**3. Osteoblast cell death and proliferation lowering**

One of the most obvious effects of bacterial pathogen on a bone tissue is the destruction of osteoblasts.

Destruction of osteoblasts includes necrotic and apoptotic pathways. Papers contributing to the study of *S. aureus'* influence on the osteoblast culture show that these two pathways work independently. Apoptosis is triggered by ligand TRAIL

#### **Figure 2.**

*Pathogenetic stages and processes associated particularly with osteoblast cell death and proliferation lowering. The link between bone matrix destruction processes and associated decrease in osteoblast proliferation rate (will be shown and illustrated in the corresponding part of the chapter).*

**141**

changes.

impairment.

*Metabolic Disorders in Patients with Chronic Osteomyelitis: Etiology and Pathogenesis*

toxins PSMα и PSMβ that destroy the osteoblast cell membrane [15, 17, 18].

linking with "death receptors" DR4 and DR5, and necrosis is triggered by *S. aureus*

Lowering of the osteoblast number leads to slowing of ossification and mineralization of the bone. The level of bone resorption can remain stable or be increased

As a result, the production of bone alkaline phosphatase lowers [15]. We must say that alkaline phosphatase itself is not very convenient as a marker: it is produced by different cell types in four different forms. In this case, we have an interest in bone alkaline phosphatase that is coded with ALPL gene [19]. For precise diagnostics, a laboratory should have a specially trained personnel and corresponding equipment. A clinician should note that children and adolescents have normally elevated levels of bone alkaline phosphatase in comparison to adults, and the association between age and serum level of BAP is inverse [20] (**Figure 2**). Deficit of D hormone is a background factor that lowers ossification and is therefore marked as yellow block [21–23]. It is well known that low level of hormone D leads to increase in PTH level and lowering of bone mineral density [24]. Presence of generalized osteoporosis can additionally intensify this negative trend [25].

Orthopedic infection and excessive production of pro-inflammatory cytokines [15] influence the bone remodeling balance. Such hyperproduction can be triggered by infection itself and can increase when the pathogen persists inside the osteoblasts. Furthermore, some pathogens can additionally increase the inflammatory response because of paracrine action of their factors, interfering with the cytokine balance [26]. As it will be shown later, the inflammatory response tends to turn into a hyperergic response because of excessive activation of the cell immunity, which is

One of the most well-studied bacterial pathogens that is convenient for illustration is *S. aureus*. Many authors [14, 15, 27] show that *S. aureus* influences both parts of the bone turnover-bone resorption and ossification. During infection, *S. aureus* not only destroys (damages) osteoblasts through necrosis and apoptosis, but also lowers their proliferation rate. Influence on bone resorption is based on rapid maturation and additional activation of the osteoclasts by this pathogen. This mechanism is based on excessive synthesis of prostaglandin Е2 (PGE2) by osteoblasts and persisting of *S. aureus* inside the osteoblasts, as well as auto and paracrine regulatory mechanisms in which PGE2 plays its biochemical role. The synthesis of osteoprotegerin (OPG) is also impaired because of lowering of the level of corresponding mRNA; [28] as a result, more RANK-ligand (RANKL) molecules remain unbound and act as osteoclast activators. Excessive activation of the osteoclasts and lowering of the number and proliferation rate of the osteoblasts lead to obvious shift of the bone turnover to bone resorption. As a result, the loss of bone tissue and impairment of its mineralization at the site of orthopedic infection (bone infection) can lead to difficulties in bone

consolidation in patients with bone defects and/or fractures (**Figure 3**).

"Red blocks" of this part include the OPG and RANK-ligand (RANKL) level

"Yellow blocks" include the pre-existing low level of the osteoprotegerin. An example is a case of chronic osteomyelitis development in a patient with preexisting low-speed bone turnover and associated osteoporosis with OPG synthesis

These markers are rarely used in routine clinical practice but can be of a certain

*DOI: http://dx.doi.org/10.5772/intechopen.92052*

at the same time (see "Bone remodeling shift").

**4. Bone remodeling (bone turnover) shift**

an important factor for chronization of the process.

value when an appropriate laboratory is available.

#### *Metabolic Disorders in Patients with Chronic Osteomyelitis: Etiology and Pathogenesis DOI: http://dx.doi.org/10.5772/intechopen.92052*

linking with "death receptors" DR4 and DR5, and necrosis is triggered by *S. aureus* toxins PSMα и PSMβ that destroy the osteoblast cell membrane [15, 17, 18].

Lowering of the osteoblast number leads to slowing of ossification and mineralization of the bone. The level of bone resorption can remain stable or be increased at the same time (see "Bone remodeling shift").

As a result, the production of bone alkaline phosphatase lowers [15]. We must say that alkaline phosphatase itself is not very convenient as a marker: it is produced by different cell types in four different forms. In this case, we have an interest in bone alkaline phosphatase that is coded with ALPL gene [19]. For precise diagnostics, a laboratory should have a specially trained personnel and corresponding equipment. A clinician should note that children and adolescents have normally elevated levels of bone alkaline phosphatase in comparison to adults, and the association between age and serum level of BAP is inverse [20] (**Figure 2**).

Deficit of D hormone is a background factor that lowers ossification and is therefore marked as yellow block [21–23]. It is well known that low level of hormone D leads to increase in PTH level and lowering of bone mineral density [24]. Presence of generalized osteoporosis can additionally intensify this negative trend [25].
