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This is from Molecular features of sexual steroids on cartilage and bone
It is a good primer for perspective of the balance and activities of sex hormones in bone and joint tissues. Knock this out of balane and you essentially have a disease state. i.e. our joint pain.
HORMONES ACTING ON CARTILAGE AND BONE FORMATION
Several factors act on bone cells during their differentiation, such as circulating molecules, hormones (parathyroid hormone - PTH, growth hormone - GH, progestogens, and androgens) or non-hormonal molecules (1,25 dihidrocholecalciferol, insulin-like growth factors types 1 and 2 - IGF 1 and 2), locally produced molecules with autocrine/paracrine action (IGF1 and 2, bone morphogenetic protein - BMP, prostaglandin E2 -PGE2, interleukin 1 - IL1, tumor necrosis factor - TNF-α, granulocyte macrophage colony-stimulating factor - GM-CSH, transforming growth factor β - TGFβ, basic fibroblast growth factor 2 - BFGF2), and molecules present in the bone extracellular matrix (FGF2, TGFβ, GM-CSF, IGF1 and 2); they are inactive when bound to bone extracellular matrix (BEM) constituent molecules, but active on bone cells when BEM breakdown takes place. Quiescent osteoblasts regulate the osteoclast access, but under the action of bone-reabsorbing factors (PTH, dihidrocholecalciferol, and PGE2), osteoblasts retract and give place to the osteoclasts, which can adhere to the extracellular matrix. Vitamin D and PTH stimulate osteoclast activity, whereas calcitonin inhibits it. Oncogenes cfos and c-myc are expressed in osteoblast proliferation5,6.
Cartilage growth regulation is complex and is under hormone action - growth hormone, IGF1 and 2, estrogens, and androgens, but also a number of locally produced factors (FGF2, TGFb, epidermal growth factor [EGF], platelet-derived growth factor [PDGF])5.
Estrogens act by hastening chondrocyte proliferation, and the androgen action on cartilage is ensured by the activation of estrogen receptors, as the androgens synthesized by gonads penetrate the chondrocytes, where they are transformed into estrogens by the enzyme aromatase7,8.
The peptide related to the parathyroid hormone (PTHrP) is synthesized in a number of bone cells in the epiphysis, in contrast with its receptor, present only in the epiphyseal plate in the transition zone among proliferating and hypertrophic chondrocytes. The Indian hedgehog protein and its receptor play a role in regulating growth and in the differentiation of the epiphyseal plate. Indian hedgehog is identified in prehypertrophic chondrocytes and acts on perichondrium cells expressing its receptor. Indeed, the receptor activation determines an increase in PTHrP secretion by perichondrium cells. There is a regulation loop: chondrocytes at the resting region (preproliferation) cause PTHrP synthesis via Indian Hedgehog, acting on epiphyseal plate chondrocytes and allowing their proliferation8.
Thyroid parafollicular cells secrete, among many hormones, calcitonin, which acts on calcium blood level regulation and calcium storage in bones. The parathyroid gland secretes PTH, which acts on bones, kidneys, and intestines in order to maintain the interstitial fluid calcium level balanced. In the bone, PTH is bound to receptors in the osteoblasts, signaling for an increased secretion of osteoclast stimulating factor by the cells9.
SEXUAL STEROIDS
Sexual hormones are steroids interacting with androgen and estrogen receptors in vertebrates. Natural sexual steroids are produced by gonads (ovaries and testicles), by adrenals, or by conversion from other sexual steroids. Sexual steroids play important roles by inducing bodily changes known as primary sexual characteristics and secondary sexual characters10.
PROGESTOGENS
Progestogens are female sexual steroids produced by the menstrual corpus luteum or up to an eight-week pregnancy, when their synthesis is taken on by the placenta. They are parent hormones of the sexual steroids estrogens and androgens and of the cortisone synthesis by the adrenal cortex. At the first stage, the cholesterol molecule is converted into pregnenolone (P5). P5 and other members of the progestogenic steroid class serve as parent hormones for all other steroids, including estrogens, androgens, mineralocorticoids, and glucocorticoids. Progesterone is the hormone that prepares women for breastfeeding, and affects women physically and emotionally, preparing her for a pregnancy. Many women who are progesterone-deficient can have amenorrhoea and recurring miscarriages11.
Progestogens further have many functions, such as the endometrium preparation for the zygote reception and implantation, milk production over breast-feeding, endometrial proliferation blocking, and estrogen predominance balance, with a key role in preventing most common symptoms in the premenstrual syndrome (PMS). In bone tissue, progestogens stimulate osteoblast proliferation and differentiation by stimulating bone formation, thus avoiding bone loss11-13.
ANDROGENS
Androgens are male hormones produced by the testicles and found in small amounts in women. They have many functions similar to estrogens, since they are estrogen parent hormones: they increase osteoblast activity, inhibit calcium removal from the body by decreasing osteoclast formation and activity, and stimulate long bone longitudinal growth at puberty, as well as epiphyseal plate ossification. When this sexual hormone secretion is reduced, the osteoclastic activity becomes higher than osteoblastic activity, and bone formation is potentially reduced6,7.
The main types of androgens are testosterone and androsterone. Testosterone is the main male hormone, produced under the influence of the luteinizing hormone from the pituitary gland, and stimulates sperm production and male sexual characteristics at puberty14,15.
ESTROGENS
Estrogens are female steroids producing the female phenotype, such as physical appearance and sexual and emotional characteristics. They are mainly produced by ovarian follicles and are found in small amounts in men. The fact that estrogens are produced by ovaries, with androgens as parent hormones, make women produce male hormones first and subsequently turn them into female hormones. Estradiol (E2), as other sexual steroids, is obtained from cholesterol. After side chain cleavage, a fraction of androstenedione is converted into testosterone, which, in turn, is converted into estradiol by an enzyme called aromatase. Alternatively, androstenedione is "aromatized" to estrone and further to estradiol10,15.
These sexual steroids have several functions in bone tissue, such as: increasing osteoblast activity, inhibiting calcium removal from the body by interfering and reducing osteoclast formation and activity, and stimulating long bone growth after puberty. They further promote rapid bone calcification, causing it to reduce the proliferation activity until it ceases4,10.
In adults, bone maintenance is due to estrogens because of their antireabsorptive and anabolic effects. In females, osteoclasts have estrogen alpha receptors (ERa), thus these hormones act by reducing osteoclast reabsorption activity; in males, however, bone formation stimulus is mediated by ERa present in osteoblasts16.
The term "estrogen receptor" refers to a receptor group activated by the hormone 17b-estradiol. There are two types of estrogen receptors - ERa and ERb -, members of an intracellular receptor nuclear family, with G protein coupled to GPR30 receptor - GPER. Estrogen and the expression of its receptor ER-a are present in the nucleus and cytoplasm of articular cartilage cells and in subchondral bone, directly affecting bone metabolism during the individual's life. Hormone therapy with estrogens (estradiol and diethylstilbestrol) has been used to inhibit bone reabsorption and prevent bone loss in postmenopausal women9,11,17.
OSTEOARTHRITIS
In Brazil, reported cases of articular cartilage degenerative diseases increase 20% every year, meaning that over 200,000 Brazilians develop joint and bone degenerative diseases yearly. There is an incidence of 35% of cases affecting the knees from the age of 30, rising dramatically with age, reaching 80% of people older than 50 years. In osteoarthritis (OA), the bone mineral density (BMD) is reduced, bone microarchitecture is broken, and the amount of noncollagenous proteins in bone is changed. Bone matrix synthesis dysfunction may occur from excess PTH production and from decreased sexual steroid secretion, such as estrogen, progestogen, and androgen, following menopause; from enzyme action on cartilage tissue degradation, or from vitamin A deficiency, as this vitamin balances the activity between osteoblasts and osteoclasts3,18.
The cartilage matrix, containing collagen fibers and proteoglicans, undergoes constant remodeling by chondrocytes, which are sources of both catabolic and anabolic activities in the cartilage. The catabolic process is mediated by metalloproteinases, such as gelatinase, stromelysin, and colagenase. Metalloprotease activity can be blocked by tissue inhibitors - TIMPs -, also produced by chondrocytes. The chondrocytes, in turn, are subject to biochemical mediator influence, with two groups mainly found, one of them predominantly related to interleukin-1 (IL-1) and tumor necrosis factor α (TNF-α) activity, whereas the other comprises growth factors (fibroblast growth factor [FGF], platelet-derived growth factor [PDGF], and insulin-like growth factor [IGF]). The initial osteoarthritis mechanism is still controversial, but an initial increased IL-1 and TNF-α production by synoviocytes is known, with IL-1 and TNF-α acting on chondrocytes and stimulating the catabolic pathway. As long as the chondrocyte can replace the catabolized material through a compensatory increase in anabolic activities, the disease is under control. However, when their repair capacity isexhausted, clinical disease supervenes. Therefore, OA can be understood as an imbalance in the physiological remodeling process of the articular cartilage18,19.
When the increase in matrix degeneration by chondrocytic enzymes exceeds the increase in new synthesized matrix, cartilages will naturally degenerate (excess chondrocytes create substances that are useful for cartilage replacement, but they also create enzymes that destroy their components). If this process continues, there will be a decrease in the osteoblast number and an increase in osteoclasts that degenerate the joint, causing cartilage loss and changes in the subchondral bone. The outcome is joint pain, deformity, and limited range of movement20.
CONCLUSION
Sexual steroids (estrogens, progestogens, and androgens) are related to cartilage and bone tissue maintenance, thus in postmenopausal women or in those with osteoarthritis, hormone administration should be evaluated.
It is a good primer for perspective of the balance and activities of sex hormones in bone and joint tissues. Knock this out of balane and you essentially have a disease state. i.e. our joint pain.
HORMONES ACTING ON CARTILAGE AND BONE FORMATION
Several factors act on bone cells during their differentiation, such as circulating molecules, hormones (parathyroid hormone - PTH, growth hormone - GH, progestogens, and androgens) or non-hormonal molecules (1,25 dihidrocholecalciferol, insulin-like growth factors types 1 and 2 - IGF 1 and 2), locally produced molecules with autocrine/paracrine action (IGF1 and 2, bone morphogenetic protein - BMP, prostaglandin E2 -PGE2, interleukin 1 - IL1, tumor necrosis factor - TNF-α, granulocyte macrophage colony-stimulating factor - GM-CSH, transforming growth factor β - TGFβ, basic fibroblast growth factor 2 - BFGF2), and molecules present in the bone extracellular matrix (FGF2, TGFβ, GM-CSF, IGF1 and 2); they are inactive when bound to bone extracellular matrix (BEM) constituent molecules, but active on bone cells when BEM breakdown takes place. Quiescent osteoblasts regulate the osteoclast access, but under the action of bone-reabsorbing factors (PTH, dihidrocholecalciferol, and PGE2), osteoblasts retract and give place to the osteoclasts, which can adhere to the extracellular matrix. Vitamin D and PTH stimulate osteoclast activity, whereas calcitonin inhibits it. Oncogenes cfos and c-myc are expressed in osteoblast proliferation5,6.
Cartilage growth regulation is complex and is under hormone action - growth hormone, IGF1 and 2, estrogens, and androgens, but also a number of locally produced factors (FGF2, TGFb, epidermal growth factor [EGF], platelet-derived growth factor [PDGF])5.
Estrogens act by hastening chondrocyte proliferation, and the androgen action on cartilage is ensured by the activation of estrogen receptors, as the androgens synthesized by gonads penetrate the chondrocytes, where they are transformed into estrogens by the enzyme aromatase7,8.
The peptide related to the parathyroid hormone (PTHrP) is synthesized in a number of bone cells in the epiphysis, in contrast with its receptor, present only in the epiphyseal plate in the transition zone among proliferating and hypertrophic chondrocytes. The Indian hedgehog protein and its receptor play a role in regulating growth and in the differentiation of the epiphyseal plate. Indian hedgehog is identified in prehypertrophic chondrocytes and acts on perichondrium cells expressing its receptor. Indeed, the receptor activation determines an increase in PTHrP secretion by perichondrium cells. There is a regulation loop: chondrocytes at the resting region (preproliferation) cause PTHrP synthesis via Indian Hedgehog, acting on epiphyseal plate chondrocytes and allowing their proliferation8.
Thyroid parafollicular cells secrete, among many hormones, calcitonin, which acts on calcium blood level regulation and calcium storage in bones. The parathyroid gland secretes PTH, which acts on bones, kidneys, and intestines in order to maintain the interstitial fluid calcium level balanced. In the bone, PTH is bound to receptors in the osteoblasts, signaling for an increased secretion of osteoclast stimulating factor by the cells9.
SEXUAL STEROIDS
Sexual hormones are steroids interacting with androgen and estrogen receptors in vertebrates. Natural sexual steroids are produced by gonads (ovaries and testicles), by adrenals, or by conversion from other sexual steroids. Sexual steroids play important roles by inducing bodily changes known as primary sexual characteristics and secondary sexual characters10.
PROGESTOGENS
Progestogens are female sexual steroids produced by the menstrual corpus luteum or up to an eight-week pregnancy, when their synthesis is taken on by the placenta. They are parent hormones of the sexual steroids estrogens and androgens and of the cortisone synthesis by the adrenal cortex. At the first stage, the cholesterol molecule is converted into pregnenolone (P5). P5 and other members of the progestogenic steroid class serve as parent hormones for all other steroids, including estrogens, androgens, mineralocorticoids, and glucocorticoids. Progesterone is the hormone that prepares women for breastfeeding, and affects women physically and emotionally, preparing her for a pregnancy. Many women who are progesterone-deficient can have amenorrhoea and recurring miscarriages11.
Progestogens further have many functions, such as the endometrium preparation for the zygote reception and implantation, milk production over breast-feeding, endometrial proliferation blocking, and estrogen predominance balance, with a key role in preventing most common symptoms in the premenstrual syndrome (PMS). In bone tissue, progestogens stimulate osteoblast proliferation and differentiation by stimulating bone formation, thus avoiding bone loss11-13.
ANDROGENS
Androgens are male hormones produced by the testicles and found in small amounts in women. They have many functions similar to estrogens, since they are estrogen parent hormones: they increase osteoblast activity, inhibit calcium removal from the body by decreasing osteoclast formation and activity, and stimulate long bone longitudinal growth at puberty, as well as epiphyseal plate ossification. When this sexual hormone secretion is reduced, the osteoclastic activity becomes higher than osteoblastic activity, and bone formation is potentially reduced6,7.
The main types of androgens are testosterone and androsterone. Testosterone is the main male hormone, produced under the influence of the luteinizing hormone from the pituitary gland, and stimulates sperm production and male sexual characteristics at puberty14,15.
ESTROGENS
Estrogens are female steroids producing the female phenotype, such as physical appearance and sexual and emotional characteristics. They are mainly produced by ovarian follicles and are found in small amounts in men. The fact that estrogens are produced by ovaries, with androgens as parent hormones, make women produce male hormones first and subsequently turn them into female hormones. Estradiol (E2), as other sexual steroids, is obtained from cholesterol. After side chain cleavage, a fraction of androstenedione is converted into testosterone, which, in turn, is converted into estradiol by an enzyme called aromatase. Alternatively, androstenedione is "aromatized" to estrone and further to estradiol10,15.
These sexual steroids have several functions in bone tissue, such as: increasing osteoblast activity, inhibiting calcium removal from the body by interfering and reducing osteoclast formation and activity, and stimulating long bone growth after puberty. They further promote rapid bone calcification, causing it to reduce the proliferation activity until it ceases4,10.
In adults, bone maintenance is due to estrogens because of their antireabsorptive and anabolic effects. In females, osteoclasts have estrogen alpha receptors (ERa), thus these hormones act by reducing osteoclast reabsorption activity; in males, however, bone formation stimulus is mediated by ERa present in osteoblasts16.
The term "estrogen receptor" refers to a receptor group activated by the hormone 17b-estradiol. There are two types of estrogen receptors - ERa and ERb -, members of an intracellular receptor nuclear family, with G protein coupled to GPR30 receptor - GPER. Estrogen and the expression of its receptor ER-a are present in the nucleus and cytoplasm of articular cartilage cells and in subchondral bone, directly affecting bone metabolism during the individual's life. Hormone therapy with estrogens (estradiol and diethylstilbestrol) has been used to inhibit bone reabsorption and prevent bone loss in postmenopausal women9,11,17.
OSTEOARTHRITIS
In Brazil, reported cases of articular cartilage degenerative diseases increase 20% every year, meaning that over 200,000 Brazilians develop joint and bone degenerative diseases yearly. There is an incidence of 35% of cases affecting the knees from the age of 30, rising dramatically with age, reaching 80% of people older than 50 years. In osteoarthritis (OA), the bone mineral density (BMD) is reduced, bone microarchitecture is broken, and the amount of noncollagenous proteins in bone is changed. Bone matrix synthesis dysfunction may occur from excess PTH production and from decreased sexual steroid secretion, such as estrogen, progestogen, and androgen, following menopause; from enzyme action on cartilage tissue degradation, or from vitamin A deficiency, as this vitamin balances the activity between osteoblasts and osteoclasts3,18.
The cartilage matrix, containing collagen fibers and proteoglicans, undergoes constant remodeling by chondrocytes, which are sources of both catabolic and anabolic activities in the cartilage. The catabolic process is mediated by metalloproteinases, such as gelatinase, stromelysin, and colagenase. Metalloprotease activity can be blocked by tissue inhibitors - TIMPs -, also produced by chondrocytes. The chondrocytes, in turn, are subject to biochemical mediator influence, with two groups mainly found, one of them predominantly related to interleukin-1 (IL-1) and tumor necrosis factor α (TNF-α) activity, whereas the other comprises growth factors (fibroblast growth factor [FGF], platelet-derived growth factor [PDGF], and insulin-like growth factor [IGF]). The initial osteoarthritis mechanism is still controversial, but an initial increased IL-1 and TNF-α production by synoviocytes is known, with IL-1 and TNF-α acting on chondrocytes and stimulating the catabolic pathway. As long as the chondrocyte can replace the catabolized material through a compensatory increase in anabolic activities, the disease is under control. However, when their repair capacity isexhausted, clinical disease supervenes. Therefore, OA can be understood as an imbalance in the physiological remodeling process of the articular cartilage18,19.
When the increase in matrix degeneration by chondrocytic enzymes exceeds the increase in new synthesized matrix, cartilages will naturally degenerate (excess chondrocytes create substances that are useful for cartilage replacement, but they also create enzymes that destroy their components). If this process continues, there will be a decrease in the osteoblast number and an increase in osteoclasts that degenerate the joint, causing cartilage loss and changes in the subchondral bone. The outcome is joint pain, deformity, and limited range of movement20.
CONCLUSION
Sexual steroids (estrogens, progestogens, and androgens) are related to cartilage and bone tissue maintenance, thus in postmenopausal women or in those with osteoarthritis, hormone administration should be evaluated.
