The mechanism and traditional Chinese medicine research of bone destruction and hypercalcemia in multiple myeloma

Xue Wang

School of Basic Medicine,Qingdao University,Shandong,China.

Abstract

Key words:Multiple myeloma,Bone destruction,Hypercalcemia,Traditional Chinese medicine research

Background

With the development of multiple myeloma,Multiple myeloma (MM) most commonly invades the bones,systemic osteoporosis,osteolytic destruction and pathological fractures,which is not only the most important clinical manifestation of MM,but also the most painful symptom of patients.

Neijing has long pointed out that "kidney generates bone marrow","the owner of five Zang organs...kidney governs bone".Kidney is the congenital foundation,kidney essence is stored,and kidney essence is enriched,then bone is strong;if kidney essence is deficient and bone is dystrophic,then "kidney disease is bone polar",such as "bone flaccidity","bone withered","bone paralysis" and other bone diseases [1].We believe that "kidney-bone" includes bone destruction caused by many reasons and bone diseases such as calcium and phosphorus metabolism.

Extensive bone destruction and hypercalcemia

At present,it is believed that osteolytic lesions are not caused by the direct erosion of bone by tumor cells,but by the activation of osteoclasts by some factors secreted by tumor cells and bone marrow stromal cells [2].These factors are collectively called osteoclast activating factor (OAF),including IL-6,tumor necrosis factor (TNF),IL-11,macrophage colony-stimulating factor (M-CSF),vascular endothelial growth factor (VEGF).These factors can activate osteoclasts,leading to osteoporosis and bone destruction [3].

Hypercalcemia is closely related to osteolytic lesions and extensive bone destruction of MM.The increase of serum calcium is due to bone destruction,which causes blood calcium to escape into the blood,decrease of calcium excretion from renal tubules and the combination of monoclonal immunoglobulin and calcium [4].But the blood phosphorus of MM patients is normal,but the decrease of phosphorus excretion can also cause the increase of blood phosphorus when bone destruction and renal dysfunction are serious.

Studies have shown that the maintenance of homeostasis of calcium and phosphorus metabolism in vitro and in vivo depends on the body's activation of a series of intracellular signaling pathways through calciumsensitive receptors.At the same time it can target parathyroid,thyroid and kidney,affect parathyroid hormone (PTH).The secretion of three hormones 1,25-(OH)2D3 and calcitonin is further regulated by the three target organs of the kidney,bone and small intestine [5].

It can be seen that three important hormones participate in the regulation of calcium and phosphorus,and play an important role in regulating MM hypercalcemia.1.Parathyroid hormone (PTH) has the effect of increasing blood calcium and decreasing blood phosphorus.2.1,25-(OH)2D3 can increase blood calcium and phosphorus.3.Calcitonin (CT) has the effect of reducing blood calcium and phosphorus [6-8].Therefore,based on the strong hypocalcemic effect of calcitonin,calcitonin is commonly used to treat MM-induced hypercalcemia,such as salmon calcitonin,which has 10 times the effect of human calcitonin.At present,salmon calcitonin is also widely used to treat senile osteoporosis,postmenopausal osteoporosis and hypercalcemia caused by various reasons.

Diphosphates are mainly used for osteolytic destruction.Their mechanism is to combine with hydroxyapatite crystals of bone to inhibit its dissolution and inhibit the activity of osteoclasts.At the same time it can induce osteoclasts apoptosis and reduce the release of calcium and bone destruction to achieve the effect of pain relief and inhibition of the progress of osteopathy [9].Pamidronate disodium,ibandronate sodium and zoledronic acid are commonly used in clinic.

In addition,systemic osteoporosis is common in postmenopausal women and the elderly.

Is there anything in common with osteoporosis?

The Yellow Emperors Internal Classicrefers says:"Seven-seven women,Ren Mai deficiency,Taichong pulse decline,exhaustion of heaven,tunnel obstruction..." ,which refers to a series of changes in the body caused by the failure of kidney qi after menopause.And "kidney is the main bone",so postmenopausal women are prone to osteoporosis as an important manifestation of kidney Qi weakness.

Modern medicine believes that postmenopausal osteoporosis is a primary osteoporosis.It is caused by low ovarian function and low estrogen levels in postmenopausal women.The bone resorption of osteoclasts is greater than that of osteoblasts.Decreased estrogen levels are the leading cause of postmenopausal osteoporosis [10,11].This is because estrogen inhibits the formation and activity of osteoclasts in a variety of ways to promote the apoptosis of osteoclasts and inhibit the immune function of lymphocytes (mainly T lymphocytes) in order to reduce bone destruction and preventing osteoporosis..

Furthermore,what is the mechanism of osteoporosis in the elderly?

It can correspond to osteoporosis caused by renal failure in the elderly.Senile osteoporosis is a physiological degeneration of bone tissue which occurs during aging,including bone remodeling decline,bone-derived stem cell reduction and osteogenic differentiation [12].

From this,we can see that although the osteolytic lesions caused by MM are different from the osteoporosis and elder osteoporosis after estrogen reduction,the pathogenesis of this disease has many commonalities.Such as the relationship between osteoclasts and osteoblasts;related to specific osteoclast activating factor (OAF);related to parathyroid,1,25-(OH)2D3,calcitonin regulation of calcium and phosphorus ;related to immune regulation factors.In Traditional Chinese medicine,they all belong to the category of "kidney bone".Therefore,there are many commonalities in the treatment,such as the application of calcium preparations,diphosphates,calcitonin,active vitamin D.

Therefore,we believe that the "kidney bone" theory includes a series of bone formation and destruction mechanisms including osteolytic destruction,osteoporosis caused by various causes,and calcium and phosphorus metabolism.We are often used to treat MM-induced multiple bone destruction.In the treatment of multiple bone destruction caused by MM,traditional Chinese medicine for reinforcing liver and kidney and strengthening muscles and bones is often used.

"kidney bone" also has profound theoretical support in the study of modern medical mechanisms.First,modern medicine found that kidneys and bones are homologous organs in the genesis,all of which occur in the embryonic ectoderm.There must be commonality and correlation between the two.Furthermore,the endocrine function of the kidney can specifically catalyze the formation of 1,2-(OH)2-D3,promote the absorption of calcium and phosphorus,increase the levels of blood calcium and blood phosphorus,and promote the deposition of calcium salts and bone formation.Also,the kidney secretes erythropoietin,which plays an important role in bone development.Finally,the kidney is the most important function in the regulation of the bone metabolism system in the hypothalamicpituitary-target gland axis.This function includes the functions of various regulatory factors in the local microenvironment of bone tissue.They exert their regulation on bone metabolism by secreting different hormones,such as the secretion function of parathyroid glands,calcitonin,estrogen,prostaglandin,interleukin,bone-derived growth factor,transforming growth factor and so on.This not only provides a modern medical mechanism for the "kidney bone",but also provides a basis for the treatment of osteolytic destruction and osteoporosis.The traditional Chinese medicines used to replenish liver and kidney and strengthen bones and muscles include psoralen,eucommia,dodder,deer grass,and Polygonum multiflorum.The traditional Chinese medicines for tonifying liver and kidney and strengthening muscles and bones are Buguzhi (psoralen),Duzhong (Guttae dicitque),Tusizi (Intremisco),Luxiancao (Pyrolae),Heshouwu (Polygonum) et al.

Buguzhi (psoralen),The Compendium of Materia Medica calls it "strong Yuanyang and rich bone marrow".Modern pharmacological studies have found that it can promote the activity of alkaline phosphatase in osteoblasts,proliferation of osteoblasts and inhibit the activity of osteoclasts [13,14].

Duzhong (Guttae dicitque) is listed as the top grade in Sheng Nong's herbal classic,which contains active ingredients directly acting on osteoblasts [15,16].

Tusizi(Intremisco),The original Sutra meets the origina said "Tusizi (Intremisco),its work is dedicated to the essence,strong muscles and bones".It can increase matrix calcium of osteoblasts,promote proliferation and alkaline phosphatase activity.At the same time it can inhibit the survival rate of osteoclasts and induce apoptosis of osteoclasts.According to The original Sutra meets the origina,the polysaccharides from Tusizi (Intremisco) can promote the repair of bone defects and adjust the relationship between bone formation and bone resorption [17,18].

Heshouwu (Polygonum),Bencao Jingshu refers to it:"long bones,good essence."Heshouwu (Polygonum) and its components inhibit bone alkaline phosphatase and promote collagen synthesis.It can directly inhibit the proliferation of pre-osteocytes,inhibit the differentiation of pre-osteocytes,and promote the proliferation of osteoblasts [19,20].