**1. Introduction**

Bone is a tough and dynamic tissue that provides shape to our body while protecting the organs [1]. Bone formation is chiefly regulated by the precise biochemical signaling pathways that maintain the action of the bone cells viz. osteoblasts and osteoclasts [2]. These bone cells act in a balanced and stable fashion in the normal functioning of the bone. Disruptions in this intricate balance results in absurd bone functions with the consequent occurrence of bone associated disorders. Osteoporosis is one such well-recognized bone disease that is patented by the decreased bone mineral density and loss of connectivity in the bone trabeculae [3]. Osteoporosis has been documented to elicit approximately 8.9 million fractures annually, targeting around 200 million osteoporotic women across the globe [4, 5]. As per the International Osteoporosis Foundation, osteoporosis results in 1.5 million fractures per year in the USA while in Europe, more than 3.5 million osteoporotic fractures have been reported each year [6, 7]. Besides, in

India approximately 61 million people are stated as diseased osteoporotic patients [8, 9]. Therefore, management of osteoporosis is the urgent need of the hour for providing relief to the masses and hence refining the quality of life. Apart from numerous therapeutic measures available for the treatment, osteoporosis is still largely undertreated and seeks improved strategies that are associated with fewer side effects.

MicroRNA (miRNA) antagonism might be a new therapeutic approach for the check of osteoporosis. miRNAs are small RNAs (21–23 nucleotides) that act as post-transcriptional regulators of gene expression [10]. In a broader sense, miRNAs execute their functions either by degrading the gene (mRNAs) or by repressing the translation of the protein for the respective gene [11]. miRNA mediated targeting of expression for the genes that are involved in bone remodeling and regeneration is a novel and specific mode of therapeutic strategy. Various miRNAs control the proliferation and differentiation potential of osteoblasts and osteoclasts that ultimately regulates the bone formation [12]. There are numerous studies that report the prominence of miRNA functions and miRNA-based antagonism in the maintenance of bone homeostasis [13]. While acting on the mRNAs, miRNAs can stimulate as well inhibit the activity of osteoblasts and osteoclasts in the bone remodeling [14]. miRNAs are able to obstruct the excessive bone loss during osteoporosis and encourages the bone formation [15]. In short, miRNAs are anticipated to serve as putative gene therapy targets for the treatment of bone-related injuries [16]. Hence the present chapter details the role and efficacy of miRNA in the management of osteoporosis. Finally, we describe the mechanism by which miRNAs can regulate the gene expression in bone formation and resorption.

## **2. Bone**

Bone is an active connective tissue that behaves like an organ as well [1]. The most fundamental function of the bone is to offer support and shape to the body [17]. Other than that, bone also serves endocrine functions and assists in hematopoiesis [18]. Broadly, the structure of bone is categorized into two types, namely cancellous or cortical bone. Cortical/compact type comprises of 80% of the bone skeleton, whereas cancellous/spongy makes up to 20% [19]. Cortical bone forms the dense outer linings of the strong bones, and spongy bone is present at the ends of the long bones [20]. Bone is associated with dynamic character and undertakes continual remodeling, wherein the aged bone is resorbed, and new bone is continually ossified [21]. The bone resorptive episode takes around 10 days to complete, whereas the formation of bone persists for a period of 3 months [22].

#### **2.1 Components of bone**

Two vital components of the bone composition are matrix and cells [23]. Matrix is further consists of organic part (30%) and inorganic part/minerals (70%) [23]. Around 90% of the bone organic matrix is made of collagen type 1 and rest 10% includes proteins such as osteocalcin, osteopontin, osteonectin, etc. [19]. In addition, bone is a storehouse for minerals, especially calcium and phosphorous, that makes the hydroxyapatite element of the bone. Hydroxyapatite provides framework and strength to the bone. Furthermore, bone is comprised

**211**

*MicroRNAs as Next Generation Therapeutics in Osteoporosis*

of four basic cell types, viz. osteoblasts, osteoclasts, osteocytes and bone lining cells [24]. Osteoblasts are bone-forming cells that arise from mesenchymal stem cells. Several growth (FGF) and transcription factors (Runx2, Osterix) are responsible for the differentiation of mesenchymal cells to the osteoblastic lineage [25]. Osteoclasts are bone-resorbing cells that originate from hematopoietic monocyte-macrophage lineage, which differentiates via the assistance of the receptor activator of nuclear factor-κB ligand (RANK ligand) and Macrophage colony-stimulating factor (M-CSF) [26]. Osteoclasts are the biggest (in size) of all other cell types of the bone. Osteocytes constitute 95% of the cells in the mature skeleton [1]. These are the mineralized differentiated osteoblast cells that regulate the process of bone remodeling. Bone lining cells are a type of flat osteoblastic cells that sheet the quiescent bone surfaces [27]. They favor to safeguard the bone, maintain the bone fluids and form a barrier between the bone and bone

Bone modeling is a specialized process wherein old bones are removed from one location and replaced by new bone at a distinct location. This process defines the ultimate shape and size of the skeleton [28]. While bone remodeling is a characteristic process in the mature skeleton that is marked by constant bone restoration via a frequent exchange of aged bone with the fresh one at the same site. The process results in the comprehensive regeneration of mature skeleton in an adult every 10 years [29]. The body tries to sustain the balance between bone formation and elimination during the process of bone remodeling. It takes place in discrete sites called basic multicellular units (BMU). The process initiates by activation phase where an initiating signal (e.g., mechanical strain on the bone, fracture healing, etc.) flags the requirement of the remodeling process [30]. After the activation, the commencement of the resorptive phase occurs, wherein osteoclasts depletes bone by proteolytic degradation and acidification. Osteoblasts travel to the eroded space and begin the ossification after the stimulation of transcription factors that encourages the bone formation [31]. Ossified bone is subsequently mineralized and eventually remodeling

**4. Biochemical signaling pathways that regulate the bone formation**

osteoblasts and osteoclasts are described as follows:

**4.1 Wnt/β-catenin pathway**

Bone formation is controlled by numerous elements including transcription factors, hormones, growth factors, oxidative processes, mechanical loading, stress, bone fractures and aging [32]. Osteoblasts and osteoclasts are able to read these external stimulants and propagate the biochemical signals via various signaling cascades. The biological response of the selected signaling pathways results either in bone formation or disruption. Some of the crucial pathways operating in the

The Wnt signaling pathway has an enormous vital role in the bone development and maintenance of bone homeostasis [33]. Wnt is a secreted protein ligand that

*DOI: http://dx.doi.org/10.5772/intechopen.91223*

**3. Physiological bone regeneration**

marrow.

cycle ends.

*MicroRNAs as Next Generation Therapeutics in Osteoporosis DOI: http://dx.doi.org/10.5772/intechopen.91223*

*Clinical Implementation of Bone Regeneration and Maintenance*

side effects.

formation and resorption.

**2. Bone**

months [22].

**2.1 Components of bone**

India approximately 61 million people are stated as diseased osteoporotic patients [8, 9]. Therefore, management of osteoporosis is the urgent need of the hour for providing relief to the masses and hence refining the quality of life. Apart from numerous therapeutic measures available for the treatment, osteoporosis is still largely undertreated and seeks improved strategies that are associated with fewer

MicroRNA (miRNA) antagonism might be a new therapeutic approach for the check of osteoporosis. miRNAs are small RNAs (21–23 nucleotides) that act as post-transcriptional regulators of gene expression [10]. In a broader sense, miRNAs execute their functions either by degrading the gene (mRNAs) or by repressing the translation of the protein for the respective gene [11]. miRNA mediated targeting of expression for the genes that are involved in bone remodeling and regeneration is a novel and specific mode of therapeutic strategy. Various miRNAs control the proliferation and differentiation potential of osteoblasts and osteoclasts that ultimately regulates the bone formation [12]. There are numerous studies that report the prominence of miRNA functions and miRNA-based antagonism in the maintenance of bone homeostasis [13]. While acting on the mRNAs, miRNAs can stimulate as well inhibit the activity of osteoblasts and osteoclasts in the bone remodeling [14]. miRNAs are able to obstruct the excessive bone loss during osteoporosis and encourages the bone formation [15]. In short, miRNAs are anticipated to serve as putative gene therapy targets for the treatment of bone-related injuries [16]. Hence the present chapter details the role and efficacy of miRNA in the management of osteoporosis. Finally, we describe the mechanism by which miRNAs can regulate the gene expression in bone

Bone is an active connective tissue that behaves like an organ as well [1]. The most fundamental function of the bone is to offer support and shape to the body [17]. Other than that, bone also serves endocrine functions and assists in hematopoiesis [18]. Broadly, the structure of bone is categorized into two types, namely cancellous or cortical bone. Cortical/compact type comprises of 80% of the bone skeleton, whereas cancellous/spongy makes up to 20% [19]. Cortical bone forms the dense outer linings of the strong bones, and spongy bone is present at the ends of the long bones [20]. Bone is associated with dynamic character and undertakes continual remodeling, wherein the aged bone is resorbed, and new bone is continually ossified [21]. The bone resorptive episode takes around 10 days to complete, whereas the formation of bone persists for a period of 3

Two vital components of the bone composition are matrix and cells [23]. Matrix is further consists of organic part (30%) and inorganic part/minerals (70%) [23]. Around 90% of the bone organic matrix is made of collagen type 1 and rest 10% includes proteins such as osteocalcin, osteopontin, osteonectin, etc. [19]. In addition, bone is a storehouse for minerals, especially calcium and phosphorous, that makes the hydroxyapatite element of the bone. Hydroxyapatite provides framework and strength to the bone. Furthermore, bone is comprised

**210**

of four basic cell types, viz. osteoblasts, osteoclasts, osteocytes and bone lining cells [24]. Osteoblasts are bone-forming cells that arise from mesenchymal stem cells. Several growth (FGF) and transcription factors (Runx2, Osterix) are responsible for the differentiation of mesenchymal cells to the osteoblastic lineage [25]. Osteoclasts are bone-resorbing cells that originate from hematopoietic monocyte-macrophage lineage, which differentiates via the assistance of the receptor activator of nuclear factor-κB ligand (RANK ligand) and Macrophage colony-stimulating factor (M-CSF) [26]. Osteoclasts are the biggest (in size) of all other cell types of the bone. Osteocytes constitute 95% of the cells in the mature skeleton [1]. These are the mineralized differentiated osteoblast cells that regulate the process of bone remodeling. Bone lining cells are a type of flat osteoblastic cells that sheet the quiescent bone surfaces [27]. They favor to safeguard the bone, maintain the bone fluids and form a barrier between the bone and bone marrow.
