diabetes, obesity, hormonal dysregulation etc, are also integrated with changes in bone, muscle and fat interaction. Peak bone mass (PBM) attained during adulthood begins decreasing after menopause in women, and with increasing age in men. Osteopenia, eventually followed by osteoporosis is the reduction of bone mass and bone quality consequently leading to decreased bone strength and increased chances of fractures [33]. Quality of bones represented by bone geometry, bone microarchitecture and bone turnover are decreased in osteoporotic condition. Presently, it has been estimated that more than 200 million people are suffering from osteoporosis globally [34]. Nearly 50 million people of India are victim of osteoporosis disease as stated by the consensus statement by Osteoporosis Society of India with higher prevalence in women owing to lower BMD at all skeletal sites due to inadequate nutrition [35]. The World Health Organization (WHO) first convened a group of experts in 1994 to assess fracture risk and its application to screening for postmenopausal osteoporosis. WHO describes osteoporosis based on bone mineral density (BMD), a standardized score, called T-score, comparing BMD to average values for young healthy subjects is used to define the categories (Figure 1). The categories for diagnosis are: 1. Normal (T-score -1.0 and above), 2. Low bone mass, referred to as osteopenia (T-score between -1.0 and -2.5), 3. Osteoporosis (T-score -2.5 and below), and 4. Severe osteoporosis (T-score -2.5 and below with history of a fracture). Osteoporosis is a “disease characterized by low bone mass and micro-architectural deterioration of bone tissue, leading to enhanced bone fragility and a consequent increase in fracture risk”. A more recent definition from the NIH Consensus Development Panel on Osteoporosis defines “osteoporosis as a skeletal disorder characterized by compromised bone strength predisposing a person to an increased risk of fracture”.”