Path Chapter 26: Bones, Joints, and Soft Tissue Tumors (1206-1254)

Path Chapter 26: Bones, Joints, and Soft Tissue Tumors (1206-1254)

Osteoprogenitor cells- pluripotent mesenchyme stem cells that are on all bony surfaces

-  When stimulated by growth factors, they proliferate into things that will form osteoblasts

-  Regulated by RUNX2/CBFA1 transcription factors, and WNT/β-catenin signaling

Osteoblasts- cells on the surface of bone that make the proteins of the matrix, initiate mineralization, and bind regulatory hormones that help them regulate osteoclasts – page 1207 bottom left

-  If an osteoblast gets surrounded by organic matrix, they form osteocytes

Osteocytes- linked together and with bone surface cells to form a network of cytoplasmic processes that go through tunnels in the matrix called canaliculi

-  Osteocytes help control calcium and phosphate levels, and sense mechanical forces and respond accordingly, called mechanotransduction

Osteoclasts- cells that do resorption, derived from the same hematopoietic progenitors as monocytes

-  Regulated during their development by macrophage colony stimulating factor (M-CSF), TNF, and Il-1

-  Mature multinucleated osteoclasts form from fusion of single nucleus precursors, and have a short life span of 2 weeks – page 1207 bottom pic right

-  Osteoclasts bind to bone surface with integrins, where they form resorption pits

-  The cell membrane over the resorption pit converts to a ruffled border of many folds, to ↑ its surface area, while adjacent cells form a tight seal with bone to prevent leak of digested stuff

-  Osteoclasts remove mineral by making an acidic environment with proton pumps, and digests organic stuff by releasing proteases

Bone homeostasis pathways:

-  One pathway of bone homeostasis involves 3 factors:

o  RANK receptor on osteoclast precursors

o  RANK ligand (RANKL) on osteoblasts and marrow stromal cells

o  Osteoprotegrin (OPG)- “decoy” receptor made by osteoblasts to bind RANKL in prevent binding to RANK

o  When stimulated by RANKL, RANK signals to activate transcription factor NF-kB, which is needed for survival of osteoclasts

-  Another pathway has M-CSF made by osteoblasts binding to M-CSF receptors on osteoclast progenitors

o  Activation of the receptor triggers tyrosine kinases needed to differentiate into an osteoclast

-  Another pathway is WNT/β-catenin, where WNT proteins made by marrow stromal cells bind to LRP5 and LRP6 receptors on osteoblasts, triggering activation of β-catenin and making of OPG

Bone formation and resorption are tightly coupled:

-  OPG and RANK oppose each other, so either bone making or resorption can be favored by tipping the RANKL/OPG ratio one way or the other

o  Hormones like PTH, estrogen, test, glucocorticoid; vitamin D, cytokines like Il-1, and growth factors like bone morphogenic factor (BMP), all work by changing levels of NF-kB and WNT/β-catenin signaling in osteoblasts

As osteoclasts disassemble matrix proteins; growth factors, cytokines, and enzymes bound to the matrix get freed and are activated

-  So as bone is broken down, things are released to initiate its renewal

Proteins of bone, including type 1 collagen, come from the osteoblasts – page 1209

-  Osteoblasts deposit collagen either in a random weave, called woven bone, or in an orderly layered way, called lamellar bone – page 1208

-  Woven bone is seen at sites of rapid bone making like the fetal skeleton or growth plates

o  It resists forces in all directions, and its presence in adults is abnormal, but not diagnostic for any disease

-  Lamellar bone replaces woven, and is deposited more slowly and is stronger than woven bone

-  Osteocalcin is found only in bone, and is measured in plasma to check for osteoblast activity

Local collections of osteocytes, osteoblasts, and osteoclasts work together to control bone formation and resorption, creating a functional unit called the basic multicellular unit (BMU)

-  During development when the skeleton is growing and enlarging, called modeling, bone formation dominates

-  Once the skeleton reaches maturity, it is remodeled through breakdown and renewal

-  BMUs remodel or replace about 10% of bone each year

Peak bone mass is reached in early adulthood once growth stops

-  Starting in your 40’s, more bone starts getting resorbed than what is formed, ↓ skeletal mass

Bone growth and development is determined by homeobox genes, which encode transcription factors needed for normal development of the skeleton

-  Most bones start with a cartilage model aka anlage, then endochondral ossification starts, and the cartilage is removed by osteoclast-like cells forming the medullary canal

o  This process progresses along the length of the bone, while at the same time the periosteum in the midshaft generates osteoblasts that deposit the beginnings of the cortex, and this area is called the primary ossification center

o  Similar events happen in the epiphysis, causing removal of cartilage and deposition of bone to form a secondary ossification center

o  This traps a plate of cartilage model between the growing centers for ossification, forming the growth plate aka physis – page 1209

§  It starts with a reserve zone, then zone of proliferation, then zone of hypertrophy, then zone of mineralization, then remnants (primary spongiosa)

o  The chondrocytes in the growth plate are responsible for longitudinal growth, as they proliferate, grow, mature, and undergo apoptosis

§  Controlled by FGF, BMP, hedgehog protein, and PTH-related protein

§  In the region of apoptosis, the matrix mineralizes and is resorbed by osteoclasts, but remnants are left behind and serve as scaffolding for deposition of bone on their surfaces

§  The remnants are called primary spongiosa, and are the first bony trabeculae

o  A similar process happens at the base of the articular cartilage, and this increases bone length

-  Bones derived from intramembranous ossification, like the cranium and clavicles, are formed by osteoblasts directly from a fibrous layer of tissue derived from mesenchyme

-  Because bone tissue is made only by osteoblasts, enlargement of bones is achieved by the deposition of new bone on a preexisting surface

o  Called appositional growth

Developmental bone problems show up early in life, while acquired problems show up later in life

Dysostoses- developmental problems with local migration of mesenchyme, a congenital malformation

-  Can be from a mutation in homeobox genes

Dysplasia- mutations to the regulators of skeleton making, like growth factors or collagen

Page 1211

Congenital malformations aka dysostoses of bone are uncommon

-  The most common are missing or extra bones, fusion of 2 digits (syndactylism), or long spider-like digits

-  Ex: problem with HOXD13 gives you an extra digit between the 3rd and 4th fingers

-  Ex: problem with RUNX2 gene gives you cleidocranial dysplasia, where the fontanelles stay open and the cranial sutures aren’t closed

Achondroplasia is the most common disease of the growth plate, and is a major cause of dwarfism

-  Caused by a mutation in the FGF3 receptor (FGFR3)

-  Activation of FGFR3 suppresses growth

-  Achondroplasia is an autosomal dominant disorder usually gotten from dad’s allele

-  Symptoms of achondroplasia are shortened proximal extremities and enlarged head with bulging forehead and depression of the root of the nose

Thanatophoric dwarfism is the most common lethal form of dwarfism

-  Also caused by mutation to FGFR3

-  Symptoms are shortening of limbs, frontal bossing (bulging forehead), big head, small chest, and a bell-shaped abdomen

-  The underdeveloped chest cavity leads to respiratory insufficiency, leading to death soon after birth

-  Histo shows at the growth plate ↓ chondrocyte proliferation, and bad column making in the zone of proliferation

Increased bone mass can happen in many diseases

-  Sometimes can be caused by a gain of function mutation to LPR5 (signals OPGN release)

-  Diseases include endosteal hyperostosis, Van Buchem disease, and autosomal dominant osteopetrosis type 1

-  They’re all characterized by ↑bone mass with cortical thickening, bigger mandible, and bigger and denser cranial vault

-  Inactivating mutations to LPR5 cause osteoporosis pseudoglioma syndrome, which has easy fractures from osteoporotic bone

Osteogenesis imperfecta- deficiency in the making of type 1 collagen, aka “brittle bone disease”

-  It’s the most common inherited disorder of connective tissue – page 1213

-  Mostly effects bone, but can also effect joints, eyes, ear, etc. that have type 1 collagen

-  The basic problem in all forms of osteogenesis imperfecta is too little bone

-  Osteogenesis imperfecta is from a mutation to the genes for the α1 and α2 chains of collagen

-  The phenotype shown depends on where the mutation is in the protein

-  Mutations that ↓making of otherwise normal collagen, have milder skeleton problems

-  More severe phenotypes have abnormal peptide chains that can’t be arranged into a triple helix

-  Mutations to cartilage-associated protein (CRTAP) and leucine proline-enriched proteoglycan 1 (LEPRE1) can cause osteogenesis imperfecta

-  There are 4 types of osteogenesis imperfecta

o  Type 2 osteogenesis imperfecta is the most severe and fatal, and shows extremely fragile bone with fractures while in the uterus

§  Radiograph may show an “accordion-like” shortening of the limbs

o  Type 1 osteogenesis imperfecta have normal life spans, and are more prone to fractures when younger, and less so when they get older

§  Also shows blue sclerae from ↓collagen, making the sclera translucent and you can see the chorioid

§  Also shows hearing loss from ear bone problems, and tooth problems, like blue-yellow teeth, from deficiency of dentin

Types 2, 9, 10, and 11 collagen are important structural parts of hyaline cartilage

-  Mutations to their genes can be anywhere from fatal to causing early destruction of joints

-  In severe cases, type 2 collagen isn’t secreted by chondrocytes, so not enough bone forms

o  In milder cases, there’s just ↓ making of normal type 2 collagen

Mucopolysaccharidoses- lysosomal storage disease caused by deficiency in acid hydrolase enzymes that degrade dermatan sulfate, heparan sulfate, and keratan sulfate

-  Mesenchyme cells, especially chondrocytes, normally metabolize ECM mucopolysaccharides, so cartilage making is severely affected

-  So skeletal problems seen in mucoplysaccharidoses are from problems with hyalne cartilage, including cartilage models, growth plates, costal cartilage, and articular surfaces

-  Bone symptoms of mucopolysaccharidoses are short stature, chest wall problems, and malformed bones

Osteopetrosis (aka marble bone disease or Albers-Schonberg disease) – group of rare genetic diseases that are characterized by ↓bone resorption, from impaired making or activity of osteoclasts

-  The bones will be very brittle and fracture easily, “like a piece of chalk”

-  Mutations causing osteopetrosis interfere with osteoclasts using acids to form the resorption pit, which needs to happen to dissolve the hydroxyapatite in the matrix

-  Ex: autosomal recessive problem with CA2 gene for carbonic anhydrase 2, which is needed in osteoclasts and the kidneys to form protons from carbon dioxide and water

o  No CA2 makes it so that osteoclasts can’t acidify the bone, and urine can’t be acidified

-  Ex: the autosomal recessive severe form is from mutation in the chloride channel gene CLCN7, which then interferes with the function of the H+ATPase proton pump on the osteoclast ruffled border

o  Another severe form is mutation to TC1RG1, which codes for part of the proton pump

-  Ex: a less severe autosomal recessive is mutation to the gene for RANKL, causing a ↓in the # of osteoclasts

-  Morphology of osteopetrosis is all from deficient osteoclast activity

o  Bones will lack a medullary canal, and the ends of long bones are bulbous and misshapen, called the Erlenmeyer flask deformity – page 1213 bottom pic

o  The foramens for nerves will be smaller and compress nerves

o  The primary spongiosa, which normally goes away after growth, will stick around and fill the medullary cavity, leaving no room for marrow & preventing mature trabeculae

o  Deposited bone isn’t remodeled and tends to be woven, and looks sclerotic

-  Severe infantile malignant osteopetrosis will be noticed in utero or soon after birth

o  Fracture, anemia, and hydrocephaly will be seen often leading to death

o  Those that survive will have cranial nerve problems (eye, ear, and face problems), and chronic and often fatal infections from too little bone marrow, & hepatosplenomegaly

-  Mild autosomal dominant benign osteopetrosis may not be seen till adulthood from easy fracture, with mild CN problems and anemia

-  Can treat osteopetrosis with bone marrow transplant, since osteoclasts come from marrow precursors, so you get new precursors to make osteoclasts that will reverse the problem

Osteoporosis- characterized by porous bones and ↓bone mass, making bone easy to fracture

-  It can be localized to certain areas, like in disuse osteoporosis, or can be systemic, like in metabolic bone diseases – page 1214

-  Unless otherwise said, osteoporosis usually refers to the most common forms of senile and postmenopausal osteoporosis, where ↓ bone mass makes the skeleton easy to fracture

-  Peak bone mass is reached by early adulthood

o  How strong the bone gets is determined mainly by genetics, but also by physical activity, muscle strength, diet, and hormones

o  Once peak bone mass is reached, resorption will be slightly more than bone formation every basic multicellular unit cycle, so you lose bone as you age

-  Age-related changes to bone- osteoblasts in elderly have ↓ability to proliferate and be made

o  Also, proteins in the ECM, like growth factors, which normally stimulate making of osteoblasts, “lose their biologic punch over time”

o  So this causes a ↓ ability to make bone as you age, and is called senile osteoporosis

-  ↓physical activity will ↑ rate of bone loss, because mechanical forces stimulate bone remodeling

o  Load magnitude in exercise affects bone density more than # of load cycles

o  Since muscle contraction is the dominant source of skeletal loading, resistance exercise like weight lifting is most effective for ↑bone mass

-  Adolescent girls tend to not get enough calcium in their diet, which stunts their peak mass

-  After menopause, more cancellous and trabecular bone is lost than cortical bone

-  Postmenopausal osteoporosis- characterized by hormone-dependent ↑bone loss after menopause

o  Estrogen deficiency is the major cause, and estrogen treatment protects against bone loss

o  The effects of estrogen on bone mass are mediated by cytokines