COMMUNICATION BETWEEN OSTEOBLAST AND OSTEOCLAST

Communication between osteoblasts and osteoclasts

Osteoclast formation is controlled by several circulating hormones, including parathyroid hormone 1a,25-dihydroxycholecalciferol (calcitriol), and the gonadal steroids, estrogen and testosterone The microenvironment of the bone marrow also plays an essential role as a source of cytokines such as tumour necrosis factors (TNFs) and interleukins , which also regulate osteoclast formation and activity. These systemic and local factors regulate osteoclast formation and activity. Hormones and cytokines act on the osteoblastic lineage cells, which possess a cell surface molecule known as RANK ligand and a cell surface receptor, osteoprotegerin . RANKL is a member of the TNF ligand family that is present in osteoblastic lineage cells and interacts with osteoclast precursors from the haematopoietic lineage. This interaction promotes the differentiation and fusion of the osteoclast precursor, thus leading to the formation of mature osteoclasts. Osteoprotegerin is a soluble member of the TNF receptor superfamily that is produced by osteoblast lineage cells and inhibits osteoclast formation.

Mechanisms of Hormone Action.

Calcitonin inhibits bone resorption by acting directly on mature osteoclasts. Bisphosphonates, which are used in treating osteoporosis, also inhibit osteoclasts, probably by interfering with the system of communication between osteoblasts and osteoclasts. They also reduce the number of osteoclasts by inhibiting either their recruitment or their survival. Estrogen and probably testosterone exert their effects on the bone resorption by inhibiting the production of cytokines, particularly TNFs, interleukin-1 and interleukin-6.

Growth factors.

Osteoblast formation requires a transcription factor named cbfa1 osf2, which controls osteoblast differentiation and bone formation in the developing skeletons as well as the function of mature differentiated osteoblasts . Several growth factors, including insulin-like growth factors (IGFs), transforming growth factor-b, fibroblast growth factors, platelet-derived growth factor, bone morphogenetic proteins and prostaglandins can stimulate the proliferation of osteoblasts in vitro. Their respective importance in vivo is not yet clear. Nevertheless, it has been suggested that the production and action of growth factors are vital to the stimulation of bone formation in response to systemic hormones such as parathyroid hormone (PTH), osteogenic agents such as fluoride, and mechanical strain

Calcium homeostasis

Virtually all (99%) of the body’s calcium is located in bone and teeth. Only 0.1% is in the extracellular compartment and the remainder is within cells. The maintenance of a constant extracellular concentration of ionized calcium is essential, because calcium influences many physiological functions and biochemical pathways. The extracellular concentration of calcium is regulated by a dynamic equilibrium between the levels calcium in the intestine, kidney and bone . In young adults, the rates of calcium entering and leaving the extracellular compartment are equal. Net intestinal absorption of calcium corresponds to the difference between the amount of calcium absorbed and that diffusing from the extracellular compartment to the intestinal lumen. The urinary excretion of calcium represents the difference between the amount filtered and that reabsorbed. In a steady state, urinary calcium excretion corresponds roughly to the net calcium fluxes entering the extracellular compartment from the intestine and bone. In the kidney 98% of the calcium filtered by the glomerulus is reabsorbed in the renal tubule. The major regulator of the intestinal absorption of calcium is calcitriol, an active metabolite of vitamin D3 , which acts as a hormone. It is formed in the kidney, and its production is controlled by PTH, IGF-1, and the extracellular concentrations of calcium and phosphate . The main regulator of the tubular reabsorption of calcium is PTH, secretion of which is controlled by the extracellular concentration of calcium.

Gain of bone

Peak bone mass

The “peak bone mass” is the amount of bone tissue present at the end of skeletal maturation. It is a major determinant of the risk of fracture due to osteoporosis since the mass of bone tissue at any time during adult life is the difference between the amount accumulated at maturity and that lost with ageing. There is, therefore, considerable interest in exploring ways to increase peak bone mass. Epidemiological studies indicate a 10% increase in peak bone mass in the Caucasian female population would decrease the risk of hip fracture by about 30%. Such an increase would roughly correspond to the difference between male and female peak bone mass as measured at the radial or femoral diaphyseal site.

Measurement of bone mass

Most information in the characteristics of skeletal growth during childhood and adolescence has been obtained by non-invasive techniques that enable bone mass to be measured at various sites in the skeleton with great precision and accuracy. The bone mass of a particular part of the skeleton is directly dependent on both the volume or size of the part concerned and the density of the mineralized tissue contained within its periosteal envelope. The mean volumetric mineral density of bony tissue (in g of hydroxyapatite per cm3) can be determined non-invasively by quantitative computed tomography (QCT) . The so-called “areal” or “surface” bone mineral density can be determined by single- or dual-energy X-ray absorptiometry (SXA and DXA). The values generated by these techniques are directly dependent on both the size and integrated mineral density of the scanned skeletal tissue. The integrated mineral density is determined by cortical thickness, the number and thickness of the trabeculae, and the “true” mineral density corresponding to the amount of hydroxyapatite per unit volume of the bone organic matrix.

Development of bone mass

There is no evidence for sex differences in bone mass of either the axial or appendicular skeleton at birth. Similarly, the volumetric BMD appears to be the same in female and male newborns. This absence of a substantial sex difference in bone mass is maintained until the onset of puberty . The difference following puberty is characterized by a more prolonged period of bone maturation in males than in females, resulting in a greater increase in bone size and cortical thickness. Puberty has a much greater effect on bone size than on the volumetric mineral density . There is no significant sex difference in the volumetric trabecular density at the end of puberty. During puberty, the rate of accumulation of BMD at both the lumbar spine and femoral neck increases 4–6-fold over a 3- and 4-year period in females and males, respectively. The rate of increase in bone mass is less marked in the disphysis of long bones than elsewhere. There is an asynchrony between the gain in standing height and the growth of bone mineral mass during puberty. This phenomenon may be responsible for the transient fragility that may contribute to the higher incidence of fracture that occurs near puberty when the dissociation between the rate of statural growth and mineral mass accrual is maximal.

Endocrine factors and calcium phosphate metabolism during growth

Various endocrine factors, including gonadal sex hormones and adrenal androgens (dehydroepiandrosterone and androstenedione) influence bone growth. The production of these steroids increases before and during puberty, but the time-course of their production does not match the accelerated gain in bone mass. In contrast, IGF-1 and

calcitriol concentrations and the tubular reabsorption of inorganic phosphate and plasma phosphate rise with the accrual of bone mass. This may be an adaptive response to the increased demand for calcium

and phosphate.

External factors

Modification of environmental factors can cause an individual to change the track of bone accrual. Nutritional factors are particularly important determinants of peak bone mass and rate of gain of bone mass. In addition to the non-specific influence of caloric intake, both experimental and clinical evidence indicate that the amount of calcium and protein in the diet modulate the gain in bone mass. Several intervention studies report that calcium supplementation significantly enhances the rate of BMD in children andadolescents . The role of physical activity is discussed later. Interactions between environmental factors such as dietary intake and physical exercise, as well as between genetic and environmental factors, might play an important role in the acquisition of bone mineral mass. Some data suggest that the magnitude of the bone response to calcium supplementation in prepubertal children varies according to the genotype of the vitamin D receptor .

Loss of bone

The onset of substantial bone loss is usually around age 65 years in men and 50 years in women . Nevertheless, even in the absence of risk factors, some bone loss can be detected before the menopause at certain skeletal sites. Indeed, a decrease in BMD of the proximal femur has been described in the third decade. There is little variation

in bone size throughout life, beyond continuous, slight expansion of the outer dimensions. This phenomenon is more marked in men than in women, and affects both the axial and the peripheral skeleton . The expansion of the periosteal surface is less than the increase in space occupied by the bone marrow which results from a greater

resorption at the endosteal surface. Under these conditions, the bone cortex becomes thinner. This process, together with increasing porosity of cortical bone and destruction of trabeculae through thinning and perforation, accounts for age-dependent bone loss.

Endocrine factors

Estrogen deficiency

Estrogen is necessary, not only for maximizing peak bone mass in men and women, but also for maintaining it. It controls bone remodelling in reproductively active women and in ageing men. Even a shortening of the luteal phase may be associated with abnormal bone in women . Estrogen deficiency and low bone mass also result from conditions such as anorexia nervosa, or exercise- induced amenorrhoea, or from the use of substances that inhibit gonadotropin secretion . Estrogen deficiency accelerates the rate of bone turnover, thereby altering the balance between bone formation and bone resorption, and appears to be the main cause of osteoporosis in women after the fifth decade, and possibly in men. It is thus directly implicated in the age-related increase in the incidence of fragility fractures . It is now clearly established that the rate of bone loss does not decrease with age, but continues throughout the whole of life, at least at peripheral skeletal sites.

Several cytokines released in the bone marrow increase the rate of bone turnover . TNF-a, interleukin-1 and interleukin-6, all stimulate bone resorption in vitro and in vivo, and may initiate the bone loss induced by estrogen deficiency. In a study using the transgenic mouse model in which the activity of TNF-a was permanently prevented by the presence of high levels of circulating soluble TNF-a receptor 1 (24), no decrease in bone mass or increase in bone turnover was observed after oophorectomy in transgenic mice when compared with control mice, suggesting a key role for TNF-a. While there is evidence that TNF-a, interleukin-1 and interleukin-6 are all involved in bone remodelling and show a considerable degree of interplay, only TNF-a appears to be required for the enhanced bone remodelling that occurs after estrogen depletion. This evidence is also consistent with the role of osteoprotegerin, an inhibitor of osteoclast formation. As osteoprotegerin is a soluble member of the TNF receptor superfamily, it has the capacity to neutralize the activity of TNF on osteoclastogenesis.

Other endocrine causes of bone loss

In addition to gonadal deficiency, which is an important cause of osteoporosis in men, other endocrine diseases can also cause bone loss by affecting the remodelling of bone . Primary hyperparathyroidism and hyperthyroidism increase the rate of bone turnover, thereby inducing bone loss . In contrast, excess glucocorticoids reduce bone formation. In addition, administration of glucocorticoids in pharmacological excess may decrease the intestinal absorption of calcium and possibly also its reabsorption by the renal tubules. These latter two effects would lead to a negative calcium balance and result in increased bone resorption through a mechanism which may include secondary hyperparathyroidism . Daily doses of 7.5 mg of prednisolone are sufficient to induce skeletal losses.